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Oncotarget1
www.impactjournals.com/oncotarget
www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2017
2017 update on the relationship between diabetes and colorectal
cancer: epidemiology, potential molecular mechanisms and
therapeutic implications
Nieves González1,*, Isabel Prieto2,*, Laura del Puerto-Nevado3,*, Sergio Portal-
Nuñez4,*, Juan Antonio Ardura4, Marta Corton5, Beatriz Fernández-Fernández6,7,
Oscar Aguilera3, Carmen Gomez-Guerrero6, Sebastián Mas6, Juan Antonio
Moreno6, Marta Ruiz-Ortega6, Ana Belen Sanz6,7, Maria Dolores Sanchez-Niño6,7,
Federico Rojo8, Fernando Vivanco9, Pedro Esbrit4, Carmen Ayuso5, Gloria Alvarez-
Llamas7,9, Jesús Egido1,6, Jesús García-Foncillas3, Alberto Ortiz6,7 and Diabetes
Cancer Connect Consortium10
1 Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network
in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
2 Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
3 Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
4 Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
5 Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
6 Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
7 REDINREN, Madrid, Spain
8 Pathology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
9 Immunology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
10 Listed at the end
* These authors have contributed equally to this work
Correspondence to: Alberto Ortiz, email: aortiz@fjd.es
Keywords: hyperglycemia, inammation, diabetic kidney disease, colon cancer, diabetes mellitus
Received: September 07, 2016 Accepted: December 26, 2016 Published: January 03, 2017
ABSTRACT
Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by
90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was
estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls.
However, there are potential confounders, information from lower income countries is
scarce, across the globe there is no correlation between DM prevalence and colorectal
cancer incidence and the association has evolved over time, suggesting the impact of
additional environmental factors. The clinical relevance of these associations depends
on understanding the mechanism involved. Although evidence is limited, insulin
use has been associated with increased and metformin with decreased incidence of
colorectal cancer. In addition, colorectal cancer shares some cellular and molecular
pathways with diabetes target organ damage, exemplied by diabetic kidney disease.
These include epithelial cell injury, activation of inammation and Wnt/β-catenin
pathways and iron homeostasis defects, among others. Indeed, some drugs have
undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide
association studies have identied diabetes-associated genes (e.g. TCF7L2) that may
also contribute to colorectal cancer. We review the epidemiological evidence, potential
pathophysiological mechanisms and therapeutic implications of the association
between DM and colorectal cancer. Further studies should clarify the worldwide
association between DM and colorectal cancer, strengthen the biological plausibility
Oncotarget2
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BACKGROUND
Diabetes mellitus (DM) and cancer are among the
most frequent causes of death worldwide. According
to Global Burden of Disease data, from 1990 to 2013
mortality from DM increased by 90% [1]. Colorectal
cancer (CRC) is among the top causes of cancer death.
From 1990 to 2013 global deaths from CRC increased by
57%, [1]. In the United States, CRC is the second leading
cause of cancer death in men and women combined (http://
www.ccalliance.org/colorectal_cancer/statistics.html)
[2]. A link between DM and cancer is now recognized
in American Diabetes Association (ADA) guidelines,
following a 2010 consensus report [3, 4]. If the association
holds, the current worldwide diabetes epidemic, fueled by
life-style changes, may trigger a wave of CRC diagnoses.
However, this knowledge has had limited impact on
clinical care in the form of specic diagnostic tests or
therapeutic approaches supported by clinical guidelines.
Furthermore, on a worldwide basis the prevalence
of DM and the incidence of CRC are not correlated,
suggesting that country-specic factors may play a role
in the association between DM and CRC (Figure 1).
Annual CRC incidence rates vary more than ten-fold
worldwide, the highest rates being in developed countries
such as Korea (age-standardized rate 45 per 100, 000),
Australia and Ireland, and the lowest in Western Africa
(e.g. Cameroon 3.3 per 100, 000) (http://globocan.iarc.
fr). By contrast, DM prevalence is highest in Egypt and
United Arab Emirates (20, 000 per 100, 000, and lowest
in Australia (5, 100), Ireland (4, 400) and Western Africa
(www.diabetesatlas.org/). A better understanding of the
factors underlying regional dierences may provide clues
to the relationship between DM and CRC. We now review
the epidemiological evidence, potential pathophysiological
mechanisms and therapeutic implications of the
association between DM and CRC and propose a research
agenda that may impact clinical practice to prevent or
treat CRC in DM patients. A Pubmed search with the key
words “(diabetes OR insulin OR hyperglycemia) AND
(colon OR colorectal) AND cancer” was performed with
no time cut-o points and further references added from
the reference list of the publications found or based on the
authors own experience knowledge.
DIABETES MELLITUS
DM is characterized by hyperglycemia resulting
from defects in insulin secretion and/or insulin action.
Chronic hyperglycemia is associated with injury to the
kidneys, heart, nerves, eyes and blood vessels [5]. In
type 1 DM (T1DM, 5-10% of DM cases), cell-mediated
autoimmune destruction of pancreatic β-cells causes
absolute insulin deciency. Type 2 DM (T2DM) is
characterized by insulin resistance and relative insulin
deciency. T2DM patients are frequently obese and older
at DM onset than T1DM patients [6]. Obesity promotes
insulin-resistance and is thought to be a major driver of the
current DM epidemic. Mendelian-inherited genetic defects
of β-cells or of the insulin signaling machinery also cause
DM [5].
Mean age at diagnosis of DM is 54 years in the US
(http://www.cdc.gov/diabetes/statistics/age/). Therapies
for DM increase insulin availability (insulin or insulin
analog administration or agents that promote insulin
secretion), improve sens itivity to insulin, decrease glucose
synthesis, delay the gut absorption of carbohydrate,
or increase urinary glucose excretion (Supplementary
Table 1). The preferred initial and most widely used
pharmacological agent for T2DM is metformin,
which decreases glucose production by inhibiting the
mitochondrial glycerophosphate dehydrogenase (GPDH,
GPD2) [7]. If adequate glucose control is not achieved
within 3-6 months, a second oral agent, a Glucagon-like
peptide-1 (GLP-1) receptor agonist, or insulin should be
added [8, 9].
COLORECTAL CANCER
CRC originates from colon epithelium [10]. Over
70% CRCs are sporadic, resulting from dietary and
environmental factors. The incidence increases with age
and they usually occur over the age of 50 years. True
inheritable CRC (<10% of cases) may be associated or not
to colonic polyps (Table 1) [11]. The familial type (25% of
cases) is associated with a family history of CRC or large
adenomas, in the absence of classic Mendelian inheritance
[12]. Right- and left-sided CRCs exhibit dierent
epidemiological patterns, sensitivities to chemotherapy
and outcomes, probably related to dierent molecular
characteristics and chromosomal instability with left-sided
tumors [13].
CRC is initiated by mutations in tumor suppressor
genes (adenomatous polyposis coli or APC, CTNNB1,
p53) and oncogenes (KRAS). Accumulation of multiple
mutations leads to a selective growth advantage for
transformed epithelial cells that is modulated by
epigenetic changes [14, 15]. Diet, the microbiota and the
inammatory response to the microbiota are potential
players [16-22]. Indeed, chronic gut inammation (e.g.
of a cause-and-eect relationship through characterization of the molecular pathways
involved, search for specic molecular signatures of colorectal cancer under diabetic
conditions, and eventually explore DM-specic strategies to prevent or treat colorectal
cancer.
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ulcerative colitis or Crohn´s disease) is associated with
increased incidence of colon cancer. A major molecular
pathway is Wnt signaling activation of the transcription
factor β-catenin to promote expression of cell proliferation
genes. Loss-of-function mutations or epigenetic silencing
of APC leads to aberrant β-catenin accumulation and
uncontrolled cell proliferation. The normal APC protein
forms a complex with glycogen synthase kinase 3-beta
(GSK-3β) that allows GSK-3β to phosphorylate β-catenin,
targeting it for ubiquitination and proteasomal degradation,
thus decreasing β-catenin-dependent transcriptional events
[23].
Early-stage CRC is treated with surgery and locally
advanced CRC (radically resected stage III and ‘high-
risk’ stage II disease) with adjuvant chemotherapy on
top of surgery. Rectal cancer with nodal disease standard
treatment includes neoadjuvant chemo-radiation [24].
Adjuvant chemotherapy schemes contain 5-uorouracil
and oxaliplatin. Metastatic CRC is treated with irinotecan
or oxaliplatin combined with a uoropyrimidine and
leucovorin (FOLFIRI or FOLFOX regimens) [25].
Addition of targeted therapies over the past 10 years has
improved overall survival. Testing for KRAS, NRAS,
BRAF, PIK3CA and PTEN mutations is used to assess the
potential clinical benet of anti-Epidermal Growth Factor
Receptor (anti-EGFR) and panitumumab treatment. Meta-
analyses suggest that mutation testing for KRAS exon 2 is
the strongest biomarker of response. The addition of anti-
Vascular Endothelial Growth Factor (anti-VEGF) agents
(bevacizumab, regorafenib) to chemotherapy of metastatic
CRC prolongs progression-free and overall survival in
rst- and second line therapy [26].
EPIDEMIOLOGICAL ASSOCIATION
BETWEEN DIABETES AND CRC
Epidemiological studies suggest that DM,
especially T2DM, is associated with increased risk of
cancer at several sites, including CRC [27] (Table 3).
The rst prospective association was reported in 1998
in US participants followed from 1960 to 1972 [28]. The
adjusted incidence density ratio of CRC was 1.30 (95%
Table 1: Genetics of colorectal cancer and potential impact of DM on colorectal cancer-related genes
Colorectal cancer Mutation Inheritance
Impact of DM on gene
expression * Reference
Familial adenomatous polyposis
Inactivating germline mutation in
adenomatous polyposis coli (APC)
Autosomal
dominant Increased APC [283,284]
MUTYH-associated polyposis Inactivating germline mutation in MUTYH Autosomal
recessive Unchanged MUTYH [283,284]
Peutz-Jeghers syndrome
Inactivating germline mutation in serine
threonine kinase 11 (STK11)
Autosomal
dominant Increased STK11 [285]
Hereditary non-polyposis colorectal
cancer (Lynch syndrome)
Inactivating germline mutation in MLH1,
MSH2, MSH6, or PMS2
Autosomal
dominant
Unchanged MLH1,
PMS2
Increased MSH2, MSH6
[286]
Chromosomal instability (frequent)
Acquired accumulation of numerical
(aneuploidy) or structural chromosomal
abnormalities and mutations in specic
oncogenes and tumor suppressor genes
(e.g. APC, PIK3CA, SMAD4, KRAS, TP53,
BRAF)
Unchanged PIK3CA,
SMAD4, BRAF
Increased KRAS, TP53
[287–289]
* Kidney gene expression in human diabetic kidney disease transcriptomics (http://www.nephromine.org).
Table 2: Key risk factors for T2DM, colorectal cancer and DM complications (Diabetic kidney disease)
Risk factor T2DM
Colorectal cancer
Diabetic kidney disease
Race
African American, Native
American African American
African American,
Native American
Obesity Yes Yes Yes
Inammation Yes Yes Yes
Microbiota Yes Yes Unknown
Low vitamin D Yes Yes Yes
High protein (meat protein) diet Yes Yes Yes
Low ber diet Yes Yes ND
No Mediterranean diet Yes Yes ND
Low magnesium intake/
hypomagnesemia Yes Yes Yes
Angiotensin II Yes Yes Yes
Age Yes Yes Unclear
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Figure 1: Relationship between incidence of colorectal cancer (CRC) and prevalence of DM in dierent parts of the
world. A. Global, B. Europe, North America and Australia/New Zealand, C. Latin America and Caribbean, D. Asia, E. Middle East, F.
European Mediterranean countries and Israel, G. Africa. IDF 2015 data for DM (www.diabetesatlas.org/) and Globocan 2012 data for
colorectal cancer (http://globocan.iarc.fr/Pages/age-specic_table_sel.aspx). Discontinuous red lines represent median values for the global
population. Regional dierences can be identied by the location of countries within the four quadrants. Note regional dierences as well
as countries that dier from others in the region. Regions are more clearly separated by CRC incidence than by DM prevalence, Europe/
North America/Australia/NZ is the only high DM/high CRC region. Latin America and Caribbean is a high DM/low CRC region with the
exception of Argentina and Uruguay where meat intake is high, while in the opposite extreme Mexico a is very high DM/low CRC country.
In the Middle East a high prevalence of DM is not associated with high CRC incidence, unlike in European Mediterranean countries which
in general behave as the rest of Europe. Korea is an example of low DM/high CRC country in Asia.
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condence interval (CI) 1.03-1.65) for diabetic males, but
not signicant for females. The association was found only
among non-smoker males. A more recent prospective US
study followed an older cohort from 1995 to 2004 and
observed an increased adjusted Hazard Ratio (HR) for
CRC in both males and females [29]. Lifestyle changes
from the 60s to the 90s may explain the change in female
risk. A similar association has been reported in Japan [30],
China [31], Australia [32] or certain European countries
(e.g. Sweden) [33], among others. A recent umbrella
review of meta-analyses of observational studies on
T2DM and cancer updated to the end of 2013 concluded
that CRC was one of only four cancer sites associated
to T2DM with robust supporting evidence and without
hints of bias [34]. Furthermore, in a meta-analysis of
prospective cohort studies encompassing near a million
participants, prediabetes (impaired fasting glucose and/
or impaired glucose tolerance) was also associated with
increased risk of CRC [35]. However, uncertainties
remain. The presence of detection bias and/or reverse
causation has been suggested by studies in Australia,
Israel and the Netherlands that found a higher risk of
cancer within 3 months of a DM diagnosis [32, 36, 37].
In this regard, in the US, respondents with diabetes were
22% more likely to be up-to-date on CRC screening than
those without diabetes [38]. A higher risk of developing
DM within 5 years of CRC diagnosis was also reported
[39]. In addition, regional dierences exist: in Norway
and the Netherlands only diabetic females had a higher
incidence of proximal colon cancer or CRC [40, 41],
while no association was found in Tyrol. Unraveling
the reasons underlying regional dierences may provide
clues to the association and to public health interventions.
Potential dierences in the use of specic antidiabetic
drugs may play a role as discussed below. Furthermore,
epidemiological data from developing countries are
scarce. This is an important piece of missing information
since almost 55% of CRC cases occur in more developed
regions (http://globocan.iarc.fr/Pages/fact_sheets_cancer.
aspx), while 80% of DM patients live in low- and middle-
income countries (www.diabetesatlas.org/).
Risk factors shared by CRC, DM, and DM target
organ damage may be confounders in epidemiological
studies (Table 2). Obesity is a major risk factor for T2DM,
cancer and diabetic kidney disease (DKD) [42, 43].
However, key studies observing an association between
DM and CRC were adjusted by BMI. In this regard, there
may be a relationship between obesity, insulin resistance
and CRC. In a prospective European study, lower CRC
risk was observed for metabolically healthy/overweight
individuals compared with metabolically unhealthy/
overweight individuals, dened as individuals with higher
C-peptide levels indicative of hyperinsulinaemia [44]. Diet
may be another confounder. A high meat intake increases
and a Mediterranean diet decreases both the risk of DM
and of CRC [45].
POTENTIAL MOLECULAR MECHANISMS
OF THE ASSOCIATION BETWEEN DM
AND CRC
The association between DM and CRC may result
from shared risk factors between T2DM and cancer but
epidemiological data suggest a potential contribution of
hyperinsulinemia, hyperglycemia or DM therapy [4, 46,
47] (Figure 2). Additionally, the DM microenvironment,
such as advanced glycation end-products (AGEs),
Figure 2: Hypotheses potentially explaining the association between diabetes and colorectal cancer. Two major potential
relationships have been depicted. A. Common risk factors (e.g. diet, genetic) favor both diabetes and colorectal cancer; B. Diabetes favors
cancer development. These potential relationships are put in context with the occurrence of other diabetes complications such a chronic
kidney disease. Obesity is a known risk factor for both colorectal cancer and diabetic kidney disease.
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hyperlipidemia, local inammation/oxidative stress,
extracellular matrix alterations, and altered microbiota
or ischemia due to vasculopathy may recruit secondary
mediators of injury that may favor the development of
both cancer and other complications of DM such as DKD.
Insulin
Insulin and insulin-like growth factor (IGF)-1 have
growth factor and antiapoptotic properties in a variety
of cultured tumor and non-tumor cell types, including
normal colon epithelium and colon cancer cells [48, 49].
These actions have been interpreted as part of a putative
tumor-enhancing eect of insulin [50, 51]. However,
insulin signaling is also required for survival and function
of healthy cells in vivo, such as podocytes, key cells in
DKD, and selective podocyte insulin resistance reproduces
features of DKD in the absence of hyperglycemia [52].
The mTOR and p21-activated protein kinase-1 (PAK-
1)/Wnt/β-catenin intracellular pathways are involved in
insulin-stimulated proto-oncogene expression in intestinal
cells [53]. These molecular pathways also mediate diabetic
complications, including DKD [54].
An increased incidence of azoxymethane-induced
intestinal tract cancer was observed in preclinical models
of obesity and T2DM, including obese Zucker rats and
KK Ay, db/db and ob/ob mice [55-57]. The addition,
the incidence and multiplicity of intestinal adenomas
was higher in db/db mice with Apc mutations than in
non-diabetic mice [58]. However, the relative role of
hyperglycemia, hyperinsulinemia or obesity was not
characterized.
The role of hyperinsulinemia was studied in a
normoglycemic model of mammary cancer growth, but
results do not necessarily extrapolate to CRC [59]. A
tyrosine kinase inhibitor specic to the insulin and IGF-
1 receptors aggravated hyperinsulinemia but prevented
insulin signaling and cancer growth. However, tyrosine
kinase inhibitors are promiscuous and are in clinical use
as anti-tumor agents. Thus, the fact that members of an
anti-tumor agent family decrease tumor growth is not
denitive evidence for a role of insulin. CL-316243, a
β3-adrenergic receptor agonist that sensitizes to insulin
action, reduced hyperinsulinemia and phosphorylation
of insulin and IGF-1 receptors and attenuated mammary
tumor progression, supporting a role for hyperinsulinemia
in T2DM associated tumor progression [60].
