Adiponectin in relation to malignancies: a review of existing basic
research and clinical evidence1–4
Diana Barb, Catherine J Williams, Anke K Neuwirth, and Christos S Mantzoros
role in diabetes and cardiovascular disease, may also be of impor-
tance in the development and progression of several malignancies.
Circulating adiponectin concentrations, which are determined
mainly by genetic factors, nutrition, and adiposity, are lower in
patients with breast, endometrial, prostate, and colon cancer. It has
thus been proposed that adiponectin may be a biological link be-
Adiponectin may influence cancer risk through its well-recognized
effects on insulin resistance, but it is also plausible that adiponectin
acts on tumor cells directly. Several cancer cell types express adi-
ponectin receptors that may mediate the effects of adiponectin on
ing cancers of the breast, endometrium, colon, and prostate. Further
in cancer diagnostics and therapeutics.
Am J Clin Nutr 2007;
Adipose tissue, which is the largest endocrine organ in the
body (1), plays an important role in regulating energy metabo-
cancers. Adiponectin, a 30-kDa complement C1q-related pro-
tein, is the most abundant gene product secreted by fat cells (2)
and is a key regulator of insulin sensitivity (3, 4) and inflamma-
tion (5, 6). Adiponectin modulates several physiologic pro-
cesses, such as metabolism of glucose and fatty acids (7), and
addition, it was recently shown that adiponectin may play a role
in the development and progression of various types of malig-
nancies, as reviewed herein.
Adiponectin, which is also referred to as gelatin-binding
protein-28 (GBP28) (10), AdipoQ (11), ACP30 (Acrp30) (12),
or gene product of the adipose most abundant gene transcript-1
(apM1) (2), is secreted predominantly by white adipose tissue.
syndrome and type 2 diabetes in whites (14).
Adiponectin is a 244–amino acid protein that circulates in
human plasma as a homopolymer or as full-length adiponectin
an N-terminal region with high structural homology to collagen
region that resembles the trimeric topology of tumor necrosis
factor-? (15). Acrp30 is highly abundant in the circulation, with
plasma concentrations in healthy humans of ?10 ?g/mL, and
accounts for ?0.01% of total plasma protein.
At least 3 distinct and stable isoforms of Acrp30 have been
isolated from Escherichia coli or cultured mammalian cells in
both mouse (16) and human (17) serum. Although most active
adiponectin appears to exist in the form of full-length or high
molecular weight (HMW) adiponectin in plasma (12, 18), low
ecule at amino acid 110 produces globular adiponectin (gAd or
gAcrp30) (20), which is thought to have enhanced potency (21).
Oligomerization and posttranslational modifications (ie, gly-
cosylation) of adiponectin are apparently critical for binding to
its receptors (22) and determining biological activity (16, 23).
Thus, different forms of adiponectin (ie, trimeric versus hexam-
eric and HMW, or globular versus full-length) show distinct
biological effects through differential activation of downstream
signaling pathways (16, 23, 24). Recent evidence suggests that
the HMW adiponectin complex may be the active form of the
hormone (25, 26), but this remains to be confirmed. HMW adi-
of HMW to total adiponectin are closely associated with im-
provements in insulin sensitivity during thiazolidinedione
1From the Division of Endocrinology, Diabetes and Metabolism and
Disease, Beth Israel Deaconess Medical Center, Harvard Medical School,
2Presented at the 8th Postgraduate Nutrition Symposium “Metabolic
Syndrome and the Onset of Cancer,” held in Boston, MA, March 15–16,
Center and by a grant-in-aid from Tanita Corporation.
4Address reprint requests to CS Mantzoros, Division of Endocrinology,
Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 330
Am J Clin Nutr 2007;86(suppl):858S–66S. Printed in USA. © 2007 American Society for Nutrition
by guest on June 8, 2013
treatment in humans, whereas changes in total adiponectin
concentrations are not (25).
Full-length adiponectin, but not gAd, down-regulates genes
involved in gluconeogenesis through 5'-AMP-activated protein
kinase (AMPK) in the liver (27). In one study, trimeric Acrp30
was the most potent isoform in terms of suppression of hepato-
Other studies have suggested that both fAd and gAd stimulate
fatty acid oxidation, glucose uptake, and lactate production
through AMP activation in C2C12 myocytes (29). However,
activation of AMPK in skeletal muscle (23). Thus, this remains
an active area of research.