Hyperglycemia
Hyperglycemia has been implicated both in colon
cancer growth and in DKD and some of the molecular
mechanisms are shared by both diseases. High glucose
levels and AGEs increase proliferation and migration
of cultured colon cancer cells [61, 62]. High glucose
levels also enhance resistance to 5-uoruracil-induced
apoptosis [63]. AGE-induced CRC cell proliferation
requires carbohydrate response element-binding protein
(ChREBP) [64], a key transcription factor also involved in
DKD [65]. The polyol and hexosamine pathways, which
increase glucose oxidation, are upregulated in diabetes
target organ epithelial cells [54] and in colon cancer [66].
Hyperglycemia and AGEs induce oxidative stress and
inammation, which can damage cellular components
and contribute to malignant cell transformation [67-69].
High glucose-induced oxidative stress plays a pivotal role
in the development of diabetes complications by activating
dierent pathways, such as the transcription factor nuclear
factor-kappa B (NF-κB) [70, 71]. Indeed, bardoxolone
methyl, a potent nuclear factor erythroid 2-related
factor 2 (Nrf2) activator/NF-κB inhibitor, improved
glomerular ltration in RCT in DKD [72]. Interestingly,
the observation that bardoxolone increased glomerular
ltration was rst made in clinical trials exploring its
anticancer potential.
The Warburg eect refers to the high glucose
uptake and metabolism of glucose through glycolysis
rather than aerobic phosphorylation in tumor cells
despite the presence of oxygen [73, 74]. Glycolysis is
less ecient but generates adenosine triphosphate (ATP)
faster, conferring a growth advantage to tumor cells.
Upregulation of insulin-independent glucose transporters
such as glucotransporter-1 (Glut-1) favors glucose
uptake by cancer cells [75, 76]. Glut overexpression is
usually translated into higher proliferation rates. The
diabetic milieu and transforming growth factor (TGF)-β1
upregulate renal cell Glut-1 and this is thought to
contribute to the pathogenesis of DKD [77].
Few preclinical studies have addressed the impact
of hyperglycemia per se (i.e. T1DM) on colon cancer.
Streptozotocin-induced hyperglycemia, an insulin-
deciency DM model, increased liver metastasis of
mouse colon cancer cells, while glycemic control with
either insulin or gliclazide was protective [78]. These
studies suggest that hyperglycemia per se may favor
colorectal tumor growth and that hyperglycemia may be a
more powerful stimulus for tumorigenesis than insulin in
experimental animals.
Wnt/β-catenin is activated in CRC as a direct
consequence of APC mutations and in kidney cells in DKD
[79], protecting glomerular mesangial cells from high-
glucose-mediated cell apoptosis [80] but causing podocyte
dysfunction and proteinuria [79]. β-catenin expression
and altered phosphorylation, and cell proliferation were
higher in normal colon epithelium surrounding tumor
tissue in diabetic than in non-diabetic patients [81]. VDR
activation antagonizes Wnt/β-catenin signaling [82]
(Figure 3). The nephroprotective action of VDR activators
has been related to Wnt/β-catenin inhibition [83]. Vitamin
D deciency is common in DM [84] and has also been
associated with increased risk of CRC [85, 86]. High-
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Figure 3: Key molecular pathways potentially linking diabetes and colorectal cancer. The example of β-catenin activation.
A. In the absence of Wnt signaling, APC-bound glycogen synthase kinase 3-beta (GSK-3β) phosphorylates β-catenin (βCat), targeting it
for ubiquitination and proteasomal degradation. In the absence of nuclear β-catenin, Groucho binds to transcription factors of the TCF
family, repressing transcription. The TCF family includes TCF7L2 which has been associated to DM, DM complications and colon cancer
by GWAS studies. B. Colon cancer is characterized by loss of function mutations of APC and in DM Wnt signaling is activated. Klotho
and vitamin D prevent Wnt signaling and are protective against tumors and against DM complications. Wnt signaling prevents β-catenin
phosphorylation and degradation allowing its nuclear migration, where it displaces Groucho and promotes transcription of genes involved
in cell proliferation as well as other genes such as miR-21. miR21 contributes to tumorigenesis and to diabetes complications such as kidney
injury. GWAS identied a GREM1 SNP associated with CRC susceptibility that facilitates TCF7L2 binding to DNA, leading to stronger
GREM1 gene expression. A GREM1 SNP also associate with diabetic kidney disease. The gene product, Gremlin, promotes kidney injury
in DM as well as colon cancer cell migration. KCNQ1 was associated with T2DM by GWAS. This locus encodes KCNQ1OT1, a β-catenin
target upregulated in CRC.
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glucose-induced inammatory and brogenic responses
in kidney cells contribute to DKD and are prevented by
vitamin D receptor (VDR) activation [87-90]
EGFR signaling contributes to tumorigenesis and
tumor progression of CRC and EGFR-targeted cetuximab
is used to treat CRC. Genetic or pharmacological EGFR
blockade slows experimental renal disease progression
[91]. High-glucose, AGE, angiotensin II, and pro-
inammatory cytokines, such as TWEAK and parathyroid
hormone-related protein (PTHrP) AGE promote EGFR
transactivation in kidney cells [92-96]In this regard,
TWEAK targeting antibodies are undergoing clinical
trials in kidney disease, while targeting the TWEAK
receptor Fn14 reduced colon cancer metastasis in
experimental animals [95, 97]. Inhibition of EGFR with
erlotinib attenuates DKD in experimental T1DM, through
inhibition of mTOR [98]. Indeed, mTOR is activated in
diabetic podocytes and mTOR targeting protects from
DKD [99]. CCN2 is a novel EGFR ligand that promotes
kidney inammation and DKD progression [100, 101]
and in CRC cells, regulates cell migration and prevents
apoptosis [102].
Klotho is an anti-aging hormone of kidney origin
with anti-inammatory and anti-brotic properties [103,
104]. Experimental and human diabetes, inammation
and hyperlipidemia are associated with decreased Klotho
expression [105-108]. Loss of Klotho contributes to
kidney injury by de-repression of Wnt/β-catenin signaling
[109] and similar mechanisms may be active in colon
cancer cells. In this regard, Klotho suppresses growth
and invasion of colon cancer cells through inhibition
of the IGF1R-mediated PI3K/Akt pathway [110] and is
frequently inactivated through promoter hypermethylation
in CRC [111].
Table 3: Epidemiological association between DM and risk of CRC. 95% condence interval shown.
Country N
(x1000)
Mean age
(years)
Period
(years) Location Males Females Overall Ref
US* 850 54 59-72 CRC 1.30 (1.03-1.65) 1.16 (0.87-1.53) Not available [28]
US** 484 62 95-06 CRC
Colon 1.24 (1.12-
1.38)
Rectum 1.34
(1.14-1.57)
Colon 1.37 (1.16-
1.60)
Rectum 1.43
(1.08-1.88)
Colon 1.27
(1.17-1.39)
Rectum 1.36
(1.18-1.56)
[29]
Japan*** 335 N.A. N.A. CRC N.A. N.A. 1.40 (1.19-
1.64) [30]
China**** 327 60 07-13 CRC
Colon 1.47 (1.29-
1.67)
Rectum 1.25
(1.09-1.43)
Colon 1.33 (1.15-
1.54)
Rectum 1.29
(1.10-1.51)
Colon 1.40
(1.27-1.55)
Rectum1.26
(1.14-1.40)
[31]
Australia**** 953 27 (T1DN)
60 (T2DN) 97-08 CRC 1.18 (1.15-1.21) 1.16 (1.13-1.20) N.A. [32]
Sweden**** 2.9
1.4 N.A. 64-10 CRC N.A. N.A.
Colon 1.33
(1.28-1.38)
Rectum 1.19
(1.13-1.25)
[33]
Norway***
751
pers/
year
71 84-96 CRC CRC 0.66 (0.35-
1.34)
CRC 1.55 (1.04-
2.31)
Colon 1.60 (1.02-
2.51)
Rectum 2.70
(1.29-5.61)
N.A. [40]
Tyrol**** 5.7 58 88-10 CRC 1.11 (0.81-1.49) 0.94 (0.62-1.36) N.A. [290]
Israel** 2186 64 02-12 CRC 1.45 (1.37-1.55) 1.48 (1.39-1.57) N.A. [36]
Netherlands** 120 62 86-06 CRC
CRC 0.95
(0.75–1.20)
Proximal 1.13
(0.76-1.68)
Distal 0.77
(0.49–1.21)
Rectum 0.50
(0.21–1.22)
CRC 1.08
(0.85–1.37)
Proximal 1.44
(1.05–1.99)
Distal 0.75
(0.44–1.27)
Rectum 1.16
(0.54–2.48)
N.A. [41]
Meta-
analysis*** 8244 N.A. N.A. CRC N.A. N.A. 1.27 (1.21-
1.34) [34]
* Adjusted incidence density ratio: ** Adjusted HR; ***RR. **** Standardized incidence ratios
N.A.: not available
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Inammation and microbiota
Inammation is a critical component of diabetes-
induced target organ injury and of CRC initiation and
progression [112, 113]. In preclinical models of T2DM,
inammation contributed to carcinogenesis and tumor
growth, which were prevented by TNF-neutralizing
monoclonal antibodies [57].
Multiple signaling pathways are involved in the
inammatory response, including MAPK, NF-κB, janus
kinase/signal transducer and activator of transcription
(JAK/STAT) and hypoxia-inducible factor-1α [68, 114-
117]. Persistent NF-κB/IL-6/STAT3 activation promotes
colitis associated CRC [118]. The non-canonical NF-
κB pathway has also been implicated in diabetes
complications and cancer [119-121]. The upstream
kinase of this pathway, NIK, contributes to β cell failure
in diet-induced obesity [122], promotes kidney injury
[123] and underlies the sensitivity of Nlrp12-/- mice to gut
inammation and tumorigenesis [124]. These intracellular
pathways amplify inammatory responses and promote
angiogenesis, cancer growth and invasiveness of malignant
cells [125, 126], as well as progression of diabetes target
organ injury such as DKD [117].
The interaction between colon epithelial cells and
the microbiota may confer susceptibility to both colon
cancer and obesity. The inammasome regulates the
microbiota and the inammatory response of epithelial
cells to the microbiota. Deciency in inammasome
components (e.g. Nlrp6) is associated with an abnormal
microbiota, exacerbated gut inammatory responses
[127] and colon tumorigenesis [128] dependent on
microbiota-induced activation of epithelial IL-6 signaling
[17]. Microbiota-dependent inammatory responses
may contribute to non-Mendelian familial aggregation
of colon cancer since in preclinical models the risk of
cancer was transmissible between co-housed individuals
with the microbiota. The gut microbiota also impacts host
metabolism, facilitating obesity, insulin resistance and
T2DM [129]. Thus, inammasome deciency-related
changes in gut microbiota are associated with insulin
resistance and obesity [130]. In this regard, T2DM is
one of three models of microbiome-associated human
conditions to be studied by the Integrative Human
Microbiome Project (iHMP, http://hmp2.org) [131].
Table 4: Examples of agents in the pipeline targeting both cancer and diabetic target organ complications exemplied
by diabetic kidney disease
Activity Agent
Successful
in animal
models of
cancer
Successful in
experimental
DKD
RCT in human
cancer
RCT in
human DKD Refs
HMGCoA reductase
inhibitors statins Yes Yes Yes Yes [253-256]
RAAS targeting
drugs
ACE inhibitors,
ARBs Yes Yes No Yes
[252, 257-
259]
VDR activator Paricalcitol Yes Yes Yes Yes [265,266,291]
Endothelin receptor
antagonists
Atrasentan and
others Yes Yes Yes Yes [262–
264,292–301]
Anti-brotic agents
Anti-CTGF mAb
FG3019 Yes Ye s Ye s Ye s [101,302,303]
Anti- TGF-β1
mAb. Yes Yes Yes Yes [304]
Anti-inammatory
agents
Chemokine
targeting agents Yes Ye s
Yes (anti-
CXCR4)
Yes (anti-
CCL2 and
others )
[270]
JAK/STAT
inhibitors Yes Yes Yes Yes [276-279]
Inhibitors of
epidermal growth
factor Receptor/
ligands
Several agents Yes Yes
Anti-EGFR
antibodies
(cetuximab)
Anti-TGF-α/
epiregulin
antibody
(LY3016859)
[305,306]
mTOR inhibitors Several agents Yes Yes Yes
No (Yes in
non-DKD
CKD)
[98-99, 269]
DKD: diabetic kidney disease, CKD: chronic kidney disease, HMGCoA: 3-hydroxy-3-methylglutaryl coenzyme A, RAAS:
renin angiotensin aldosterone system, ACE: angiotensin converting enzyme, ARB: angiotensin receptor blocker; CTGF:
Connective tissue growth factor, TGF-beta: Transforming growth factor beta, EGFR: Epidermal growth factor receptor,
CXCR4: Chemokine Receptor type 4, CCL2: Chemokine Ligand 2
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Human T2DM and CRC share some microbiota features,
such a decrease in the abundance of butyrate-producing
bacteria [18, 132]. Butyrate is a breakdown product of
dietary ber that has anti-tumorigenic properties and is
associated with decreased incidence of CRC [18]. In mice,
the microbiota potential for butyrate production negatively
correlated with tumor count [133]. Butyrate also has
nephroprotective properties in DKD [134].
Iron metabolism. Altered iron metabolism
facilitates rapid proliferation in cancer cells [135].
Indeed, constitutive Wnt/β-catenin signaling in colon
cancer cells is iron-dependent [136] and iron chelation
limits cell proliferation and has anti-inammatory eects
through NF-κB blockade [137]. Iron overload causes
DM and is present in target organs of diabetes, such as
the kidneys, while iron depletion upregulates glucose
uptake and insulin signaling in liver and decreases kidney
inammation in experimental diabetes [138-140]. Indeed,
the Trial to Assess Chelation Therapy (TACT) disclosed
a benet of ethylenediaminetetraacetic acid (EDTA), a
chelator that also binds iron, on cardiovascular outcomes,
especially in DM patients [141]. Thus, excess cellular iron
may facilitate CRC growth, DM and DM complications.
Heme iron may be the common denominator in the
association of red meat intake with both DM and CRC
[142, 143].
Epigenetic changes
CRC and DM also share some epigenetic changes.
Thus, both CRC and DM were associated with a positive
septin 9 (SEPT9) DNA-methylation assay (Epi-proColon)
result [144]. In this regard, SEPT9 is dierentially
methylated in human T2DM islet cells and was shown to
perturb insulin and glucagon secretion [145].
miRNAs are small non-coding RNA molecules
that regulate gene expression. Pathogenic miRNAs
may be shared by CRC and DKD [146-148]. In murine
DKD, renal miR-21 expression was increased and miR-
21 knockdown ameliorated renal damage [149]. The
pathogenic potential of miR-21 is supported by some,
but not all additional reports [150, 151]. miR-21 is also
part of a six-miRNA-based classier that reliably predicts
CRC recurrence [148, 152]. Functional studies support a
role for miR-21 in colon cancer proliferation and invasion
[153, 154] and targeting miR-21 enhanced the sensitivity
of human colon cancer cells to chemoradiotherapy and
reduced angiogenesis [154, 155]. Metformin synergy
with 5-uorouracil and oxaliplatin to induce death of
chemoresistant colon cancer cells was also associated with
a reduction in miR-21 [156].
Table 5: Key points
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ADDITIONAL INFORMATION FROM
SYSTEMS BIOLOGY APPROACHES
Genome-wide association studies (GWAS) have
identied susceptibility genes for DM or CRC that provide
insights into potentially shared pathogenic pathways, such
as TCF7L2, KCNQ1, HMGA2, RHPN2 and GREM1.
TCF7L2 harbors common genetic variants with
the strongest eect on T2DM risk [157-159] and on DM
complications such as DKD [160] and is also susceptibility
locus for CRC loci in East Asians [161]. TCF7L2 is a
transcription factor and β-catenin transcriptional partner
in the Wnt-signaling pathway. DNA-bound TCFs repress
gene transcription in the absence of β-catenin, but are
required for β-catenin transcriptional activity [162].
TCF7L2 also promotes miR-21 expression [163]. Another
CRC-associated Single Nucleotide Polymorphism (SNP),
rs6983267, is located at a TCF7L2 binding site and the risk
allele results in stronger TCF7L2 binding, facilitating Wnt
signaling [164]. A common GREM1 SNP, rs16969681,
associated with CRC susceptibility facilitates TCF7L2
binding to DNA leading to stronger gene expression
[165]. A germline duplication upstream of GREM1 causes
hereditary mixed polyposis syndrome and Mendelian-
dominant predisposition to CRC through ectopic GREM1
overexpression in the intestinal epithelium [166, 167].
GREM1 was initially identied as one of the most
upregulated genes in cultured mesangial cells exposed
to high glucose [168] and GREM1 gene variants also
associate with DKD [169]. Gremlin, the protein codied
by GREM1, has been proposed as a key mediator of
DKD [170-173]Gremlin promotes the motility of CRC
cells [174] and the epithelial to mesenchymal transition
in kidney tubular cells, also associated with increased
motility [175, 176]. The precise role of TCF7L2 in CRC
should be further dened. Thus, TCF7L2 mutations
identied in cancer samples abolish its ability to function
as a transcriptional regulator and result in increased CRC
cell growth [177]. Given the multitude of target genes, this
is not surprising.
KCNQ1 was associated with T2DM [178]. This
locus encodes both KCNQ1 and the long noncoding
RNAs (lncRNAs) KCNQ1OT1, which is a β-catenin target
dysregulated in CRC [179]. In human CRC, low KCNQ1
expression was associated with poor survival and mutation
of the murine homologue Kcnq1 increased the risk for
intestinal tumors [180].
HMGA2 is a further gene associated to risk of T2DM
and DKD in GWAS [158, 181]. HMGA2 expression is
increased in and promotes the malignant behavior of CRC
[182, 183]. Conversely, CRC GWAS identied RHPN2 as
a susceptibility loci and RHPN2 expression is upregulated
in experimental DKD [184, 185].