Two adiponectin receptor isoforms (AdipoR1 and AdipoR2)
have been cloned (30). Structurally, these 7-transmembrane-
region proteins have an internal N terminus region and an exter-
nal C terminus, as opposed to the usual topology of G protein-
coupled receptors (30). Both have unique distributions and
affinities for the different forms of circulating adiponectin. Adi-
poR1 is a high-affinity receptor for gAd with a low affinity for
fAd. AdipoR1 is expressed ubiquitously; it is most abundant in
skeletal muscle but is also expressed in endothelial cells and
other tissues. AdipoR2 is predominantly expressed in the liver
and has intermediate affinity for both forms of adiponectin (18,
21). Both adiponectin receptors are markedly expressed in pan-
creatic ?-cells, at levels similar to liver for AdipoR2 and even
greater than in muscle for AdipoR1 (31).
Of note, several tumor cell lines express AdipoR1 and Adi-
poR2, which suggests that adiponectin could exert direct effects
on these cells via signaling through its receptors. Adiponectin
receptors are expressed not only by prostate (32–34) and hepa-
and neuroblastoma cancer cell lines (C Mantzoros, unpublished
data, 2007). Although it has not yet been clarified whether the
presence of adiponectin receptors in tumor cells has any func-
tional relevance, initial studies indicate that activation of adi-
ponectin receptors by adiponectin limits the proliferation of
breast cancer cells in vitro (37). Finally, T-cadherin, a cell-
surface receptor involved in calcium mediated cell-cell interac-
tions and signaling located in endothelial and smooth muscle
cells, was also found to bind strongly to HMW adiponectin.
a co-receptor (22).
The expression of adiponectin receptors is negatively regu-
lated by insulin through activation of phosphoinositide 3
kinase and inactivation of Foxo1 (40). Thus, the expression of
trations in vivo under physiologic (ie, increase with fasting and
decrease with feeding) and pathologic conditions (40). Reduced
reported in skeletal muscle and adipose tissue in leptin-deficient
ob/ob (40) and db/db (41) mice, as well as in fa/fa Zucker rats
tin receptor regulation. We recently reported that aging and pro-
longed exposure to high-fat feeding down-regulate adiponectin
concentrations and up-regulate the expression of adiponectin
receptors (43). In addition, adiponectin receptor expression is
also regulated by peroxisome proliferator-activated receptor-?
and peroxisome proliferator-activated receptor-?, with in-
creased expression in adipose tissue and cultured adipocytes but
not in cultured myocytes (40, 44, 45).
ADIPONECTIN PHYSIOLOGY AND
Certain polymorphisms of the adiponectin gene promoter
have been associated with lower serum adiponectin concentra-
tions in persons with diabetes (46), but whether these polymor-
phisms are also associated with risk of malignancies remains to
be studied. Dietary factors may also modulate plasma adiponec-
tin concentrations (47). Adiponectin concentrations have been
inversely associated with glycemic load in a dose-dependent
manner (48). Higher intakes of fiber and magnesium have been
associated with increased plasma adiponectin concentrations in
food items, we recently showed that closer adherence to a
Mediterranean-style dietary pattern is significantly associated
with circulating adiponectin concentrations (49).
Women have higher adiponectin concentrations than do men
production of HMW adiponectin in vivo and in cultured adipo-
tin sensitivity or adiponectin production rates, and their
pathophysiologic significance remains to be determined.
Circulating concentrations of adiponectin are reduced in obe-
syndromes (55) and have a strong inverse association with pa-
rameters of central and overall obesity, independently of age,
menopausal status, and estradiol concentrations (56, 57).
Chronic caloric restriction leading to weight loss increases adi-
tin concentrations are more closely related to insulin sensitivity
tin concentrations at baseline (before and after adjustment for
body fat) precede a decrease in insulin sensitivity (61). Cross-
sectionally, adiponectin concentrations are associated with hor-
monal markers of insulin sensitivity (62).