Pathway-based enrichment analysis of 23
Table 6: Standing questions on the relationship between DM and colorectal cancer
Standing question Relevance What is required to address it
Is there an association between T2DM and
colorectal cancer across all countries and
cultures?
Provides insights into etiologic and
pathophysiologic factors, may prevent
a colorectal cancer epidemic in the
developing world
Head-to-head comparison between
developed and developing country cohorts
Is there an association between development of
cancer and development of other complications
of DM?
Provides the epidemiological basis to
search for common mediators of disease
Epidemiological studies, ideally
prospective
What molecular mediators explain the
association between DM and cancer? Are they
shared by other complications of DM?
Identication of potential diagnostic
signatures and therapeutic targets
Interventional preclinical models that
address function of key molecules.
These may have been identied by non-
biased systems biology approaches and
hypothesis-driven studies designed from
the analysis of available literature
Has DM-associated colorectal cancer a specic
molecular signature?
This may identify diagnostic signatures
and therapeutic targets specic for DM-
associated colorectal cancer
Systems biology comparison between DM
and non-DM associated colorectal cancer
with DM and non-DM healthy colon as
control
Can DM patients at high risk for cancer
development be identied by diagnostic tests? Early diagnosis of risk or cancer
Prospective systems biology approach to
relevant biological samples (feces, urine,
blood or others)
Can DM patients at high risk or early colorectal
cancer be treated by specic, DM-tailored
approaches? Do these approaches also prevent/
treat other diabetic complications?
New preventive/therapeutic approaches
that address both cancer and non-cancer
DM complications
Early identication of patients at high risk
or with early disease
Unraveling of common pathogenic
pathways
Are there common microbiota signatures for
colorectal cancer and other DM complications?
New preventive/therapeutic approaches
that address both cancer and non-cancer
DM complications
Metagenomic studies
What is the optimal therapeutic approach for
colorectal cancer in diabetic individuals and
the optimal therapeutic approaches for DM in
colorectal cancer patients?
Therapy individualization and improved
outcomes
Hypothesis-generating observational
studies followed by randomized clinical
trials
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independent gene expression proling studies on prognosis
of CRC observed overrepresentation of the oxidative
phosphorylation chain, the extracellular matrix receptor
interaction category, and a general category related to
cell proliferation and apoptosis [186]. These categories
are functionally related with cancer progression. Eight of
the genes were also present in a previous meta-analysis
of ten expression proling studies of dierentially
expressed genes in CRC with good versus bad prognosis,
including IQGAP1, YWHAH and TP53. [186]. IQGAP1
is part of the podocyte lter for proteins and regulates the
occurrence of proteinuria, the hallmark of DKD [187]
and YWHAH expression was increased in human DKD
transcriptomics studies [188, 189]. Furthermore, human
DKD transcriptomics revealed that 25% of apoptosis-
related genes were dierentially regulated in kidney
tissue [190-192]. Some of the specic factors identied
by human DKD transcriptomics and functionally
characterized to contribute to kidney injury, also promote
CRC growth, such as the MIF/CD74 system which is
under study as a therapeutic target in colon cancer [193,
194]. Furthermore, elements of the JAK/STAT, VEGFR
signaling and inammation-related pathways were also
overrepresented in human DKD [184, 189]. JAK/STAT,
VEGF and inammation are therapeutic targets in cancer.
As part of the Human Proteome Project, the
Biology/Disease-driven Human Proteome Project (B/D-
HPP) consortium leads specic projects on diabetes
(HDPP) and cancer that may shed some additional
light on the relationship between both diseases [195].
Protein candidate markers responding to CRC existence
(diagnosis), stratication (dierent response related
to stage) or prognosis (survival/metastasis) have been
identied [196-199]. Most studies compared normal
(healthy) tissue with tumor. The top four regulated
proteins in a systematic review of CRC were 60-kDa
heat shock protein (HSP60) and Nucleoside diphosphate
kinase A (nm23-H1), up-regulated, and Selenium-binding
protein 1 (SELENBP1) and Carbonic anhydrase I (CAI),
down-regulated [200]. Interestingly, expression of the
HSPD1 gene encoding HSP60 was upregulated and
SELENBP1 downregulated in human DKD, according
to the Nephromine database, further suggesting potential
common pathogenic pathways between DKD and colon
cancer (http://www.nephromine.org/).
Bioinformatics approaches may be used to integrate
the growing systems biology databases. One such
approach, the Drug-specic Signaling Pathway Network
(DSPathNet) was used to tentatively identify seven genes
(CDKN1A, ESR1, MAX, MYC, PPARGC1A, SP1, and
STK11) and one novel MYC-centered pathway that might
play a role in metformin antidiabetic and anticancer
eects [201]. Interestingly, PPARGC1A protects from
kidney injury and the expression is downregulated by
inammation [202].
IMPLICATIONS FOR THERAPY
Given the high and increasing incidence and
prevalence of DM and CRC, it is likely that, independently
from any common pathogenic pathways or associations,
many DM patients will develop CRC. This brings the
question whether physicians need to modify the approach
to therapy of DM or CRC in diabetic patients with
both conditions. In this regard, a diagnosis of cancer
is frequently associated to a subsequent decrease in
adherence to antidiabetic medication [203].
Choice of antidiabetic agent in the patient with
CRC
The ADA Standards of Medical Care in Diabetes
indicates that patients with DM should be encouraged
to undergo recommended age- and sex-appropriate
cancer screenings and to reduce their modiable cancer
risk factors (obesity, smoking, physical inactivity) [9].
In the presence of cancer, higher HbA1c goals should
be considered: <8% in the absence of metastases and
<8.5% for patients with metastatic cancer. If indeed
hyperglycemia underlies the higher incidence of colon
cancer in DM, these higher thresholds may theoretically
impair cancer-related outcomes.
ADA 2016 does not provide recommendations on
the choice of antidiabetic treatment in patients with cancer
or CRC [204]. However, the initial antidiabetic agent
recommended for standard T2DM patients, metformin,
has been associated with decreased incidence or better
outcomes in cancer patients [205-207]. Thus, even if
prospective clinical studies conrmed the superiority of
metformin on cancer incidence or outcome, this would
not change the current standard therapeutic approach
for T2DM in the cancer patient. The debate about the
association of specic antidiabetic drugs and cancer risk
has been marred by the lack of properly designed studies.
Although observational studies suggest that the
choice of treatment for DM may modify cancer risk [208],
no prospective studies have been specically designed
to address this issue. Thus, no rm conclusions can be
reached at this point. The crux of the debate has been
whether insulin or analogs are associated to an increased
risk of CRC (and cancer in general) [209] and whether
metformin is associated with a decreased risk of CRC
[210]. This may represent two sides of the same coin: if
one drug does modify the risk of CRC, by comparison
the other may appear to modify the risk in the opposite
direction. Confounders may exist. Thus, insulin is
generally prescribed and metformin remains formally
contraindicated in advanced chronic kidney disease
(CKD), a late event in the course of T2DM, despite recent
clinical recommendations [211]. Renal insuciency is
associated with higher risk for all-cause cancer [212],
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although this association has not been demonstrated for
CRC [213].
Recent meta-analyses have attempted to unravel
the potential relationship between antidiabetic therapy
and cancer or colorectal cancer. However, meta-analysis
results heavily depend on the quality of the included
studies. A recent meta-analysis involving approximately
7.6 million and 137, 540 patients with diabetes from
observational studies and randomized controlled trials
(RCTs), respectively, suggested that metformin or
thiazolidinediones were associated with a lower risk of all
cancer incidence, while insulin, sulfonylureas and alpha
glucosidase inhibitors were associated with an increased
risk of cancer incidence [214]. Another large (491,
384 individuals) meta-analysis addressing specically
the impact of insulin, found it to be associated with a
signicant 69% increased risk of CRC in T2DM only in
case-control but not in cohort studies [215]. The Barcelona
nested case-control study of 275, 164 T2DM patients did
not nd an increased risk of cancer for any insulin or oral
antidiabetic agent [216]. Finally, a metaanalysis of 19
publications representing data for 1, 332, 120 individuals,
insulin had no eect and insulin glargine was associated
with a decreased risk of CRC [217].
Metformin use has been associated with a decreased
risk of colon cancer and increased survival [210, 218,
219]. A systematic review of 12 randomized controlled
trials (21, 595 patients) and 41 observational studies (1,
029, 389 patients) found that in observational studies
the risk of CRC was 17% lower among DM patients
treated with metformin than in those not on metformin
[210]. In a meta-analysis of 21 observational studies
metformin was associated with a reduction in cancer-
specic mortality, including a reduction in mortality for
colon cancer (4 studies, HR 0.65, 0.56-0.76) [205, 220].
Several mechanisms may account for the antitumor eect
of metformin. It reduces circulating insulin, promotes
weight loss and activates 5’ adenosine monophosphate-
activated protein kinase (AMPK), thus inhibiting growth
of colon cancer cells [221, 222]. In mice with Apc
mutations, metformin suppressed polyp growth [223]
and in diabetic mice metformin, alone or in combination
with oxaliplatin, reduced the severity of colorectal tumors
[224]. Older literature described increased expression of
mitochondrial GPDH, the target of metformin, in rapidly
growing, undierentiated tumors [225, 226]. However,
there are no data on CRC expression of mitochondrial
GPDH. In non-diabetic subjects, oral short-term low-
dose metformin suppressed the development of colorectal
aberrant crypt foci in a clinical trial [227]. In phase 3 RCT,
low-dose (250 mg/day) metformin was safe and reduced
the prevalence and number of metachronous adenomas or
polyps after polypectomy in non-diabetic patients [228].
Conicting results are available on
thiazolidinediones and cancer. A systematic review
and meta-analysis of 840, 787 diabetic patients did not
support an association between thiazolidinediones and
CRC [229, 230]. In a 6-year population-based cohort
study, thiazolidinediones were associated with decreased
cancer risk including CRC and the association was dose-
dependent [231]. Thiazolidinediones have cytostatic
eects and inhibit growth and metastasis of colon cancer
cells as they induce dierentiation and modulate the
E-cadherin/β-catenin system [232-234]. However, some
studies point to a mitogenic potential of troglitazone which
induced colon tumors in normal C57BL/6J mice and
increased colon carcinogenesis in Apc1638 N/+Mlh1+/−
double mutant mice [235].
In systematic meta-analyses, sulphonylureas
were associated with increased risk of pancreatic and
hepatocellular cancer but not of CRC [229, 236, 237].
A cohort of 275, 164 T2DM patients found no evidence
for altered cancer risk for repaglinide or α-glucosidase
inhibitors compared to insulin-based therapies or other
oral glucose-lowering drugs [216]. In other reports,
acarbose was associated with reduced the risk of incident
CRC in patients with diabetes in a dose-dependent manner
[238, 239]. Acarbose may alter the microbiota [240] and
decreased the size of gastrointestinal adenomas in Apc
knockout mice [241].
Empaglifozin dramatically decreased mortality
and slowed DKD progression and sodium-linked glucose
transporter-2 (SGLT2) inhibitors may soon become the
new standard of therapy [242]. A safety warning was
issued by the FDA regarding bladder and breast cancer risk
from early clinical trials of dapagliozin but not for CRC
(http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/
UCM262994.pdf). Adenocarcinomas express SGLT2 and
SGLT2 inhibitors blocked glucose uptake and reduced
growth of tumor xenografts [243]. Whether this applies to
CRC is unknown.
No relationship between GLP-1-based therapies and
CRC have been reported [244, 245]. However, exenatide
inhibited proliferation and induced apoptosis in cultured
murine CT26 colon cancer cells [246, 247].
Choice of chemotherapy for colorectal rectal
cancer in patients with diabetes
Studies addressing chemotherapy ecacy or safety
in DM are very limited and there is no evidence supporting
specic chemotherapy approaches for CRC patients with
DM. No dierences in the survival benet or severe
adverse eects associated to chemotherapy were observed
in 5, 330 elderly CRC patients with (n=950) and without
(n=4, 380) DM [248]. By contrast, a cohort study within
the INT-0089 randomized adjuvant chemotherapy trial
of 3, 759 patients with high-risk stage II/III colon cancer
concluded that in DM patients overall mortality and cancer
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recurrence were higher than in non-diabetic patients [249].
Treatment-related toxicities were similar between DM and
non-DM patients, except for a higher risk of treatment-
related diarrhea among DM patients [249]. However,
disease-free survival was lower and neurotoxicity more
frequent in DM patients treated with capecitabine and
oxaliplatin (CAPOX) chemotherapy than in non-diabetics
[250]. It is likely that whether DM modies the risk of
severe adverse eects that limit chemotherapy depends on
the specic chemotherapeutic regimen.
AGENTS IN THE PIPELINE TARGETING
BOTH CRC AND DIABETIC
COMPLICATIONS
Some therapeutic targets are undergoing or have
undergone RCTs in both diabetes complications (e.g.
DKD) and cancer or are in clinical use in one condition
and have been successfully used for the other condition
in preclinical settings. These include statins, renin
angiotensin aldosterone system (RAAS) blockers,
endothelin receptor antagonists, VDR activators, mTOR
inhibitors, anti-inammatory molecules and inhibitors of
EGF ligands/receptors (Table 4) [251, 252].
Statins are commonly used to treat hyperlipidemia
and have been linked with a small reduction in the
risk for colon cancer in diabetic patients [253] and
improved prognosis of curatively resected CRC [254].
In an obesity-related colon cancer model associated
with hyperlipidemia and hyperinsulinemia, pitavastatin
prevented carcinogenesis and inhibited colon proliferation
and inammation [255], while simvastatin inhibited the
release of inammatory cytokines by colorectal cell lines
[256]. Clinical trials are exploring statins in the treatment
of human CRC.
RAAS blockers are the mainstay of therapy for
human DKD [252]. Angiotensin-converting enzyme
inhibitors and angiotensin-II type 1 receptor blockers
suppress chemically-induced colonic preneoplasic lesions
in diabetic animals [257-259]. However, their clinical use
to prevent colon cancer is not being pursued.
The endothelin receptor antagonist atrasentan is
undergoing RCTs for DKD [260, 261], and as add-on to
docetaxel and prednisone for stage IV hormone therapy-
resistant prostate cancer bone metastases (NCT00134056)
[262-264]. However, no trial is exploring CRC.
Paricalcitol is a VDR activator that may have
antiproteinuric eects on DKD as suggested by RCTs
[265] and may also slow cancer cell growth [266]. Phase
I trials have tested combinations of paricalcitol and
chemotherapeutic agents (NCT00217477). Additionally,
vitamin D has been explored for colon cancer prevention.
However, a combination of calcitriol, aspirin, and calcium
carbonate or vitamin D/calcium did not prevent recurrence
of colorectal adenomas over a 3- to 5-year period [267,
268].
mTOR inhibitors are used as anticancer agents and
also improve experimental DKD [99, 269]. The mTOR
inhibitors RAD001 (NCT01058655) and everolimus
and the dual PI3K/mTOR inhibitor PF-05212384
(NCT01937715, NCT01154335) are undergoing clinical
trials for metastatic CRC.
Several agents targeting cytokines and chemokines
have been tested both in T2DM and cancer [251, 252,
270-273]. Plerixafor is a CXCR4 antagonist undergoing
trials for advanced CRC (NCT02179970). Although not
specically tested in DM, a selective CXCR4 antagonist
AMD3465 decreased mineralocorticoid-dependent renal
brosis in mice [274] and targeting CXCR4 prevented
glomerular injury associated to high podocyte CXCR4
expression in mice [275].
JAK2 targeting prevented high-glucose-induced
brogenic responses in renal cells and prevented kidney
and vascular injury in experimental diabetes [276-279].
An ongoing phase II RCT is testing the JAK1 and JAK2
inhibitor baricitinib as add-on to RAS blockade in patients
with DKD (NCT01683409) while another will explore the
JAK2/FLT3 inhibitor pacritinib in patients with refractory
CRC and KRAS mutations (NCT02277093).
UNANSWERED QUESTIONS AND THE
WAY FORWARD
Table 5 summarizes the key points of the review.
The association between DM and CRC is recognized by
scientic consensus [4]. However, a number of issues
require more detailed studies (Table 6).
An overview of T2DM and CRC country-based
prevalence/incidence suggests that environmental,
development-associated or other factors may interact
with the T2DM milieu to increase the risk of CRC.
Identication of these putative factors and whether
DM associates with increased CRC risk in dierent
cultures and countries may provide further insights into
mechanisms underlying the relationship between DM and
cancer.
The case for a causal association should be
strengthened by the characterization of the DM-initiated
molecular pathways involved. This information may
also lead to the development of specic preventive
or therapeutic approaches. Studies should address the
relationship between DM-associated CRC and the
development of other DM-associated complications, i.e.,
whether there is a patient prole prone to develop any
DM-related complications. If this were the case, tools
should be developed for the early identication of such
patients. Urine proteomics holds promise in this regard,
as it allows identication of DKD at earlier stages than
currently available methods and predicts progression [280,
281] and may also be useful for the diagnosis of cancer
outside the urogenital system [282]. Early identication
of the subpopulation of DM patients at highest risk for
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developing cancer or classical complications may allow
enrollment in trials assessing the ecacy of drugs
targeting shared molecular mechanisms for prevention
and/or therapy. Additional systems biology approaches
may also contribute to dene molecular pathways leading
to DM-associated cancer or target organ damage. The most
promising approaches should undergo clinical trial testing,
ideally in high-risk populations or in early disease stages
identied by the study of specic molecular signatures.
Research is needed to dene the optimal therapeutic
approach for the patient with T2DM and CRC. Studies
of the impact of dierent antidiabetic agents on cancer
incidence are marred by the fact that both sides of the
comparison may theoretically modulate cancer incidence.
Additionally, there are potential biases related to the
indication of the specic agent. These research eorts
have the potential to decrease the incidence of DM-
associated complications and to improve outcomes.
The DiabetesCancerConnect Consortium funded by the
Spanish Government is attempting to answer some of
these questions.
Abbreviators
DM-Diabetes mellitus
CRC-Colorectal cancer
ADA- American Diabetes Association
T1DM- Type 1 DM
T2DM- Type 2 DM
MODY─ Maturity-onset diabetes of the young
GLP-1- Glucagon like peptide-1
GPDH- Glycerophosphate dehydrogenase
GPD2- Glycerol-3-phosphate dehydrogenase 2
GSK-3β- Glycogen synthase kinase 3-beta
EGFR- Epidermal growth factor receptor
HR- Hazard Ratio
SIR- Standardized incidence ratios
RR- Relative risk
CI- Condence interval
BMI- Body mass index
OR- Odds Ratio
HbA1c- Glycated hemoglobin
AGEs- Advanced Glycation End-products
RELMβ- Resistin-like molecule β
IGF-1- Insulin-like growth factor
MAPK- Mitogen activated protein kinase
PI3K- Phosphatidyl-inositol-3-kinase
PAK-1- Activated protein kinase-1
mRNA- Messenger RNA
ChREBP- Carbohydrate response element-binding
protein
NF-κB- Factor-kappa B
Nrf2- Nuclear factor erythroid 2–related factor 2
ATP- Adenosine triphosphate
Glut-1- Glucotransporter-1
TGF- Transforming growth factor
VDR- Vitamin D receptor
PTHrP- Parathyroid hormone-related protein-
Grem1- Gremlin
S1P- Sphingosine-1-phosphate
iHMP- Integrative Human Microbiome Project
TACT- Trial to Assess Chelation Therapy
EDTA- Ethylenediaminetetraacetic acid
miRNAs- MicroRNAs
GWAS- Genome-wide association studies
lncRNA- Long non-coding RNA
SNP- Single Nucleotide Polymorphism
eQTL- Expression quantitative trait loci
KEGG- Kyoto Encyclopedia of Genes and Genomes
VEGFR- Vascular endothelial growth factor receptor
B/D-HPP- Biology/Disease-driven Human
Proteome Project
HDPP- Human Diabetes Proteome Project
SELENBP1- Selenium-binding protein 1
CAI- Carbonic anhydrase I
DSPathNet- Drug-specic Signaling Pathway
Network
RCTs- Randomized controlled trials
CKD- Chronic kidney disease
ROS- Reactive Oxygen species
PPARγ- peroxisome proliferator–activated receptor
γ
DNA- Deoxyribonucleic acid
RNA- Ribonucleic acid
FDA- Food and Drug Administration
CAPOX- Capecitabine and oxaliplatin
RAAS- Renin angiotensin aldosterone system
mAb- Monoclonal antibody
HG- Hyperglycemia
DKD- Diabetic kidney disease
ARB- Angiotensin receptor blocker
HMGCoA- 3-hydroxy-3-methylglutaryl coenzyme
A
ACE- Angiotensin converting enzyme-
iNOS- Inducible nitric oxide synthase
NF-κB- Nuclear factor kappa-light-chain-enhancer
of activated B cells
ERK- Extracellular Signal-regulated Kinase
CTGF- Connective tissue growth factor
TGF-beta- Transforming growth factor beta
CXCR4- Chemokine Receptor type 4
CCL2- Chemokine Ligand 2
FUNDING
Research was supported by the grants FIS/
FEDER PI14/01650, PI13/00047, PI14/00386,
PIE13/00051, PI13/01873, PI13/00802, PI14/00883,
PI15/00298, PI15/01460, PI16/02057, PI16/01900,
CP09/00229, CP14/00133, CPII15/00027, SAF2012-
38830, CP12/03262 ISCIII-RETIC REDinREN
RD12/0021 RD16/0009 and RETICEF RD12/0043/0008,
Oncotarget16
www.impactjournals.com/oncotarget
CIBER in Diabetes and Associated Metabolic
Disorders (CIBERDEM, ISCIII), Biobanco IIS-FJD
PT13/0010/0012, FP7-HEALTH-2013-INNOVATION-1-
602422 e-PREDICE, Comunidad de Madrid S2010/
BMD-2378, CYTED IBERERC, Programa Intensicación
Actividad Investigadora (ISCIII) to AO and CA, Sociedad
Española de Nefrología y Fundación Renal Iñigo Alvarez
de Toledo to JAM, Programa Miguel Servet to NG, MC,
JAM, MDSN, ABS and GALL, and Programa Joan Rodes
to BFF.
CONFLICT OF INTERESTS
The authors have no competing nancial interests.
Members of the DiabetesCancerConnect
Consortium
Zaida Moreno Villegas, Maria Estrella Martin-
Crespo Aznar, Alberto Ortiz, Marta Ruiz Ortega, Maria
Jose Trujillo Tiebas, Alvaro Conrado Ucero Herreria,
Maria Concepcion Izquierdo Carnero, Irene Gutierrez
Rojas, Rebeca Manso Alonso, Cristina Chamizo Garcia,
Alfonso Rubio Navarro, Marta Corton Perez, Carmen
Gomez Guerrero, Manuel Jesus Hernandez Perez, Matilde
Alique Aguilar, Socorro Maria Rodriguez Pinilla, Gloria
Alvarez Llamas, Oscar Aguilera Martinez, Maria Posada
Ayala, Sergio Portal Nuñez, Jesus Egido De Los Rios,
Jesus Miguel Garcia-Foncillas Lopez, Federico Gustavo
Rojo Todo, Juan Madoz Gurpide, Carlos Antonio Tarin
Cerezo, Iolanda Lazaro Lopez, Juan Antonio Moreno
Gutierrez, Maria Rodriguez Remirez, Aurea Borrero
Palacios, Patricia Fernandez San Jose, Jonay Poveda
Nuñez, Rocio Sanchez Alcudia, Clara Isabel Gomez
Sanchez, Ana Belen Sanz Bartolome, Fernando Vivanco
Martinez, Maria Esther Martin Aparicio, Oscar Lorenzo
Gonzalez, Pedro Esbrit Arguelles, Beatriz Fernandez
Fernandez, Sandra Zazo Hernandez, Ruth Fernandez
Sanchez, Fiona Blanco Kelly, Raquel Perez Carro, Juan
Antonio Ardura Rodriguez, Carmen Ayuso Garcia,
Laura Del Puerto Nevado, Almudena Avila Fernandez,
Ana Maria Ramos Verde, Carlos Pastor Vargas, Nieves
Gonzalez Gomez, Iker Sanchez Navarro, Javier Martinez
Useros, Rosa Riveiro Alvarez, Laura Gonzalez Calero,
Catalina Martin Cleary, Olga Ruiz Andres, Luis Carlos
Tabara Rodriguez, Paula Gonzalez Alonso, Marta Martin
Lorenzo, Ion Cristobal Yoldi, Elena Burillo Ipiens, Ainhoa
Oguiza Bilbao, Carlota Recio Cruz, Sorina Daniela Tatu,
Adrian Ramos Cortassa, Jorge Enrique Rojas Rivera,
Liliana Gonzalez Espinoza, Carolina Lavoz Barria,
Maria Vanessa Perez Gomez, Pablo Minguez Paniagua,
Sebastian Mas Fontao, Ana María Díez Rodríguez.
REFERENCES
1. GBD 2013 Mortality and Causes of Death Collaborators.
Global, regional, and national age-sex specic all-cause and
cause-specic mortality for 240 causes of death, 1990-2013:
a systematic analysis for the Global Burden of Disease
Study 2013. Lancet. 2015; 385: 117-71.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA
Cancer J Clin. 2016; 66: 7-30.
3. American Diabetes Association. 3. Foundations of Care and
Comprehensive Medical Evaluation. Diabetes Care. 2016;
39 Suppl 1: S23-35.
4. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM,
Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee
D. Diabetes and cancer: a consensus report. Diabetes Care.
2010; 33: 1674-85.
5. American Diabetes Association. Diagnosis and
classication of diabetes mellitus. Diabetes Care. 2004; 27
Suppl 1: S5-10.
6. Rimm AA, Werner LH, Yserloo B V, Bernstein RA.
Relationship of ovesity and disease in 73, 532 weight-
conscious women. Public Health Rep; 90: 44-51.
7. Madiraju AK, Erion DM, Rahimi Y, Zhang X-M,
Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot
S, MacDonald MJ, Jurczak MJ, Camporez J-P, Lee H-Y,
et al. Metformin suppresses gluconeogenesis by inhibiting
mitochondrial glycerophosphate dehydrogenase. Nature.
2014; 510: 542-6.
8. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM,
Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe
P, Block L, Nicholson WK, Hutess S, Bass EB, et al.
Comparative eectiveness and safety of medications for
type 2 diabetes: an update including new drugs and 2-drug
combinations. Ann Intern Med. 2011; 154: 602-13.
9. American Diabetes Association. Standards of medical care
in diabetes—2014. Diabetes Care. 2014; 37 Suppl 1: S14-
80.
10. Chan AT, Giovannucci EL. Primary prevention of colorectal
cancer. Gastroenterology. 2010; 138: 2029-2043.e10.
11. Jo W-S, Chung DC. Genetics of hereditary colorectal
cancer. Semin Oncol. 2005; 32: 11-23.
12. Imperiale TF, Ransoho DF. Risk for colorectal cancer
in persons with a family history of adenomatous polyps: a
systematic review. Ann Intern Med. 2012; 156: 703-9.
13. Iacopetta B. Are there two sides to colorectal cancer? Int J
cancer. 2002; 101: 403-8.
14. Fearon ER, Vogelstein B. A genetic model for colorectal
tumorigenesis. Cell. 1990; 61: 759-67.
15. Cancer Genome Atlas Network. Comprehensive molecular
characterization of human colon and rectal cancer. Nature.
2012; 487: 330-7.
16. Vetrano S, Danese S. Colitis, microbiota, and colon cancer:
an infernal triangle. Gastroenterology. 2013; 144: 461-3.
Oncotarget17
www.impactjournals.com/oncotarget
17. Hu B, Elinav E, Huber S, Strowig T, Hao L, Hafemann
A, Jin C, Wunderlich C, Wunderlich T, Eisenbarth SC,
Flavell RA. Microbiota-induced activation of epithelial
IL-6 signaling links inammasome-driven inammation
with transmissible cancer. Proc Natl Acad Sci U S A. 2013;
110: 9862-7.
18. Abreu MT, Peek RM. Gastrointestinal malignancy and the
microbiome. Gastroenterology 2014; 146: 1534-1546.e3.
19. Sears CL, Garrett WS. Microbes, microbiota, and colon
cancer. Cell Host Microbe. 2014; 15: 317-28.
20. Song X, Gao H, Lin Y, Yao Y, Zhu S, Wang J, Liu Y, Yao
X, Meng G, Shen N, Shi Y, Iwakura Y, Qian Y. Alterations
in the microbiota drive interleukin-17C production from
intestinal epithelial cells to promote tumorigenesis.
Immunity. 2014; 40: 140-52.
21. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R,
Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn
DH, Lee JR, Oermanns S, Ganapathy V. Activation
of Gpr109a, receptor for niacin and the commensal
metabolite butyrate, suppresses colonic inammation and
carcinogenesis. Immunity. 2014; 40: 128-39.
22. Belcheva A, Irrazabal T, Robertson SJ, Streutker C,
Maughan H, Rubino S, Moriyama EH, Copeland JK,
Kumar S, Green B, Geddes K, Pezo RC, Navarre WW,
et al. Gut microbial metabolism drives transformation of
MSH2-decient colon epithelial cells. Cell. 2014; 158: 288-
99.
23. Tezcan G, Tunca B, Ak S, Cecener G, Egeli U. Molecular
approach to genetic and epigenetic pathogenesis of early-
onset colorectal cancer. World J Gastrointest Oncol. 2016;
8: 83-98.
24. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative
chemoradiation for non-metastatic locally advanced rectal
cancer. Cochrane database Syst Rev. 2012; 12: CD008368.
25. André T, Boni C, Mounedji-Boudiaf L, Navarro M,
Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P,
Bridgewater J, Tabah-Fisch I, de Gramont A, Multicenter
International Study of Oxaliplatin/5-Fluorouracil/
Leucovorin in the Adjuvant Treatment of Colon Cancer
(MOSAIC) Investigators. Oxaliplatin, uorouracil, and
leucovorin as adjuvant treatment for colon cancer. N Engl J
Med. 2004; 350: 2343-51.
26. Therkildsen C, Bergmann TK, Henrichsen-Schnack T,
Ladelund S, Nilbert M. The predictive value of KRAS,
NRAS, BRAF, PIK3CA and PTEN for anti-EGFR
treatment in metastatic colorectal cancer: A systematic
review and meta-analysis. Acta Oncol. 2014; 53: 852-64.
27. Suh S, Kim K-W. Diabetes and cancer: is diabetes causally
related to cancer? Diabetes Metab J 2011; 35: 193-8.
28. Will JC, Galuska DA, Vinicor F, Calle EE. Colorectal
cancer: another complication of diabetes mellitus? Am J
Epidemiol. 1998; 147: 816-25.
29. Jarvandi S, Davidson NO, Schootman M. Increased risk of
colorectal cancer in type 2 diabetes is independent of diet
quality. PLoS One. 2013; 8: e74616.
30. Kasuga M, Ueki K, Tajima N, Noda M, Ohashi K, Noto
H, Goto A, Ogawa W, Sakai R, Tsugane S, Hamajima N,
Nakagama H, Tajima K, et al. Report of the Japan Diabetes
Society/Japanese Cancer Association Joint Committee on
Diabetes and Cancer. Cancer Sci. 2013; 104: 965-76.
31. Wang M, Hu R-Y, Wu H-B, Pan J, Gong W-W, Guo
L-H, Zhong J-M, Fei F-R, Yu M. Cancer risk among
patients with type 2 diabetes mellitus: a population-based
prospective study in China. Sci Rep. 2015; 5: 11503.
32. Harding JL, Shaw JE, Peeters A, Cartensen B, Magliano DJ.
Cancer risk among people with type 1 and type 2 diabetes:
disentangling true associations, detection bias, and reverse
causation. Diabetes Care. 2015; 38: 264-70.
33. Liu X, Hemminki K, Försti A, Sundquist K, Sundquist J, Ji
J. Cancer risk in patients with type 2 diabetes mellitus and
their relatives. Int J cancer. 2015; 137: 903-10.
34. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis
JPA. Type 2 diabetes and cancer: umbrella review of meta-
analyses of observational studies. BMJ. 2015; 350: g7607.
35. Huang Y, Cai X, Qiu M, Chen P, Tang H, Hu Y, Huang
Y. Prediabetes and the risk of cancer: a meta-analysis.
Diabetologia. 2014; 57: 2261-9.
36. Dankner R, Boetta P, Balicer RD, Boker LK, Sadeh M,
Berlin A, Olmer L, Goldfracht M, Freedman LS. Time-
Dependent Risk of Cancer After a Diabetes Diagnosis in a
Cohort of 2.3 Million Adults. Am J Epidemiol. 2016; 183:
1098-106.
37. De Bruijn KMJ, Ruiter R, de Keyser CE, Hofman A,
Stricker BH, van Eijck CHJ. Detection bias may be the
main cause of increased cancer incidence among diabetics:
results from the Rotterdam Study. Eur J Cancer. 2014; 50:
2449-55.
38. Porter NR, Eberth JM, Samson ME, Garcia-Dominic
O, Lengerich EJ, Schootman M. Diabetes Status and
Being Up-to-Date on Colorectal Cancer Screening, 2012
Behavioral Risk Factor Surveillance System. Prev Chronic
Dis. 2016; 13: E19.
39. Singh S, Earle CC, Bae SJ, Fischer HD, Yun L, Austin
PC, Rochon PA, Anderson GM, Lipscombe L. Incidence
of Diabetes in Colorectal Cancer Survivors. J Natl Cancer
Inst. 2016; 108: djv402.
40. Nilsen TI, Vatten LJ. Prospective study of colorectal cancer
risk and physical activity, diabetes, blood glucose and BMI:
exploring the hyperinsulinaemia hypothesis. Br J Cancer.
2001; 84: 417-22.
41. de Kort S, Simons CCJM, van den Brandt PA, Goldbohm
RAS, Arts ICW, de Bruine AP, Janssen-Heijnen MLG,
Sanduleanu S, Masclee AAM, Weijenberg MP. Diabetes
mellitus type 2 and subsite-specic colorectal cancer risk in
men and women: results from the Netherlands Cohort Study
on diet and cancer. Eur J Gastroenterol Hepatol. 2016; 28:
896-903.
42. Bardou M, Barkun AN, Martel M. Obesity and colorectal
Oncotarget18
www.impactjournals.com/oncotarget
cancer. Gut 2013; 62: 933-47.
43. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon
DA, Smeeth L. Body-mass index and risk of 22 specic
cancers: a population-based cohort study of 5·24 million
UK adults. Lancet (London, England) 2014; 384: 755-65.
44. Murphy N, Cross AJ, Abubakar M, Jenab M, Aleksandrova
K, Boutron-Ruault M-C, Dossus L, Racine A, Kühn T,
Katzke VA, Tjønneland A, Petersen KEN, Overvad K, et
al. A Nested Case-Control Study of Metabolically Dened
Body Size Phenotypes and Risk of Colorectal Cancer in
the European Prospective Investigation into Cancer and
Nutrition (EPIC). PLoS Med 2016; 13: e1001988.
45. Bloomeld HE, Koeller E, Greer N, MacDonald R, Kane
R, Wilt TJ. Eects on Health Outcomes of a Mediterranean
Diet With No Restriction on Fat Intake: A Systematic
Review and Meta-analysis. Ann Intern Med 2016; 165: 491-
500.
46. Gallagher EJ, LeRoith D. Obesity and Diabetes: The
Increased Risk of Cancer and Cancer-Related Mortality.
Physiol Rev 2015]; 95: 727-48.
47. Hua F, Yu J-J, Hu Z-W. Diabetes and cancer, common
threads and missing links. Cancer Lett 2016; 374: 54-61.
48. Björk J, Nilsson J, Hultcrantz R, Johansson C. Growth-
regulatory eects of sensory neuropeptides, epidermal
growth factor, insulin, and somatostatin on the non-
transformed intestinal epithelial cell line IEC-6 and the
colon cancer cell line HT 29. Scand J Gastroenterol 1993;
28: 879-84.