In addition to the strong and consistent inverse association
has also been linked to several inflammatory markers, such as
C-reactive protein and fibrinogen (1, 65). Plasma adiponectin
concentrations in humans have also been found to be positively
correlated with HDL cholesterol and negatively correlated with
triacylglycerols and apolipoprotein B-100 (65). Higher adi-
in risk of coronary artery disease in diabetic men (66) and with
inflammation in diabetic women (67).
ADIPONECTIN AND CANCER EPIDEMIOLOGY
Studies conducted by our research group found lower circu-
lating adiponectin concentrations to be associated with an in-
creased risk of breast cancer in postmenopausal women, inde-
pendently of body mass index (BMI), leptin, and insulin-like
ADIPONECTIN AND CANCER
by guest on June 8, 2013
growth factor-I (IGF-I) concentrations (37, 68). Others have
confirmed this association regardless of menopausal status (69,
70). We also conducted a large, prospective case-control study
II cohorts to examine the association between plasma adiponec-
tin concentrations and breast cancer risk (62). Similar to our
previous results in a retrospective study (68), the inverse asso-
ciation between adiponectin concentrations and breast cancer
lower estrogen concentrations in postmenopausal women may
partially explain the lower adiponectin concentrations in these
breast cancer etiology, particularly in a low-estrogen environ-
ment. It remains unclear whether stage or grade of disease is
associated with adiponectin concentrations; one study reported
these results (62, 70).
Our research group has also shown that adiponectin is in-
versely associated with risk of endometrial cancer; in addition,
endometrial cancer that is 6.5-fold that in women with normal
under 65 y of age (72). Recent studies have confirmed these
findings (73, 74). More recently, a large, case-control, prospec-
tive study nested within the European Prospective Investigation
into Cancer and Nutrition (EPIC) Study confirmed the relation
between lower pre-diagnostic plasma adiponectin concentra-
tions and a higher risk of endometrial cancer in both pre-and
postmenopausal women regardless of BMI status (obese versus
nonobese) or other obesity-related risk factors, such as endoge-
nous insulin concentrations, IGF binding proteins, or hormonal
Another large, prospective, nested case-control study con-
ducted by our group found that plasma adiponectin concentra-
tions were inversely associated with risk of colorectal cancer in
men (75). Men with the highest concentrations had an ?60%
reduced risk for colorectal cancer compared with those with the
design provides the time sequence criterion for causality, al-
adiponectin receptors, and that this expression is significantly
higher than in nontumorous colorectal tissue from colorectal
cancer patients (C Mantzoros, unpublished data, 2007). The el-
evated expression of AdipoR1 and AdipoR2 further indicate a
potential role of adiponectin in the pathogenesis of colorectal
A small case-control study (76) also reported that plasma
adiponectin concentrations are significantly lower in subjects
with prostate cancer than in patients with benign prostatic hy-
perplasia or in healthy control subjects. We replicated these re-
risk for men with the highest relative to men with the lowest
age, BMI, and other classic risk factors. In addition, our group
(77) and others (76) have shown that plasma adiponectin con-
centrations are negatively correlated with histologic grade and
(78) did not find any association between adipokines (and adi-
ponectin in particular) and prostate cancer, it is of note that the
technology used to measure adiponectin concentrations was not
the results from reaching statistical significance.
cancer and in leukemia (73, 81). Plasma adiponectin concentra-
tions have been found to be lower in patients with gastric cancer
than in healthy control subjects and to be inversely correlated
with tumor size, depth of invasion, and tumor stage (79). In a
small, case-control, retrospective study of patients with histo-
logically confirmed renal cell carcinoma and healthy control
tin concentrations were significantly and inversely associated
with renal cell carcinoma after control for BMI; however, after
adjustment for central obesity (waist-to-hip ratio), the associa-
tion between adiponectin and renal cell carcinoma became not
significant. This finding indicates that altered concentrations of
adiponectin may mediate the effect of intraabdominal obesity
(80). Finally, in a case-control study, we found that adiponectin
concentrations were lower in patients with acute myeloblastic
of myelomonocyte cell lines (82).
circulating adiponectin concentrations in vivo are inversely as-
sociated with the risk of obesity-related malignancies, including
84) cancer, and may also play a role in gastric cancer (79) and
an increased risk of postmenopausal breast (62), endometrial
tions (Table 1). Thus, both prospective observational and inter-
underlying the effects of adiponectin.