49. Nagel JM, Staa J, Renner-Müller I, Horst D, Vogeser M,
Langkamp M, Hoeich A, Göke B, Kolligs FT, Mantzoros
CS. Insulin glargine and NPH insulin increase to a similar
degree epithelial cell proliferation and aberrant crypt foci
formation in colons of diabetic mice. Horm Cancer 2010;
1: 320-30.
50. Belore A, Frasca F, Pandini G, Sciacca L, Vigneri R.
Insulin receptor isoforms and insulin receptor/insulin-like
growth factor receptor hybrids in physiology and disease.
Endocr Rev 2009; 30: 586-623.
51. Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B.
Diabetes mellitus and breast cancer. Lancet Oncol 2005; 6:
103-11.
52. Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa
Y, Lennon R, Pons DA, Owen RJ, Satchell SC, Miles
MJ, Caunt CJ, McArdle CA, Pavenstädt H, et al. Insulin
signaling to the glomerular podocyte is critical for normal
kidney function. Cell Metab 2010; 12: 329-40.
53. Sun J, Khalid S, Rozakis-Adcock M, Fantus IG, Jin T. P-21-
activated protein kinase-1 functions as a linker between
insulin and Wnt signaling pathways in the intestine.
Oncogene 2009; 28: 3132-44.
54. Reidy K, Kang HM, Hostetter T, Susztak K. Molecular
mechanisms of diabetic kidney disease. J Clin Invest 2014;
124: 2333-40.
55. Jain SS, Bird RP. Elevated expression of tumor necrosis
factor-alpha signaling molecules in colonic tumors of
Zucker obese (fa/fa) rats. Int J cancer 2010; 127: 2042-50.
56. Teraoka N, Mutoh M, Takasu S, Ueno T, Nakano K,
Takahashi M, Imai T, Masuda S, Sugimura T, Wakabayashi
K. High susceptibility to azoxymethane-induced colorectal
carcinogenesis in obese KK-Ay mice. Int J cancer 2011;
129: 528-35.
57. Flores MBS, Rocha GZ, Damas-Souza DM, Osório-Costa
F, Dias MM, Ropelle ER, Camargo JA, de Carvalho RB,
Carvalho HF, Saad MJA, Carvalheira JBC. Obesity-induced
increase in tumor necrosis factor-α leads to development of
colon cancer in mice. Gastroenterology 2012; 143: 741-53-
4.
58. Hata K, Kubota M, Shimizu M, Moriwaki H, Kuno T,
Tanaka T, Hara A, Hirose Y. C57BL/KsJ-db/db-Apc mice
exhibit an increased incidence of intestinal neoplasms. Int J
Mol Sci 2011; 12: 8133-45.
59. LeRoith D. Can endogenous hyperinsulinaemia explain the
increased risk of cancer development and mortality in type
2 diabetes: evidence from mouse models. Diabetes Metab
Res Rev 2010; 26: 599-601.
60. Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith
D. Insulin-sensitizing therapy attenuates type 2 diabetes-
mediated mammary tumor progression. Diabetes 2010; 59:
686-93.
61. Masur K, Vetter C, Hinz A, Tomas N, Henrich H,
Niggemann B, Zänker KS. Diabetogenic glucose and
insulin concentrations modulate transcriptome and protein
levels involved in tumour cell migration, adhesion and
proliferation. Br J Cancer 2011; 104: 345-52.
62. Tomas NM, Masur K, Piecha JC, Niggemann B, Zänker KS.
Akt and phospholipase Cγ are involved in the regulation of
growth and migration of MDA-MB-468 breast cancer and
SW480 colon cancer cells when cultured with diabetogenic
levels of glucose and insulin. BMC Res Notes 2012; 5: 214.
63. Ma Y-S, Yang I-P, Tsai H-L, Huang C-W, Juo S-HH, Wang
J-Y. High glucose modulates antiproliferative eect and
cytotoxicity of 5-uorouracil in human colon cancer cells.
DNA Cell Biol 2014; 33: 64-72.
64. Chen H, Wu L, Li Y, Meng J, Lin N, Yang D, Zhu Y, Li X,
Li M, Xu Y, Wu Y, Tong X, Su Q. Advanced glycation end
products increase carbohydrate responsive element binding
protein expression and promote cancer cell proliferation.
Mol Cell Endocrinol 2014; 395: 69-78.
65. Park M-J, Kim D-I, Lim S-K, Choi J-H, Han H-J, Yoon
K-C, Park S-H. High glucose-induced O-GlcNAcylated
carbohydrate response element-binding protein (ChREBP)
mediates mesangial cell lipogenesis and brosis: the
possible role in the development of diabetic nephropathy.
J Biol Chem 2014; 289: 13519-30.
66. Uzozie A, Nanni P, Staiano T, Grossmann J, Barkow-
Oesterreicher S, Shay JW, Tiwari A, Buoli F, Laczko
E, Marra G. Sorbitol dehydrogenase overexpression
and other aspects of dysregulated protein expression in
Oncotarget19
www.impactjournals.com/oncotarget
human precancerous colorectal neoplasms: a quantitative
proteomics study. Mol Cell Proteomics 2014; 13: 1198-218.
67. Wu Y, Zhou BP. Inammation: a driving force speeds
cancer metastasis. Cell Cycle 2009; 8: 3267-73.
68. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-
related inammation. Nature 2008; 454: 436-44.
69. Rojas A, Figueroa H, Morales E. Fueling inammation at
tumor microenvironment: the role of multiligand/RAGE
axis. Carcinogenesis 2010; 31: 334-41.
70. Giacco F, Brownlee M. Oxidative stress and diabetic
complications. Circ Res 2010; 107: 1058-70.
71. Yao D, Brownlee M. Hyperglycemia-induced reactive
oxygen species increase expression of the receptor for
advanced glycation end products (RAGE) and RAGE
ligands. Diabetes 2010; 59: 249-55.
72. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M,
Christ-Schmidt H, Goldsberry A, Houser M, Krauth M,
Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving
H-H, et al. Bardoxolone methyl in type 2 diabetes and stage
4 chronic kidney disease. N Engl J Med 2013; 369: 2492-
503.
73. WARBURG O. On the origin of cancer cells. Science 1956;
123: 309-14.
74. Vander Heiden MG, Cantley LC, Thompson CB.
Understanding the Warburg eect: the metabolic
requirements of cell proliferation. Science 2009; 324: 1029-
33.
75. Macheda ML, Rogers S, Best JD. Molecular and cellular
regulation of glucose transporter (GLUT) proteins in
cancer. J Cell Physiol 2005; 202: 654-62.
76. Szablewski L. Expression of glucose transporters in cancers.
Biochim Biophys Acta. 2013; 1835: 164-9.
77. Gnudi L, Thomas SM, Viberti G. Mechanical forces in
diabetic kidney disease: a trigger for impaired glucose
metabolism. J Am Soc Nephrol 2007; 18: 2226-32.
78. Luo Y, Ohmori H, Shimomoto T, Fujii K, Sasahira T,
Chihara Y, Kuniyasu H. Anti-angiotensin and hypoglycemic
treatments suppress liver metastasis of colon cancer cells.
Pathobiology 2011; 78: 285-90.
79. Dai C, Stolz DB, Kiss LP, Monga SP, Holzman LB, Liu Y.
Wnt/beta-catenin signaling promotes podocyte dysfunction
and albuminuria. J Am Soc Nephrol 2009; 20: 1997-2008.
80. Lin C-L, Wang J-Y, Huang Y-T, Kuo Y-H, Surendran K,
Wang F-S. Wnt/beta-catenin signaling modulates survival
of high glucose-stressed mesangial cells. J Am Soc Nephrol
2006; 17: 2812-20.
81. Li J-Y, Yu T, Xia Z-S, Chen G-C, Yuan Y-H, Zhong W,
Zhao L-N, Chen Q-K. Enhanced proliferation in colorectal
epithelium of patients with type 2 diabetes correlates with
β-catenin accumulation. J Diabetes Complications; 28: 689-
97.
82. Larriba MJ, González-Sancho JM, Barbáchano A, Niell N,
Ferrer-Mayorga G, Muñoz A. Vitamin D Is a Multilevel
Repressor of Wnt/b-Catenin Signaling in Cancer Cells.
Cancers (Basel) 2013; 5: 1242-60.
83. He W, Kang YS, Dai C, Liu Y. Blockade of Wnt/β-catenin
signaling by paricalcitol ameliorates proteinuria and kidney
injury. J Am Soc Nephrol 2011; 22: 90-103.
84. Holick MF. Vitamin D deciency. N Engl J Med 2007; 357:
266-81.
85. Feldman D, Krishnan A V, Swami S, Giovannucci E,
Feldman BJ. The role of vitamin D in reducing cancer risk
and progression. Nat Rev Cancer 2014; 14: 342-57.
86. Pereira F, Larriba MJ, Muñoz A. Vitamin D and colon
cancer. Endocr Relat Cancer 2012; 19: R51-71.
87. Ortiz A, Ziyadeh FN, Neilson EG. Expression of apoptosis-
regulatory genes in renal proximal tubular epithelial cells
exposed to high ambient glucose and in diabetic kidneys. J
Investig Med 1997; 45: 50-6. Available from http://www.
ncbi.nlm.nih.gov/pubmed/9084575
88. Sanchez-Niño M-D, Bozic M, Córdoba-Lanús E, Valcheva
P, Gracia O, Ibarz M, Fernandez E, Navarro-Gonzalez
JF, Ortiz A, Valdivielso JM. Beyond proteinuria: VDR
activation reduces renal inammation in experimental
diabetic nephropathy.
89. Sanchez-Niño M-D, Benito-Martin A, Ortiz A. New
paradigms in cell death in human diabetic nephropathy.
Kidney Int 2010; 78: 737-44.
90. Pérez-Gómez MV, Ortiz-Arduán A, Lorenzo-Sellares V.
Vitamin D and proteinuria: a critical review of molecular
bases and clinical experience. Nefrologia 2013; 33: 716-26.
91. Lautrette A, Li S, Alili R, Sunnarborg SW, Burtin M,
Lee DC, Friedlander G, Terzi F. Angiotensin II and EGF
receptor cross-talk in chronic kidney diseases: a new
therapeutic approach. Nat Med 2005; 11: 867-74.
92. Cai W, He JC, Zhu L, Lu C, Vlassara H. Advanced
glycation end product (AGE) receptor 1 suppresses cell
oxidant stress and activation signaling via EGF receptor.
Proc Natl Acad Sci U S A 2006; 103: 13801-6.
93. Taniguchi K, Xia L, Goldberg HJ, Lee KWK, Shah A,
Stavar L, Masson EAY, Momen A, Shikatani EA, John
R, Husain M, Fantus IG. Inhibition of Src kinase blocks
high glucose-induced EGFR transactivation and collagen
synthesis in mesangial cells and prevents diabetic
nephropathy in mice. Diabetes 2013; 62: 3874-86.
94. Rayego-Mateos S, Morgado-Pascual JL, Sanz AB, Ramos
AM, Eguchi S, Batlle D, Pato J, Keri G, Egido J, Ortiz A,
Ruiz-Ortega M. TWEAK transactivation of the epidermal
growth factor receptor mediates renal inammation. J
Pathol 2013; 231: 480-94.
95. Sanz AB, Izquierdo MC, Sanchez-Niño MD, Ucero AC,
Egido J, Ruiz-Ortega M, Ramos AM, Putterman C, Ortiz
A. TWEAK and the progression of renal disease: clinical
translation. Nephrol Dial Transplant 2014; 29 Suppl 1: i54-
62.
96. Ardura JA, Rayego-Mateos S, Rámila D, Ruiz-Ortega M,
Esbrit P. Parathyroid hormone-related protein promotes
epithelial-mesenchymal transition. J Am Soc Nephrol 2010;
Oncotarget20
www.impactjournals.com/oncotarget
21: 237-48.
97. Trebing J, Lang I, Chopra M, Salzmann S, Moshir M,
Silence K, Riedel SS, Siegmund D, Beilhack A, Otto C,
Wajant H. A novel llama antibody targeting Fn14 exhibits
anti-metastatic activity in vivo. MAbs; 6: 297-308.
98. Zhang M-Z, Wang Y, Paueksakon P, Harris RC. Epidermal
growth factor receptor inhibition slows progression of
diabetic nephropathy in association with a decrease in
endoplasmic reticulum stress and an increase in autophagy.
Diabetes 2014; 63: 2063-72.
99. Gödel M, Hartleben B, Herbach N, Liu S, Zschiedrich S,
Lu S, Debreczeni-Mór A, Lindenmeyer MT, Rastaldi M-P,
Hartleben G, Wiech T, Fornoni A, Nelson RG, et al. Role
of mTOR in podocyte function and diabetic nephropathy in
humans and mice. J Clin Invest 2011; 121: 2197-209.
100. Rayego-Mateos S, Rodrigues-Díez R, Morgado-Pascual JL,
Rodrigues Díez RR, Mas S, Lavoz C, Alique M, Pato J,
Keri G, Ortiz A, Egido J, Ruiz-Ortega M. Connective tissue
growth factor is a new ligand of epidermal growth factor
receptor. J Mol Cell Biol 2013; 5: 323-35.
101. Guha M, Xu Z-G, Tung D, Lanting L, Natarajan R.
Specic down-regulation of connective tissue growth factor
attenuates progression of nephropathy in mouse models of
type 1 and type 2 diabetes. FASEB J 2007; 21: 3355-68.
102. Chang C-C, Lin B-R, Wu T-S, Jeng Y-M, Kuo M-L. Input
of microenvironmental regulation on colorectal cancer: role
of the CCN family. World J Gastroenterol 2014; 20: 6826-
31.
103. Izquierdo MC, Perez-Gomez M V, Sanchez-Niño MD, Sanz
AB, Ruiz-Andres O, Poveda J, Moreno JA, Egido J, Ortiz
A. Klotho, phosphate and inammation/ageing in chronic
kidney disease. Nephrol Dial Transplant 2012; 27 Suppl 4:
iv6-10.
104. Sanchez-Niño MD, Sanz AB, Ortiz A. Klotho to treat
kidney brosis. J Am Soc Nephrol 2013; 24: 687-9.
105. Wu C, Wang Q, Lv C, Qin N, Lei S, Yuan Q, Wang G.
The changes of serum sKlotho and NGAL levels and their
correlation in type 2 diabetes mellitus patients with dierent
stages of urinary albumin. Diabetes Res Clin Pract 2014;
106: 343-50.
106. Cheng M-F, Chen L-J, Cheng J-T. Decrease of Klotho in
the kidney of streptozotocin-induced diabetic rats. J Biomed
Biotechnol 2010; 2010: 513853.
107. Moreno JA, Izquierdo MC, Sanchez-Niño MD, Suárez-
Alvarez B, Lopez-Larrea C, Jakubowski A, Blanco J,
Ramirez R, Selgas R, Ruiz-Ortega M, Egido J, Ortiz A,
Sanz AB. The inammatory cytokines TWEAK and TNFα
reduce renal klotho expression through NFκB. J Am Soc
Nephrol 2011 [; 22: 1315-25.
108. Sastre C, Rubio-Navarro A, Buendía I, Gómez-Guerrero
C, Blanco J, Mas S, Egido J, Blanco-Colio LM, Ortiz A,
Moreno JA. Hyperlipidemia-associated renal damage
decreases Klotho expression in kidneys from ApoE
knockout mice. PLoS One 2013; 8: e83713.
109. Zhou L, Li Y, Zhou D, Tan RJ, Liu Y. Loss of Klotho
contributes to kidney injury by derepression of Wnt/β-
catenin signaling. J Am Soc Nephrol 2013; 24: 771-85.
110. Li X-X, Huang L-Y, Peng J-J, Liang L, Shi D-B, Zheng
H-T, Cai S-J. Klotho suppresses growth and invasion of
colon cancer cells through inhibition of IGF1R-mediated
PI3K/AKT pathway. Int J Oncol 2014; 45: 611-8.
111. Pan J, Zhong J, Gan LH, Chen SJ, Jin HC, Wang X, Wang
LJ. Klotho, an anti-senescence related gene, is frequently
inactivated through promoter hypermethylation in colorectal
cancer. Tumour Biol 2011; 32: 729-35.
112. Odegaard JI, Chawla A. Pleiotropic actions of insulin
resistance and inammation in metabolic homeostasis.
Science 2013; 339: 172-7.
113. Nguyen A V, Wu Y-Y, Lin EY. STAT3 and sphingosine-
1-phosphate in inammation-associated colorectal cancer.
World J Gastroenterol 2014; 20: 10279-87.
114. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S,
Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E,
Ben-Neriah Y. NF-kappaB functions as a tumour promoter
in inammation-associated cancer. Nature 2004; 431: 461-
6.
115. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y,
Pestell RG, Albanese C, Darnell JE. Stat3 as an oncogene.
Cell 1999; 98: 295-303.
116. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in
immunity, immunodeciency, and cancer. N Engl J Med
2013; 368: 161-70.
117. Sanz AB, Sanchez-Niño MD, Ramos AM, Moreno JA,
Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A. NF-
kappaB in renal inammation. J Am Soc Nephrol 2010; 21:
1254-62.
118. Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada
A, Huang W-C, Hait NC, Allegood JC, Price MM, Avni
D, Takabe K, Kordula T, Milstien S, et al. Sphingosine-
1-phosphate links persistent STAT3 activation, chronic
intestinal inammation, and development of colitis-
associated cancer. Cancer Cell 2013; 23: 107-20.
119. Sheng L, Zhou Y, Chen Z, Ren D, Cho KW, Jiang L,
Shen H, Sasaki Y, Rui L. NF-κB-inducing kinase (NIK)
promotes hyperglycemia and glucose intolerance in obesity
by augmenting glucagon action. Nat Med 2012; 18: 943-9.
120. Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A,
Hamoudi RA, Noels H, Sagaert X, Van Loo P, Baens M,
Du M-Q, Lucas PC, et al. Cleavage of NIK by the API2-
MALT1 fusion oncoprotein leads to noncanonical NF-
kappaB activation. Science 2011; 331: 468-72.
121. Gochman E, Mahajna J, Reznick AZ. NF-κB activation
by peroxynitrite through IκBα-dependent phosphorylation
versus nitration in colon cancer cells. Anticancer Res 2011;
31: 1607-17.
122. Malle EK, Zammit NW, Walters SN, Koay YC, Wu J,
Tan BM, Villanueva JE, Brink R, Loudovaris T, Cantley
J, McAlpine SR, Hesselson D, Grey ST. Nuclear factor κB-
Oncotarget21
www.impactjournals.com/oncotarget
inducing kinase activation as a mechanism of pancreatic β
cell failure in obesity. J Exp Med 2015; 212: 1239-54.
123. Ortiz A, Husi H, Gonzalez-Lafuente L, Valiño-Rivas
L, Fresno M, Sanz AB, Mullen W, Albalat A, Mezzano
S, Vlahou T, Mischak H, Sanchez-Niño MD. Mitogen-
Activated Protein Kinase 14 Promotes AKI. J Am Soc
Nephrol. 2017; .
124. Allen IC, Wilson JE, Schneider M, Lich JD, Roberts
RA, Arthur JC, Woodford R-MT, Davis BK, Uronis JM,
Herfarth HH, Jobin C, Rogers AB, Ting JP-Y. NLRP12
suppresses colon inammation and tumorigenesis through
the negative regulation of noncanonical NF-κB signaling.
Immunity 2012; 36: 742-54.
125. Sciacca L, Vigneri R, Tumminia A, Frasca F, Squatrito S,
Frittitta L, Vigneri P. Clinical and molecular mechanisms
favoring cancer initiation and progression in diabetic
patients. Nutr Metab Cardiovasc Dis 2013; 23: 808-15.
126. He G, Karin M. NF-κB and STAT3 - key players in liver
inammation and cancer. Cell Res 2011; 21: 159-68.
127. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA,
Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon
JI, Flavell RA. NLRP6 inammasome regulates colonic
microbial ecology and risk for colitis. Cell 2011; 145: 745-
57.
128. Chen GY, Liu M, Wang F, Bertin J, Núñez G. A functional
role for Nlrp6 in intestinal inammation and tumorigenesis.
J Immunol 2011; 186: 7187-94.
129. Khan MT, Nieuwdorp M, Bäckhed F. Microbial modulation
of insulin sensitivity. Cell Metab 2014; 20: 753-60.
130. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ,
Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak
MJ, Camporez J-P, Shulman GI, Gordon JI, et al.
Inammasome-mediated dysbiosis regulates progression
of NAFLD and obesity. Nature 2012; 482: 179-85.
131. Integrative HMP (iHMP) Research Network Consortium.
The Integrative Human Microbiome Project: dynamic
analysis of microbiome-host omics proles during periods
of human health and disease. Cell Host Microbe 2014; 16:
276-89.
132. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang
W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, et al. A
metagenome-wide association study of gut microbiota in
type 2 diabetes. Nature 2012; 490: 55-60.
133. Baxter NT, Zackular JP, Chen GY, Schloss PD. Structure
of the gut microbiome following colonization with human
feces determines colonic tumor burden. Microbiome 2014;
2: 20.
134. Khan S, Jena G. Sodium butyrate, a HDAC inhibitor
ameliorates eNOS, iNOS and TGF-β1-induced brogenesis,
apoptosis and DNA damage in the kidney of juvenile
diabetic rats. Food Chem Toxicol 2014; 73: 127-39.
135. Lui GYL, Kovacevic Z, Richardson V, Merlot AM,
Kalinowski DS, Richardson DR. Targeting cancer by
binding iron: Dissecting cellular signaling pathways.
Oncotarget 2015; 6: 18748-79.
136. Song S, Christova T, Perusini S, Alizadeh S, Bao R-Y,
Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M,
Joseph B, Subramaniam R, Aman A, et al. Wnt inhibitor
screen reveals iron dependence of β-catenin signaling in
cancers. Cancer Res 2011; 71: 7628-39.
137. Banerjee A, Mifsud NA, Bird R, Forsyth C, Szer J, Tam
C, Kellner S, Grigg A, Motum P, Bentley M, Opat S,
Grigoriadis G. The oral iron chelator deferasirox inhibits
NF-κB mediated gene expression without impacting on
proximal activation: implications for myelodysplasia and
aplastic anaemia. Br J Haematol 2015; 168: 576-82.
138. Dongiovanni P, Valenti L, Ludovica Fracanzani A, Gatti
S, Cairo G, Fargion S. Iron depletion by deferoxamine up-
regulates glucose uptake and insulin signaling in hepatoma
cells and in rat liver. Am J Pathol 2008; 172: 738-47. 7
139. Fernández-Real JM, McClain D, Manco M. Mechanisms
Linking Glucose Homeostasis and Iron Metabolism Toward
the Onset and Progression of Type 2 Diabetes. Diabetes
Care 2015; 38: 2169-76.
140. Morita T, Nakano D, Kitada K, Morimoto S, Ichihara A,
Hitomi H, Kobori H, Shiojima I, Nishiyama A. Chelation
of dietary iron prevents iron accumulation and macrophage
inltration in the type I diabetic kidney. Eur J Pharmacol
2015; 756: 85-91.
141. Lamas GA, Goertz C, Boineau R, Mark DB, Rozema
T, Nahin RL, Lindblad L, Lewis EF, Drisko J, Lee KL,
TACT Investigators. Eect of disodium EDTA chelation
regimen on cardiovascular events in patients with previous
myocardial infarction: the TACT randomized trial. JAMA
2013; 309: 1241-50.
142. Bastide NM, Chenni F, Audebert M, Santarelli RL, Taché
S, Naud N, Baradat M, Jouanin I, Surya R, Hobbs DA,
Kuhnle GG, Raymond-Letron I, Gueraud F, et al. A central
role for heme iron in colon carcinogenesis associated with
red meat intake. Cancer Res 2015; 75: 870-9.
143. Kim Y, Keogh J, Clifton P. A review of potential metabolic
etiologies of the observed association between red meat
consumption and development of type 2 diabetes mellitus.
Metabolism 2015; 64: 768-79.
144. Ørntoft M-BW, Nielsen HJ, Ørntoft TF, Andersen CL,
Danish Study Group on Early Detection of Colorectal
Cancer. Performance of the colorectal cancer screening
marker Sept9 is inuenced by age, diabetes and arthritis: a
nested case-control study. BMC Cancer 2015; 15: 819.
145. Dayeh T, Volkov P, Salö S, Hall E, Nilsson E, Olsson
AH, Kirkpatrick CL, Wollheim CB, Eliasson L, Rönn T,
Bacos K, Ling C. Genome-wide DNA methylation analysis
of human pancreatic islets from type 2 diabetic and non-
diabetic donors identies candidate genes that inuence
insulin secretion. PLoS Genet 2014; 10: e1004160.
146. Trionni P, Benigni A, Remuzzi G. MicroRNAs in kidney
physiology and disease. Nat Rev Nephrol 2015; 11: 23-33.
147. Goossens-Beumer IJ, Derr RS, Buermans HPJ, Goeman
Oncotarget22
www.impactjournals.com/oncotarget
JJ, Böhringer S, Morreau H, Nitsche U, Janssen K-P, van
de Velde CJH, Kuppen PJK. MicroRNA classier and
nomogram for metastasis prediction in colon cancer. Cancer
Epidemiol Biomarkers Prev 2015; 24: 187-97.
148. Zhang J-X, Song W, Chen Z-H, Wei J-H, Liao Y-J, Lei J,
Hu M, Chen G-Z, Liao B, Lu J, Zhao H-W, Chen W, He
Y-L, et al. Prognostic and predictive value of a microRNA
signature in stage II colon cancer: a microRNA expression
analysis. Lancet Oncol 2013; 14: 1295-306.
149. Zhong X, Chung ACK, Chen HY, Dong Y, Meng XM, Li
R, Yang W, Hou FF, Lan HY. miR-21 is a key therapeutic
target for renal injury in a mouse model of type 2 diabetes.
Diabetologia 2013; 56: 663-74.
150. Dey N, Das F, Mariappan MM, Mandal CC, Ghosh-
Choudhury N, Kasinath BS, Choudhury GG. MicroRNA-21
orchestrates high glucose-induced signals to TOR complex
1, resulting in renal cell pathology in diabetes. J Biol Chem
2011; 286: 25586-603.
151. Zhang Z, Peng H, Chen J, Chen X, Han F, Xu X, He X, Yan
N. MicroRNA-21 protects from mesangial cell proliferation
induced by diabetic nephropathy in db/db mice. FEBS Lett
2009; 583: 2009-14.
152. Hansen TF, Kjær-Frifeldt S, Christensen RD, Morgenthaler
S, Blondal T, Lindebjerg J, Sørensen FB, Jakobsen A.
Redening high-risk patients with stage II colon cancer by
risk index and microRNA-21: results from a population-
based cohort. Br J Cancer 2014; 111: 1285-92.
153. Zhang J, Xiao Z, Lai D, Sun J, He C, Chu Z, Ye H,
Chen S, Wang J. miR-21, miR-17 and miR-19a induced
by phosphatase of regenerating liver-3 promote the
proliferation and metastasis of colon cancer. Br J Cancer
2012; 107: 352-9.
154. Deng J, Lei W, Fu J-C, Zhang L, Li J-H, Xiong J-P.
Targeting miR-21 enhances the sensitivity of human colon
cancer HT-29 cells to chemoradiotherapy in vitro. Biochem
Biophys Res Commun 2014; 443: 789-95.
155. Song M-S, Rossi JJ. The anti-miR21 antagomir, a
therapeutic tool for colorectal cancer, has a potential
synergistic eect by perturbing an angiogenesis-associated
miR30. Front Genet 2014; 4: 301.
156. Nangia-Makker P, Yu Y, Vasudevan A, Farhana L,
Rajendra SG, Levi E, Majumdar APN. Metformin: a
potential therapeutic agent for recurrent colon cancer. PLoS
One 2014; 9: e84369.
157. Grant SFA, Thorleifsson G, Reynisdottir I, Benediktsson R,
Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson
V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters
GB, et al. Variant of transcription factor 7-like 2 (TCF7L2)
gene confers risk of type 2 diabetes. Nat Genet 2006; 38:
320-3.
158. Saxena R, Elbers CC, Guo Y, Peter I, Gaunt TR, Mega
JL, Lanktree MB, Tare A, Castillo BA, Li YR, Johnson
T, Bruinenberg M, Gilbert-Diamond D, et al. Large-scale
gene-centric meta-analysis across 39 studies identies type
2 diabetes loci. Am J Hum Genet 2012; 90: 410-25.
159. Ng MCY, Shriner D, Chen BH, Li J, Chen W-M, Guo X,
Liu J, Bielinski SJ, Yanek LR, Nalls MA, Comeau ME,
Rasmussen-Torvik LJ, Jensen RA, et al. Meta-analysis of
genome-wide association studies in African Americans
provides insights into the genetic architecture of type 2
diabetes. PLoS Genet 2014; 10: e1004517.
160. Franceschini N, Shara NM, Wang H, Voruganti VS, Laston
S, Haack K, Lee ET, Best LG, Maccluer JW, Cochran BJ,
Dyer TD, Howard B V, Cole SA, et al. The association of
genetic variants of type 2 diabetes with kidney function.
Kidney Int 2012; 82: 220-5.
161. Zhang B, Jia W-H, Matsuda K, Kweon S-S, Matsuo K,
Xiang Y-B, Shin A, Jee SH, Kim D-H, Cai Q, Long J, Shi
J, Wen W, et al. Large-scale genetic study in East Asians
identies six new loci associated with colorectal cancer risk.
Nat Genet 2014; 46: 533-42.
162. Clevers H, Nusse R. Wnt/β-catenin signaling and disease.
Cell 2012; 149: 1192-205.
163. Lan F, Yue X, Han L, Shi Z, Yang Y, Pu P, Yao Z, Kang
C. Genome-wide identication of TCF7L2/TCF4 target
miRNAs reveals a role for miR-21 in Wnt-driven epithelial
cancer. Int J Oncol 2012; 40: 519-26.
164. Tuupanen S, Turunen M, Lehtonen R, Hallikas O,
Vanharanta S, Kivioja T, Björklund M, Wei G, Yan J,
Niittymäki I, Mecklin J-P, Järvinen H, Ristimäki A, et
al. The common colorectal cancer predisposition SNP
rs6983267 at chromosome 8q24 confers potential to
enhanced Wnt signaling. Nat Genet 2009; 41: 885-90.
165. Lewis A, Freeman-Mills L, de la Calle-Mustienes E,
Giráldez-Pérez RM, Davis H, Jaeger E, Becker M, Hubner
NC, Nguyen LN, Zeron-Medina J, Bond G, Stunnenberg
HG, Carvajal JJ, et al. A polymorphic enhancer near
GREM1 inuences bowel cancer risk through dierential
CDX2 and TCF7L2 binding. Cell Rep 2014; 8: 983-90.
166. Jaeger E, Leedham S, Lewis A, Segditsas S, Becker M,
Cuadrado PR, Davis H, Kaur K, Heinimann K, Howarth
K, East J, Taylor J, Thomas H, et al. Hereditary mixed
polyposis syndrome is caused by a 40-kb upstream
duplication that leads to increased and ectopic expression
of the BMP antagonist GREM1. Nat Genet 2012; 44: 699-
703.
167. Davis H, Irshad S, Bansal M, Raerty H, Boitsova T,
Bardella C, Jaeger E, Lewis A, Freeman-Mills L, Giner
FC, Rodenas-Cuadrado P, Mallappa S, Clark S, et al.
Aberrant epithelial GREM1 expression initiates colonic
tumorigenesis from cells outside the stem cell niche. Nat
Med 2015; 21: 62-70.
168. McMahon R, Murphy M, Clarkson M, Taal M, Mackenzie
HS, Godson C, Martin F, Brady HR. IHG-2, a mesangial
cell gene induced by high glucose, is human gremlin.
Regulation by extracellular glucose concentration, cyclic
mechanical strain, and transforming growth factor-beta1. J
Biol Chem 2000; 275: 9901-4.
Oncotarget23
www.impactjournals.com/oncotarget
169. McKnight AJ, Patterson CC, Pettigrew KA, Savage DA,
Kilner J, Murphy M, Sadlier D, Maxwell AP, Warren
3/U.K. Genetics of Kidneys in Diabetes (GoKinD) Study
Group. A GREM1 gene variant associates with diabetic
nephropathy. J Am Soc Nephrol 2010; 21: 773-81.
170. Wada J, Sun L, Kanwar YS. Discovery of genes related to
diabetic nephropathy in various animal models by current
techniques. Contrib Nephrol 2011; 169: 161-74.
171. Marchant V, Droguett A, Valderrama G, Burgos ME,
Carpio D, Kerr B, Ruiz-Ortega M, Egido J, Mezzano S.
Tubular overexpression of Gremlin in transgenic mice
aggravates renal damage in diabetic nephropathy. Am J
Physiol Renal Physiol 2015; 309: F559-68.
172. Lavoz C, Alique M, Rodrigues-Diez R, Pato J, Keri G,
Mezzano S, Egido J, Ruiz-Ortega M. Gremlin regulates
renal inammation via the vascular endothelial growth
factor receptor 2 pathway. J Pathol 2015; 236: 407-20.
173. Roxburgh SA, Kattla JJ, Curran SP, O’Meara YM, Pollock
CA, Goldschmeding R, Godson C, Martin F, Brazil DP.
Allelic depletion of grem1 attenuates diabetic kidney
disease. Diabetes 2009; 58: 1641-50.
174. Karagiannis GS, Berk A, Dimitromanolakis A, Diamandis
EP. Enrichment map proling of the cancer invasion front
suggests regulation of colorectal cancer progression by the
bone morphogenetic protein antagonist, gremlin-1. Mol
Oncol 2013; 7: 826-39.
175. Rodrigues-Diez R, Lavoz C, Carvajal G, Rayego-Mateos
S, Rodrigues Diez RR, Ortiz A, Egido J, Mezzano S, Ruiz-
Ortega M. Gremlin is a downstream probrotic mediator
of transforming growth factor-beta in cultured renal cells.
Nephron Exp Nephrol 2012; 122: 62-74.
176. Malnutrition and tissue injury in the chronic alcoholic.
A symposium. London, U.K., 16 October 1984. Alcohol
Alcohol 1985; 20: 87-249.
177. Tang W, Dodge M, Gundapaneni D, Michno C, Roth M,
Lum L. A genome-wide RNAi screen for Wnt/beta-catenin
pathway components identies unexpected roles for TCF
transcription factors in cancer. Proc Natl Acad Sci U S A
2008; 105: 9697-702
178. Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H,
Furuta H, Hirota Y, Mori H, Jonsson A, Sato Y, Yamagata
K, Hinokio Y, Wang H-Y, et al. Variants in KCNQ1 are
associated with susceptibility to type 2 diabetes mellitus.
Nat Genet 2008; 40: 1092-7.
179. Sunamura N, Ohira T, Kataoka M, Inaoka D, Tanabe
H, Nakayama Y, Oshimura M, Kugoh H. Regulation of
functional KCNQ1OT1 lncRNA by β-catenin. Sci Rep
2016; 6: 20690.
180. Than BLN, Goos JACM, Sarver AL, O’Sullivan MG, Rod
A, Starr TK, Fijneman RJA, Meijer GA, Zhao L, Zhang
Y, Largaespada DA, Scott PM, Cormier RT. The role of
KCNQ1 in mouse and human gastrointestinal cancers.
Oncogene 2014; 33: 3861-8.
181. Alkayyali S, Lajer M, Deshmukh H, Ahlqvist E, Colhoun
H, Isomaa B, Rossing P, Groop L, Lyssenko V. Common
variant in the HMGA2 gene increases susceptibility to
nephropathy in patients with type 2 diabetes. Diabetologia
2013; 56: 323-9.