POTENTIAL MECHANISMS UNDERLYING THE
PROTECTIVE ROLE OF ADIPONECTIN IN
tant regulator of cell proliferation. Adiponectin may act either
directly on cancer cells or indirectly by regulating whole-body
Adiponectin has been shown to drastically suppress the
growth of myelomonocyte leukemia cells in vitro (82). More-
by down-regulating antiapoptotic genes (82). Other recent stud-
MB-231 (38, 85), MCF-7 (35, 86), and T47D (37, 38) breast
cancer cell lines. Interestingly, only the HMW form of fAd (not
LMW fAd or gAd) inhibited the proliferation of androgen-
dependent (LNCaP-FGC) and androgen-independent (DU145
and PC-3) prostate cancer cell lines as well as hepatocellular
carcinoma cells (HepG2) (34) at subphysiologic concentrations
to inhibit dihydrotestosterone- or IGF-1–stimulated cell growth
and to enhance doxorubicin inhibition of prostate cancer cell
BARB ET AL
by guest on June 8, 2013
Epidemiologic studies that show an inverse, independent association between adiponectin concentrations and risk of different types of cancers shown as
odds ratios (ORs)
Cancer and studyType of study
No. of cases/controls
OR (95% CI) or
significance Additional results, analysis, and comments
Mantzoros et al, 2004 (68)Retrospective
174/167 Greek 0.84 (0.71, 0.99) for 1-SD
increase in adiponectin
versus lowest tertile of
P ? 0.009
Association found only in postmenopausal
Association present in pre- and postmenopausal
women. Lower adiponectin concentrations
with more advanced stage disease.
Lower adiponectin concentrations in cases
(pre- and postmenopausal women)
Lower adiponectin concentrations in cases;
HMW adiponectin measurements produced
The first prospective study of adiponectin in
breast cancer; adiponectin was found to be
inversely associated with postmenopausal
breast cancer risk only.
Miyoshi et al, 2003 (69)102/100 Japanese
Chen et al, 2005 (70)Retrospective
Korner et al, 2006 (37)74/76 Greek 0.35 (0.14–0.87)2
Tworoger et al, 2007 (62)Prospective
NHS and NHSII
0.89 (0.71–1.11) for all
0.73 (0.55–0.98) for
Dal Maso et al, 2004 (71)Retrospective
87/132 Italian 0.42 (0.19–0.94) for 1-SD
increase in adiponectin
BMI and adiponectin showed multiplicative
effects on endometrial carcinogenesis
(OR ? 6.45 for highest level of BMI and
lowest of adiponectin).
Adjusted OR per quintile increase in
adiponectin was 0.74 (0.56–0.97) for all.
Petridou et al, 2003 (72)Retrospective
84/84 Greek 0.44 (0.24–0.81)2,3for
1-SD increase in
lowest tertile of
adiponectin vs controls
0.56 (0.36–0.86) top vs
bottom quartile of
Soliman et al, 2006 (83)Retrospective
117/238 AmericanConfirms the previously published case-control
studies from Europe. The association was
also strong in nonobese women.
First prospective study of adiponectin in
The inverse association was independent of
other obesity-related risk factors
Cust et al, 2007 (74) Prospective
Freedland et al, 2005 (84)Retrospective
236 cases American0.94 (0.87–1.01)4
P ? 0.09
Shows association between adiponectin and
high-grade disease only in overweight and
obese (80 advanced stage/160 organ-
Lower adiponectin concentrations in cases and
negative association with histologic grade
and disease stage.
Nonstatistically significant results observed; the
method used is not the standard one because
questions about sensitivity of the assay used
Goktas et al, 2005 (76)Retrospective
P ? 0.001
Baillargeon et al, 2006 (78) Prospective
for Biomarkers of
Risk of Prostate
0.87 (0.46–1.65) highest
vs lowest tertile of
Michalakis et al, 2007 (77)Retrospective
0.29 (0.10–0.89) highest
vs lowest quartile of
Association was independent of age, BMI,
smoking, alcohol, insulin, and testosterone.
Wei et al, 2005 (75)Prospective
vs lowest quintile of
The first prospective study, on adiponectin in
relation to colorectal malignancy in men.
Ishikawa et al, 2005 (79)Retrospective
75/52 Japanese0.89 (0.84–0.95)2
The stage was inversely related to adiponectin
concentrations in undifferentiated gastric
cancer (n ? 32).
ADIPONECTIN AND CANCER
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In contrast with findings in breast and prostate cancer cell
lines, both full-length and globular adiponectin stimulated co-
effects of adiponectin on the apoptosis of cancer cells in vitro,
which may well differ from the in vivo condition, remains in-
by adiponectin treatment, but this was not observed in other
of note that all these in vitro proliferation studies have limita-
tions; one is the fact that these studies were performed in a
proliferation or inhibit cell growth.
administration on tumor growth (38, 88). In vivo intratumoral
administration of murine adiponectin to mice resulted in signif-
icant suppression of T241 fibrosarcoma tumor growth (60% re-
duction of tumor volumes and weights after weeks of treatment;
88). More recently, mammary tumorigenesis of MDA-MB-231
cells in female nude mice was substantially reduced by either
supplementation with recombinant adiponectin or adenovirus-
mediated overexpression of adiponectin at 7 or 14 d after initial
to discriminate whether this decrease was caused by the direct
or was secondary to the reduced size of primary tumors in the
of adiponectin in breast carcinogenesis.
Despite the mounting experimental data, the mechanisms un-
derlying the antiproliferative effects of adiponectin are not fully
understood. It has been hypothesized that the beneficial actions
way. AMPK activation suppresses cell proliferation through
multiple mechanisms, including inhibition of enzymes impli-
cated in the regulation of protein (mammalian target of rapamy-
cin) and fatty acids and triacylglycerol synthesis (acetyl-CoA
carboxylase and fatty acid synthase). It also decreases the ex-
pression of the transcriptional regulator sterol-regulatory-
and apoptosis: p21 and p53 (89).
may constitute a general intracellular response to adiponectin,
because it is activated in response to adiponectin treatment in
myocytes and hepatocytes (29), adipocytes (90), pancreatic
?-cells (91), cardiomyocytes (92, 93), and endothelial cells (94,
95). This has also been confirmed in MCF-7 breast cancer cells
(35), and we found that adiponectin activates AMPK and one of
and CWR22Rv1 prostate cell lines (C Mantzoros, unpublished
data, 2007). Similarly to previous studies, the activation of the
AMPK pathway was rapid and transient (the effect is maximum
in the first 10 min and gone within 30–60 min).
In addition to AMPK activation in MCF-7 cells, longer treat-
c-myc and one of the important G1 regulatory cyclins, cyclin D1
and inhibition of cell-cycle progression was observed in MDA-
modulation of the ?-catenin–Wnt pathway.
The stabilization and nuclear translocation of ?-catenin and
overexpression of cyclin D1 have been observed in many types
of human cancer (96). Glycogen synthase kinase-3? (GSK-3?)
is one of the enzymes of the ?-catenin degradation complex,
which facilitates ubiquitination and proteolysis of ?-catenin by
phosphorylation at N-terminal sites (97). Akt can phosphorylate
TABLE 1 (Continued)
Cancer and studyType of study
No. of cases/controls
OR (95% CI) or
significance Additional results, analysis, and comments
Spyridopoulos et al, 2007 (80)Retrospective
70/280 Greek0.76 (0.57–1.00)
P ? 0.05
Serum adiponectin concentrations were
inversely associated with renal cancer after
controlling for BMI but not after controlling
for central obesity (WHR).
Petridou et al, 2006 (81)Retrospective
201/201 (22 AML,
161 ALL-B, 18
0.56 (0.34–0.94) for AML
for ALL-B 1.08
(0.67–1.72) for ALL-T
Inverse correlation between adiponectin
concentrations and AML. Association was
not significant between adiponectin and
either ALL-B or ALL-T.
CLL and MPD
Avcu et al, 2006 (73) Retrospective
19/19 CLL 30/30
P ? 0.001 for CLL
P ? 0.001 for MPD
Shows lower adiponectin concentrations in
CLL and MPD patients than in controls.