182. Fedele M, Bandiera A, Chiappetta G, Battista S, Viglietto
G, Manoletti G, Casamassimi A, Santoro M, Giancotti V,
Fusco A. Human colorectal carcinomas express high levels
of high mobility group HMGI(Y) proteins. Cancer Res
1996; 56: 1896-901.
183. Wu J, Wang Y, Xu X, Cao H, Sahengbieke S, Sheng H,
Huang Q, Lai M. Transcriptional activation of FN1 and
IL11 by HMGA2 promotes the malignant behavior of
colorectal cancer. Carcinogenesis 2016; 37: 511-21.
184. Hodgin JB, Nair V, Zhang H, Randolph A, Harris RC,
Nelson RG, Weil EJ, Cavalcoli JD, Patel JM, Brosius
FC, Kretzler M. Identication of cross-species shared
transcriptional networks of diabetic nephropathy in human
and mouse glomeruli. Diabetes 2013; 62: 299-308.
185. Kang BW, Jeon H-S, Chae YS, Lee SJ, Park JY, Choi JE,
Park JS, Choi GS, Kim JG. Association between GWAS-
identied genetic variations and disease prognosis for
patients with colorectal cancer. PLoS One 2015; 10:
e0119649.
186. Lascorz J, Chen B, Hemminki K, Försti A. Consensus
pathways implicated in prognosis of colorectal cancer
identied through systematic enrichment analysis of gene
expression proling studies. PLoS One 2011; 6: e18867.
187. Rigothier C, Auguste P, Welsh GI, Lepreux S, Deminière C,
Mathieson PW, Saleem MA, Ripoche J, Combe C. IQGAP1
interacts with components of the slit diaphragm complex
in podocytes and is involved in podocyte migration and
permeability in vitro. PLoS One 2012; 7: e37695.
188. Schmid H, Boucherot A, Yasuda Y, Henger A, Brunner
B, Eichinger F, Nitsche A, Kiss E, Bleich M, Gröne H-J,
Nelson PJ, Schlöndor D, Cohen CD, et al. Modular
activation of nuclear factor-kappaB transcriptional
programs in human diabetic nephropathy. Diabetes 2006;
55: 2993-3003.
189. Woroniecka KI, Park ASD, Mohtat D, Thomas DB,
Pullman JM, Susztak K. Transcriptome analysis of human
diabetic kidney disease. Diabetes 2011; 60: 2354-69.
190. Lorz C, Benito-Martín A, Boucherot A, Ucero AC, Rastaldi
MP, Henger A, Armelloni S, Santamaría B, Berthier CC,
Kretzler M, Egido J, Ortiz A. The death ligand TRAIL in
diabetic nephropathy. J Am Soc Nephrol 2008; 19: 904-14.
191. Sanchez-Niño MD, Sanz AB, Lorz C, Gnirke A, Rastaldi
MP, Nair V, Egido J, Ruiz-Ortega M, Kretzler M, Ortiz A.
BASP1 promotes apoptosis in diabetic nephropathy. J Am
Soc Nephrol 2010; 21: 610-21.
192. Sanchez-Niño MD, Sanz AB, Ihalmo P, Lassila M,
Holthofer H, Mezzano S, Aros C, Groop P-H, Saleem M a,
Mathieson PW, Langham R, Kretzler M, Nair V, et al. The
MIF receptor CD74 in diabetic podocyte injury. J Am Soc
Nephrol. 2009; 20: 353-62.
Oncotarget24
www.impactjournals.com/oncotarget
193. Ioannou K, Cheng KF, Crichlow G V, Birmpilis AI, Lolis
EJ, Tsitsilonis OE, Al-Abed Y. ISO-66, a novel inhibitor
of macrophage migration, shows ecacy in melanoma and
colon cancer models. Int J Oncol 2014; 45: 1457-68.
194. Sanchez-Niño MD, Sanz AB, Ruiz-Andres O, Poveda J,
Izquierdo MC, Selgas R, Egido J, Ortiz A. MIF, CD74 and
other partners in kidney disease: tales of a promiscuous
couple. Cytokine Growth Factor Rev 2013; 24: 23-40.
195. Aebersold R, Bader GD, Edwards AM, van Eyk JE,
Kussmann M, Qin J, Omenn GS. The biology/disease-
driven human proteome project (B/D-HPP): enabling
protein research for the life sciences community. J Proteome
Res 2013; 12: 23-7.
196. Alvarez-Chaver P, Otero-Estévez O, Páez de la Cadena M,
Rodríguez-Berrocal FJ, Martínez-Zorzano VS. Proteomics
for discovery of candidate colorectal cancer biomarkers.
World J Gastroenterol 2014; 20: 3804-24.
197. Jimenez CR, Knol JC, Meijer GA, Fijneman RJA.
Proteomics of colorectal cancer: overview of discovery
studies and identication of commonly identied cancer-
associated proteins and candidate CRC serum markers. J
Proteomics 2010; 73: 1873-95.
198. Wang K, Huang C, Nice EC. Proteomics, genomics and
transcriptomics: their emerging roles in the discovery and
validation of colorectal cancer biomarkers. Expert Rev
Proteomics 2014; 11: 179-205.
199. de Wit M, Fijneman RJA, Verheul HMW, Meijer GA,
Jimenez CR. Proteomics in colorectal cancer translational
research: biomarker discovery for clinical applications. Clin
Biochem 2013; 46: 466-79.
200. Ma Y, Zhang P, Wang F, Qin H. Searching for consistently
reported up- and down-regulated biomarkers in colorectal
cancer: a systematic review of proteomic studies. Mol Biol
Rep 2012; 39: 8483-90.
201. Sun J, Zhao M, Jia P, Wang L, Wu Y, Iverson C, Zhou Y,
Bowton E, Roden DM, Denny JC, Aldrich MC, Xu H, Zhao
Z. Deciphering Signaling Pathway Networks to Understand
the Molecular Mechanisms of Metformin Action. PLoS
Comput Biol 2015; 11: e1004202.
202. Ruiz-Andres O, Suarez-Alvarez B, Sánchez-Ramos C,
Monsalve M, Sanchez-Niño MD, Ruiz-Ortega M, Egido
J, Ortiz A, Sanz AB. The inammatory cytokine TWEAK
decreases PGC-1α expression and mitochondrial function in
acute kidney injury. Kidney Int 2016; 89: 399-410.
203. Zanders MMJ, Haak HR, van Herk-Sukel MPP, van de Poll-
Franse L V, Johnson JA. Impact of cancer on adherence
to glucose-lowering drug treatment in individuals with
diabetes. Diabetologia 2015; 58: 951-60.
204. Chamberlain JJ, Rhinehart AS, Shaefer CF, Neuman A.
Diagnosis and Management of Diabetes: Synopsis of the
2016 American Diabetes Association Standards of Medical
Care in Diabetes. Ann Intern Med 2016; 164: 542-52.
205. Mei Z-B, Zhang Z-J, Liu C-Y, Liu Y, Cui A, Liang Z-L,
Wang G-H, Cui L. Survival benets of metformin for
colorectal cancer patients with diabetes: a systematic review
and meta-analysis. PLoS One 2014; 9: e91818.
206. Rizos C V, Elisaf MS. Metformin and cancer. Eur J
Pharmacol 2013; 705: 96-108.
207. Morales DR, Morris AD. Metformin in cancer treatment
and prevention. Annu Rev Med 2015; 66: 17-29.
208. Wild SH. Diabetes, treatments for diabetes and their eect
on cancer incidence and mortality: attempts to disentangle
the web of associations. Diabetologia 2011; 54: 1589-92.
209. Yang Y-X, Hennessy S, Lewis JD. Insulin therapy and
colorectal cancer risk among type 2 diabetes mellitus
patients. Gastroenterology 2004; 127: 1044-50.
210. Franciosi M, Lucisano G, Lapice E, Strippoli GFM,
Pellegrini F, Nicolucci A. Metformin therapy and risk of
cancer in patients with type 2 diabetes: systematic review.
PLoS One 2013; 8: e71583.
211. Guideline development group. Clinical Practice Guideline
on management of patients with diabetes and chronic
kidney disease stage 3b or higher (eGFR. Nephrol Dial
Transplant 2015; 30 Suppl 2: ii1-142.
212. Ortiz A, Covic A, Fliser D, Fouque D, Goldsmith D, Kanbay
M, Mallamaci F, Massy ZA, Rossignol P, Vanholder R,
Wiecek A, Zoccali C, London GM, et al. Epidemiology,
contributors to, and clinical trials of mortality risk in
chronic kidney failure. Lancet (London, England) 2014;
383: 1831-43.
213. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti
G, Lowenfels AB, Wolfe RA, Jones E, Disney AP, Briggs
D, McCredie M, Boyle P. Cancer in patients on dialysis for
end-stage renal disease: an international collaborative study.
Lancet (London, England) 1999; 354: 93-9.
214. Wu L, Zhu J, Prokop LJ, Murad MH. Pharmacologic
Therapy of Diabetes and Overall Cancer Risk and Mortality:
A Meta-Analysis of 265 Studies. Sci Rep 2015; 5: 10147.
215. Yin S, Bai H, Jing D. Insulin therapy and colorectal cancer
risk among type 2 diabetes mellitus patients: a systemic
review and meta-analysis. Diagn Pathol 2014; 9: 91.
216. Simó R, Plana-Ripoll O, Puente D, Morros R, Mundet X,
Vilca LM, Hernández C, Fuentes I, Procupet A, Tabernero
JM, Violán C. Impact of glucose-lowering agents on the
risk of cancer in type 2 diabetic patients. The Barcelona
case-control study. PLoS One 2013; 8: e79968.
217. Colmers IN, Bowker SL, Tjosvold LA, Johnson JA.
Insulin use and cancer risk in patients with type 2 diabetes:
a systematic review and meta-analysis of observational
studies. Diabetes Metab 2012; 38: 485-506.
218. Sehdev A, Shih Y-CT, Vekhter B, Bissonnette MB,
Olopade OI, Polite BN. Metformin for primary colorectal
cancer prevention in patients with diabetes: a case-control
study in a US population. Cancer 2015; 121: 1071-8.
219. Rokkas T, Portincasa P. Colon neoplasia in patients with
type 2 diabetes on metformin: A meta-analysis. Eur J Intern
Med 2016; 33: 60-6.
220. Lega IC, Shah PS, Margel D, Beyene J, Rochon PA,
Oncotarget25
www.impactjournals.com/oncotarget
Lipscombe LL. The eect of metformin on mortality
following cancer among patients with diabetes. Cancer
Epidemiol Biomarkers Prev 2014; 23: 1974-84.
221. Lee A, Morley JE. Metformin decreases food consumption
and induces weight loss in subjects with obesity with type II
non-insulin-dependent diabetes. Obes Res 1998; 6: 47-53.
222. Zakikhani M, Dowling RJO, Sonenberg N, Pollak MN. The
eects of adiponectin and metformin on prostate and colon
neoplasia involve activation of AMP-activated protein
kinase. Cancer Prev Res (Phila) 2008; 1: 369-75.
223. Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono
K, Takahashi H, Nakajima N, Nagashima Y, Wada K,
Nakagama H, Nakajima A. Metformin suppresses intestinal
polyp growth in ApcMin/+ mice. Cancer Sci 2008; 99:
2136-41.
224. Zaafar DK, Zaitone SA, Moustafa YM. Role of metformin
in suppressing 1, 2-dimethylhydrazine-induced colon
cancer in diabetic and non-diabetic mice: eect on tumor
angiogenesis and cell proliferation. PLoS One 2014; 9:
e100562.
225. Hunt SM, Osnos M, Rivlin RS. Thyroid hormone regulation
of mitochondrial alpha-glycerophosphate dehydrogenase in
liver and hepatoma. Cancer Res 1970; 30: 1764-8.
226. Karsten U, Sydow G, Wollenberger A, Gra A. Rat liver
glycerolphosphate dehydrogenases: activity changes and
induction by thyroid hormone of the mitochondrial enzyme
in hepatomas and in precancerous and growing liver. Acta
Biol Med Ger 1971; 26: 1131-40.
227. Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E,
Uchiyama T, Suzuki K, Iida H, Sakamoto Y, Yoneda K,
Koide T, Tokoro C, Abe Y, et al. Metformin suppresses
colorectal aberrant crypt foci in a short-term clinical trial.
Cancer Prev Res (Phila) 2010; 3: 1077-83.
228. Higurashi T, Hosono K, Takahashi H, Komiya Y, Umezawa
S, Sakai E, Uchiyama T, Taniguchi L, Hata Y, Uchiyama
S, Hattori A, Nagase H, Kessoku T, et al. Metformin for
chemoprevention of metachronous colorectal adenoma or
polyps in post-polypectomy patients without diabetes: a
multicentre double-blind, placebo-controlled, randomised
phase 3 trial. Lancet Oncol 2016; 17: 475-83.
229. Singh S, Singh H, Singh PP, Murad MH, Limburg PJ.
Antidiabetic medications and the risk of colorectal cancer
in patients with diabetes mellitus: a systematic review and
meta-analysis. Cancer Epidemiol Biomarkers Prev 2013;
22: 2258-68.
230. Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER,
Midathada M V, Kim L, Kim PJ, Owens RJ, Lang NP.
Thiazolidinediones and the risk of lung, prostate, and colon
cancer in patients with diabetes. J Clin Oncol 2007; 25:
1476-81.
231. Lin HC, Hsu YT, Kachingwe BH, Hsu CY, Uang YS, Wang
LH. Dose eect of thiazolidinedione on cancer risk in type
2 diabetes mellitus patients: a six-year population-based
cohort study. J Clin Pharm Ther 2014; 39: 354-60.
232. Yoshizumi T, Ohta T, Ninomiya I, Terada I, Fushida S,
Fujimura T, Nishimura G-I, Shimizu K, Yi S, Miwa K.
Thiazolidinedione, a peroxisome proliferator-activated
receptor-gamma ligand, inhibits growth and metastasis of
HT-29 human colon cancer cells through dierentiation-
promoting eects. Int J Oncol 2004; 25: 631-9.
233. Kitamura S, Miyazaki Y, Shinomura Y, Kondo S,
Kanayama S, Matsuzawa Y. Peroxisome proliferator-
activated receptor gamma induces growth arrest and
dierentiation markers of human colon cancer cells. Jpn J
Cancer Res 1999; 90: 75-80.
234. Su W, Necela BM, Fujiwara K, Kurakata S, Murray NR,
Fields AP, Thompson EA. The high anity peroxisome
proliferator-activated receptor-gamma agonist RS5444
inhibits both initiation and progression of colon tumors in
azoxymethane-treated mice. Int J cancer 2008; 123: 991-7.
235. Yang K, Fan K-H, Lamprecht SA, Edelmann W,
Kopelovich L, Kucherlapati R, Lipkin M. Peroxisome
proliferator-activated receptor gamma agonist troglitazone
induces colon tumors in normal C57BL/6J mice and
enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/-
double mutant mice. Int J cancer 2005; 116: 495-9.
236. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W.
Anti-diabetic medications and the risk of hepatocellular
cancer: a systematic review and meta-analysis. Am J
Gastroenterol 2013; 108: 881-91; quiz 892.
237. Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR,
Chari ST. Anti-diabetic medications and risk of pancreatic
cancer in patients with diabetes mellitus: a systematic
review and meta-analysis. Am J Gastroenterol 2013; 108:
510-9; quiz 520.
238. Tseng Y-H, Tsan Y-T, Chan W-C, Sheu WH-H, Chen
P-C. Use of an α-Glucosidase Inhibitor and the Risk of
Colorectal Cancer in Patients With Diabetes: A Nationwide,
Population-Based Cohort Study. Diabetes Care 2015; 38:
2068-74.
239. Lin C-M, Huang H-L, Chu F-Y, Fan H-C, Chen H-A,
Chu D-M, Wu L-W, Wang C-C, Chen W-L, Lin S-H, Ho
S-Y. Association between Gastroenterological Malignancy
and Diabetes Mellitus and Anti-Diabetic Therapy: A
Nationwide, Population-Based Cohort Study. PLoS One
2015; 10: e0125421.
240. Su B, Liu H, Li J, Sunli Y, Liu B, Liu D, Zhang P, Meng X.
Acarbose treatment aects the serum levels of inammatory
cytokines and the gut content of bidobacteria in Chinese
patients with type 2 diabetes mellitus. J Diabetes 2015; 7:
729-39.
241. Quesada CF, Kimata H, Mori M, Nishimura M, Tsuneyoshi
T, Baba S. Piroxicam and acarbose as chemopreventive
agents for spontaneous intestinal adenomas in APC gene
1309 knockout mice. Jpn J Cancer Res 1998; 89: 392-6.
242. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E,
Hantel S, Mattheus M, Devins T, Johansen OE, Woerle
HJ, Broedl UC, Inzucchi SE, EMPA-REG OUTCOME
Investigators. Empagliozin, Cardiovascular Outcomes,
Oncotarget26
www.impactjournals.com/oncotarget
and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:
2117-28.
243. Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C,
Satyamurthy N, Moatamed NA, Huang J, Koepsell H,
Barrio JR, Wright EM. Functional expression of sodium-
glucose transporters in cancer. Proc Natl Acad Sci U S A
2015; 112: E4111-9.
244. Elasho M, Matveyenko A V, Gier B, Elasho R, Butler
PC. Pancreatitis, pancreatic, and thyroid cancer with
glucagon-like peptide-1-based therapies. Gastroenterology
2011; 141: 150-6.
245. Lee PH, Stockton MD, Franks AS. Acute pancreatitis
associated with liraglutide. Ann Pharmacother 2011; 45:
e22.
246. Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1
receptor activation inhibits growth and augments apoptosis
in murine CT26 colon cancer cells. Endocrinology 2011;
152: 3362-72.
247. Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S,
Karasik A, Kaufman B, Rubinek T. The peptide-hormone
glucagon-like peptide-1 activates cAMP and inhibits growth
of breast cancer cells. Breast Cancer Res Treat 2012; 132:
449-61
248. Gross CP, McAvay GJ, Guo Z, Tinetti ME. The impact of
chronic illnesses on the use and eectiveness of adjuvant
chemotherapy for colon cancer. Cancer 2007; 109: 2410-9.
249. Meyerhardt JA, Catalano PJ, Haller DG, Mayer RJ,
Macdonald JS, Benson AB, Fuchs CS. Impact of diabetes
mellitus on outcomes in patients with colon cancer. J Clin
Oncol 2003; 21: 433-40.
250. Ottaiano A, Nappi A, Tafuto S, Nasti G, De Divitiis C,
Romano C, Cassata A, Casaretti R, Silvestro L, Avallone
A, Capuozzo M, Capozzi M, Maiolino P, et al. Diabetes
and Body Mass Index Are Associated with Neuropathy
and Prognosis in Colon Cancer Patients Treated with
Capecitabine and Oxaliplatin Adjuvant Chemotherapy.
Oncology 2016; 90: 36-42.
251. Perez-Gomez MV, Sanchez-Niño MD, Sanz AB, Martín-
Cleary C, Ruiz-Ortega M, Egido J, Navarro-González JF,
Ortiz A, Fernandez-Fernandez B. Horizon 2020 in Diabetic
Kidney Disease: The Clinical Trial Pipeline for Add-On
Therapies on Top of Renin Angiotensin System Blockade.
J Clin Med 2015; 4: 1325-47.
252. Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C,
Egido J. Therapeutic approaches to diabetic nephropathy—
beyond the RAS. Nat Rev Nephrol 2014; 10: 325-46.
253. Poynter JN, Gruber SB, Higgins PDR, Almog R, Bonner
JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins
and the risk of colorectal cancer. N Engl J Med 2005; 352:
2184-92.
254. Shao Y-Y, Hsu C-H, Yeh K-H, Chen H-M, Yeh Y-C,
Lai C-L, Lin Z-Z, Cheng A-L, Lai M-S. Statin Use Is
Associated With Improved Prognosis of Colorectal Cancer
in Taiwan. Clin Colorectal Cancer 2015; 14: 177-184.e4.
255. Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota
M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki
H. Pitavastatin inhibits azoxymethane-induced colonic
preneoplastic lesions in C57BL/KsJ-db/db obese mice.
Cancer Sci 2010; 101: 1701-7.
256. Malicki S, Winiarski M, Matlok M, Kostarczyk W, Guzdek
A, Konturek PC. IL-6 and IL-8 responses of colorectal
cancer in vivo and in vitro cancer cells subjected to
simvastatin. J Physiol Pharmacol 2009; 60: 141-6.
257. Kubota M, Shimizu M, Sakai H, Yasuda Y, Ohno T, Kochi
T, Tsurumi H, Tanaka T, Moriwaki H. Renin-angiotensin
system inhibitors suppress azoxymethane-induced colonic
preneoplastic lesions in C57BL/KsJ-db/db obese mice.
Biochem Biophys Res Commun 2011; 410: 108-13.
258. Kochi T, Shimizu M, Ohno T, Baba A, Sumi T, Kubota
M, Shirakami Y, Tsurumi H, Tanaka T, Moriwaki H.
Preventive eects of the angiotensin-converting enzyme
inhibitor, captopril, on the development of azoxymethane-
induced colonic preneoplastic lesions in diabetic and
hypertensive rats. Oncol Lett 2014; 8: 223-9.
259. Yoshiji H, Noguchi R, Kaji K, Ikenaka Y, Shirai Y,
Namisaki T, Kitade M, Tsujimoto T, Kawaratani
H, Fukui H. Attenuation of insulin-resistance-based
hepatocarcinogenesis and angiogenesis by combined
treatment with branched-chain amino acids and angiotensin-
converting enzyme inhibitor in obese diabetic rats. J
Gastroenterol 2010; 45: 443-50.
260. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T,
Audhya P, Andress DL. Addition of atrasentan to renin-
angiotensin system blockade reduces albuminuria in
diabetic nephropathy. J Am Soc Nephrol 2011; 22: 763-72.
261. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H,
Houser M, Correa-Rotter R, Kohan D, Lambers Heerspink
HJ, Makino H, Perkovic V, Pritchett Y, Remuzzi G, et
al. The endothelin antagonist atrasentan lowers residual
albuminuria in patients with type 2 diabetic nephropathy. J
Am Soc Nephrol 2014; 25: 1083-93.
262. Goldkorn A, Ely B, Quinn DI, Tangen CM, Fink LM, Xu T,
Twardowski P, Van Veldhuizen PJ, Agarwal N, Carducci
MA, Monk JP, Datar RH, Garzotto M, et al. Circulating
tumor cell counts are prognostic of overall survival in
SWOG S0421: a phase III trial of docetaxel with or without
atrasentan for metastatic castration-resistant prostate cancer.
J Clin Oncol 2014; 32: 1136-42.
263. Lara PN, Ely B, Quinn DI, Mack PC, Tangen C, Gertz E,
Twardowski PW, Goldkorn A, Hussain M, Vogelzang NJ,
Thompson IM, Van Loan MD. Serum biomarkers of bone
metabolism in castration-resistant prostate cancer patients
with skeletal metastases: results from SWOG 0421. J Natl
Cancer Inst 2014; 106: dju013.
264. Quinn DI, Tangen CM, Hussain M, Lara PN, Goldkorn
A, Moinpour CM, Garzotto MG, Mack PC, Carducci MA,
Monk JP, Twardowski PW, Van Veldhuizen PJ, Agarwal
N, et al. Docetaxel and atrasentan versus docetaxel and
placebo for men with advanced castration-resistant prostate
Oncotarget27
www.impactjournals.com/oncotarget
cancer (SWOG S0421): a randomised phase 3 trial. Lancet
Oncol 2013; 14: 893-900.
265. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D,
Garimella T, Parving H-H, Pritchett Y, Remuzzi G, Ritz
E, Andress D. Selective vitamin D receptor activation with
paricalcitol for reduction of albuminuria in patients with
type 2 diabetes (VITAL study): a randomised controlled
trial. Lancet (London, England) 2010; 376: 1543-51.
266. Lawrence JA, Akman SA, Melin SA, Case LD, Schwartz
GG. Oral paricalcitol (19-nor-1, 25-dihydroxyvitamin D2)
in women receiving chemotherapy for metastatic breast
cancer: a feasibility trial. Cancer Biol Ther 2013; 14: 476-
80.
267. Pommergaard H-C, Burcharth J, Rosenberg J, Raskov
H. Aspirin, Calcitriol, and Calcium Do Not Prevent
Adenoma Recurrence in a Randomized Controlled Trial.
Gastroenterology 2016; 150: 114-122.e4.
268. Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover
DC, Bostick RM, Ivanova A, Cole BF, Ahnen DJ, Beck
GJ, Bresalier RS, Burke CA, et al. A Trial of Calcium and
Vitamin D for the Prevention of Colorectal Adenomas. N
Engl J Med 2015; 373: 1519-30.
269. Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida
S, Blattner SM, Ikenoue T, Rüegg MA, Hall MN,
Kwiatkowski DJ, Rastaldi MP, Huber TB, et al. mTORC1
activation in podocytes is a critical step in the development
of diabetic nephropathy in mice. J Clin Invest 2011; 121:
2181-96.
270. Moreno JA, Moreno S, Rubio-Navarro A, Gómez-Guerrero
C, Ortiz A, Egido J. Role of chemokines in proteinuric
kidney disorders. Expert Rev Mol Med 2014; 16: e3.
271. Donath MY. Targeting inammation in the treatment of
type 2 diabetes: time to start. Nat Rev Drug Discov 2014;
13: 465-76.
272. Crusz SM, Balkwill FR. Inammation and cancer: advances
and new agents. Nat Rev Clin Oncol 2015; 12: 584-96.
273. Perez-Gomez MV, Sanchez-Niño MD, Sanz AB, Zheng
B, Martín-Cleary C, Ruiz-Ortega M, Ortiz A, Fernandez-
Fernandez B. Targeting inammation in diabetic kidney
disease: early clinical trials. Expert Opin Investig Drugs
2016; 1-14.
274. Chu P-Y, Zatta A, Kiriazis H, Chin-Dusting J, Du X-J,
Marshall T, Kaye DM. CXCR4 antagonism attenuates the
cardiorenal consequences of mineralocorticoid excess. Circ
Heart Fail 2011; 4: 651-8.
275. Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM, Marsden
PA, Pippin J, Shankland S, Rastaldi MP, Cohen CD,
Kretzler M, Quaggin SE. Loss of the tumor suppressor
Vhlh leads to upregulation of Cxcr4 and rapidly progressive
glomerulonephritis in mice. Nat Med 2006; 12: 1081-7.
276. Wang X, Shaw S, Amiri F, Eaton DC, Marrero MB.
Inhibition of the Jak/STAT signaling pathway prevents the
high glucose-induced increase in tgf-beta and bronectin
synthesis in mesangial cells. Diabetes 2002; 51: 3505-9.
277. Huang JS, Guh JY, Hung WC, Yang ML, Lai YH, Chen
HC, Chuang LY. Role of the Janus kinase (JAK)/signal
transducters and activators of transcription (STAT) cascade
in advanced glycation end-product-induced cellular
mitogenesis in NRK-49F cells. Biochem J. 1999;342:231-8.
278. Recio C, Oguiza A, Lazaro I, Mallavia B, Egido J,
Gomez-Guerrero C. Suppressor of cytokine signaling
1-derived peptide inhibits Janus kinase/signal transducers
and activators of transcription pathway and improves
inammation and atherosclerosis in diabetic mice.
Arterioscler Thromb Vasc Biol 2014; 34: 1953-60.
279. Ortiz-Muñoz G, Lopez-Parra V, Lopez-Franco O,
Fernandez-Vizarra P, Mallavia B, Flores C, Sanz A,
Blanco J, Mezzano S, Ortiz A, Egido J, Gomez-Guerrero
C. Suppressors of cytokine signaling abrogate diabetic
nephropathy. J Am Soc Nephrol 2010; 21: 763-72.
280. Schanstra JP, Zürbig P, Alkhalaf A, Argiles A, Bakker SJL,
Beige J, Bilo HJG, Chatzikyrkou C, Dakna M, Dawson
J, Delles C, Haller H, Haubitz M, et al. Diagnosis and
Prediction of CKD Progression by Assessment of Urinary
Peptides. J Am Soc Nephrol 2015; 26: 1999-2010.
281. Siwy J, Schanstra JP, Argiles A, Bakker SJL, Beige J,
Boucek P, Brand K, Delles C, Duranton F, Fernandez-
Fernandez B, Jankowski M-L, Al Khatib M, Kunt T, et al.
Multicentre prospective validation of a urinary peptidome-
based classier for the diagnosis of type 2 diabetic
nephropathy. Nephrol Dial Transplant 2014; 29: 1563-70.
282. Metzger J, Negm AA, Plentz RR, Weismüller TJ,
Wedemeyer J, Karlsen TH, Dakna M, Mullen W, Mischak
H, Manns MP, Lankisch TO. Urine proteomic analysis
dierentiates cholangiocarcinoma from primary sclerosing
cholangitis and other benign biliary disorders. Gut 2013; 62:
122-30.
283. Half E, Bercovich D, Rozen P. Familial adenomatous
polyposis. Orphanet J Rare Dis 2009; 4: 22.
284. Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr
J. Familial adenomatous polyposis (FAP): frequency,
penetrance, and mutation rate. Hum Mutat 1994; 3: 121-5.
285. Bourke B, Broderick A, Bohane T. Peutz-Jeghers syndrome
and management recommendations. Clin Gastroenterol
Hepatol 2006; 4: 1550; author reply 1550.
286. Shiovitz S, Copeland WK, Passarelli MN, Burnett-Hartman
AN, Grady WM, Potter JD, Gallinger S, Buchanan DD,
Rosty C, Win AK, Jenkins M, Thibodeau SN, Haile R, et
al. Characterisation of familial colorectal cancer Type X,
Lynch syndrome, and non-familial colorectal cancer. Br J
Cancer 2014; 111: 598-602.
287. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability
in colorectal cancers. Nature 1997; 386: 623-7.
288. Salazar R, Roepman P, Capella G, Moreno V, Simon
I, Dreezen C, Lopez-Doriga A, Santos C, Marijnen C,
Westerga J, Bruin S, Kerr D, Kuppen P, et al. Gene
expression signature to improve prognosis prediction of
stage II and III colorectal cancer. J Clin Oncol 2011; 29:
Oncotarget28
www.impactjournals.com/oncotarget
17-24.
289. Budinska E, Popovici V, Tejpar S, D’Ario G, Lapique N,
Sikora KO, Di Narzo AF, Yan P, Hodgson JG, Weinrich S,
Bosman F, Roth A, Delorenzi M. Gene expression patterns
unveil a new level of molecular heterogeneity in colorectal
cancer. J Pathol 2013; 231: 63-76.
290. Oberaigner W, Ebenbichler C, Oberaigner K, Juchum M,
Schönherr HR, Lechleitner M. Increased cancer incidence
risk in type 2 diabetes mellitus: results from a cohort study
in Tyrol/Austria. BMC Public Health 2014; 14: 1058.
291. Flanagan JN, Zheng S, Chiang K-C, Kittaka A, Sakaki
T, Nakabayashi S, Zhao X, Spanjaard RA, Persons KS,
Mathieu JS, Holick MF, Chen TC. Evaluation of 19-nor-
2alpha-(3-hydroxypropyl)-1alpha, 25-dihydroxyvitamin
D3 as a therapeutic agent for androgen-dependent prostate
cancer. Anticancer Res 2009; 29: 3547-53.
292. Saleh MA, Boesen EI, Pollock JS, Savin VJ, Pollock DM.
Endothelin receptor A-specic stimulation of glomerular
inammation and injury in a streptozotocin-induced rat
model of diabetes. Diabetologia 2011; 54: 979-88.
293. Younis IR, George DJ, McManus TJ, Hurwitz H, Creel P,
Armstrong AJ, Yu JJ, Bacon K, Hobbs G, Peer CJ, Petros
WP. Clinical pharmacology of an atrasentan and docetaxel
regimen in men with hormone-refractory prostate cancer.
Cancer Chemother Pharmacol 2014; 73: 991-7.
294. Groenewegen G, Walraven M, Vermaat J, de Gast B,
Witteveen E, Giles R, Haanen J, Voest E. Targeting the
endothelin axis with atrasentan, in combination with IFN-
alpha, in metastatic renal cell carcinoma. Br J Cancer 2012;
106: 284-9.
295. Witteveen PO, van der Mijn KJC, Los M, Kronemeijer
RH, Groenewegen G, Voest EE. Phase 1/2 study of
atrasentan combined with pegylated liposomal doxorubicin
in platinum-resistant recurrent ovarian cancer. Neoplasia
2010; 12: 941-5.
296. Armstrong AJ, Creel P, Turnbull J, Moore C, Jae TA,
Haley S, Petros W, Yenser S, Gockerman JP, Sleep D,
Hurwitz H, George DJ. A phase I-II study of docetaxel
and atrasentan in men with castration-resistant metastatic
prostate cancer. Clin Cancer Res 2008; 14: 6270-6.
297. Nelson JB, Love W, Chin JL, Saad F, Schulman CC,
Sleep DJ, Qian J, Steinberg J, Carducci M, Atrasentan
Phase 3 Study Group. Phase 3, randomized, controlled
trial of atrasentan in patients with nonmetastatic, hormone-
refractory prostate cancer. Cancer 2008; 113: 2478-87.
298. Phuphanich S, Carson KA, Grossman SA, Lesser G, Olson
J, Mikkelsen T, Desideri S, Fisher JD, New Approaches to
Brain Tumor Therapy (NABTT) CNS Consortium. Phase I
safety study of escalating doses of atrasentan in adults with
recurrent malignant glioma. Neuro Oncol 2008; 10: 617-23.
299. Chiappori AA, Haura E, Rodriguez FA, Boulware D,
Kapoor R, Neuger AM, Lush R, Padilla B, Burton M,
Williams C, Simon G, Antonia S, Sullivan DM, et al. Phase
I/II study of atrasentan, an endothelin A receptor antagonist,
in combination with paclitaxel and carboplatin as rst-line
therapy in advanced non-small cell lung cancer. Clin Cancer
Res 2008; 14: 1464-9.
300. Carducci MA, Saad F, Abrahamsson P-A, Dearnaley DP,
Schulman CC, North SA, Sleep DJ, Isaacson JD, Nelson
JB, Atrasentan Phase III Study Group Institutions. A phase
3 randomized controlled trial of the ecacy and safety
of atrasentan in men with metastatic hormone-refractory
prostate cancer. Cancer 2007; 110: 1959-66.
301. Carducci MA, Manola J, Nair SG, Liu G, Rousey S, Dutcher
JP, Wilding G. Atrasentan in Patients With Advanced Renal
Cell Carcinoma: A Phase 2 Trial of the ECOG-ACRIN
Cancer Research Group (E6800). Clin Genitourin Cancer.
2015;13:531-539.e1.
302. Finger EC, Cheng C-F, Williams TR, Rankin EB, Bedogni
B, Tachiki L, Spong S, Giaccia AJ, Powell MB. CTGF is
a therapeutic target for metastatic melanoma. Oncogene
2014; 33: 1093-100.
303. Adler SG, Schwartz S, Williams ME, Arauz-Pacheco C,
Bolton WK, Lee T, Li D, Ne TB, Urquilla PR, Sewell
KL. Phase 1 study of anti-CTGF monoclonal antibody in
patients with diabetes and microalbuminuria. Clin J Am Soc
Nephrol 2010; 5: 1420-8.
304. Eccles SA. Metastasis and the Tumor Microenvironment:
A Joint Metastasis Research Society-AACR Conference -
Research on Metastasis: part 2. IDrugs 2010; 13: 768-71.
305. Advani A, Wiggins KJ, Cox AJ, Zhang Y, Gilbert RE,
Kelly DJ. Inhibition of the epidermal growth factor
receptor preserves podocytes and attenuates albuminuria in
experimental diabetic nephropathy. Nephrology (Carlton)
2011; 16: 573-81.
306. Wassef L, Kelly DJ, Gilbert RE. Epidermal growth factor
receptor inhibition attenuates early kidney enlargement in
experimental diabetes. Kidney Int. 2004; 66: 1805-14.