Higher adiponectin concentrations in
1HMW, high molecular weight; NHS, Nurses’ Health Study; WHR, waist-to-hip ratio; AML, acute myeloblastic leukaemia; ALL-B or -T, acute
lymphoblastic leukemia of B- or T-cell origin; CLL, chronic lymphocytic leukemia; MPD, myeloproliferative diseases; IFN, interferon.
2Controlled for BMI or BMI and other variables.
3Analysis in women younger than 65 y.
4Analysis in overweight and obese subjects.
BARB ET AL
by guest on June 8, 2013
and inactivate GSK-3?, leading to stabilization and increased
concentrations of ?-catenin (96).
Although there was no direct evidence in this study of direct
alteration of Akt phosphorylation status by adiponectin, chronic
recombinant adiponectin treatment suppressed serum-induced
phosphorylation of Akt and GSK-3? in MDA-MB-231 cells;
subsequently, the intracellular accumulation and nuclear trans-
location of ?-catenin and the expression of one of its transcrip-
tional targets, cyclin D1, was decreased (38). However, these
effects do not seem to be mediated through adiponectin recep-
tors, because simultaneous down-regulation of both AdipoR1
and AdipoR2 had no effects on adiponectin-mediated inhibition
cells (38); action at the prereceptor level, ie, by sequestration of
growth factors (see paragraph below) may be one possibility. In
addition, this suppressive effect of adiponectin on ?-catenin in
MDA-MB-231 breast cells may be cell type specific, ie, adi-
ponectin treatment did not alter ?-catenin concentrations in
T47D cells (38). These findings, however, support the hypothe-
effects of adiponectin on breast cancer (38). Nevertheless, the
way could be especially important in cancers that are PTEN
deficient and subsequently have constitutive activation of the
phosphoinositide 3 kinase–Akt pathway that may contribute to
Wnt-1–induced ?-catenin stabilization (ie, advanced prostate
Finally, another potential mechanism by which adiponectin
may exert antiproliferative, and thus anticarcinogenic, effects in
vitro and in vivo could be by regulating the bioavailability of
certain growth factors, as was recently and thoroughly reviewed
elsewhere (98). In cultured smooth muscle cells, adiponectin in
physiologic concentrations significantly reduces DNA synthe-
sis, cell proliferation, and migration induced by several growth
factors (99, 100). Another study also showed that adiponectin
selectively binds not only platelet-derived growth factor-BB
(PDGF-BB), but also heparin-binding epidermal growth factor-
It also inhibits the interaction of these factors with their mem-
brane receptors (100), which suggests that the antiproliferative
effect of adiponectin is at least partly due to its selective seques-
of these growth factors by adiponectin is specific and involves
different oligomeric forms and binding sites of adiponectin for
each growth factor; ie, HB-EGF binds all 3 oligomeric com-
plexes of adiponectin (HMW, MMW, and LMW), PDGF-BB
binds to the HMW and MMW forms but not the LMW form of
adiponectin, and fibroblast growth factor binds preferably
HMW. This affirms that oligomerization may play an essential
Clearly, there is more to be studied to better understand the
tin. A summary of the possible mechanisms reviewed herein is
presented in Figure 1.
Insulin-sensitizing and antiinflammatory effects
Adiponectin’s anticancer properties are also likely explained,
at least in part, by its antiinflammatory and insulin-sensitizing
effects (8). Intraperitoneal injection of ACRP30 lowers glucose
concentrations in mice (101) and eliminates hyperglycemia in
and the rate of endogenous glucose production (27, 101). Al-
though the mechanisms underlying the insulin-sensitizing ef-
induced phosphorylation and activation of AMPK (27, 29), p38
mitogen-activated protein kinase (MAPK), and peroxisome
proliferator-activated receptor-? effects (29, 30, 102) have been
proposed to account for increased insulin sensitivity and fatty
acid oxidation in response to adiponectin treatment. Moreover,
adiponectin as well as increased concentrations of other adipokines [eg, tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6)] in obesity. Compensatory
hyperinsulinemia can in turn reduce liver synthesis and serum concentrations of insulin-like growth factor binding proteins (IGFBPs) and thus increase
and increased conversion of “weak” or less biologically active sex hormones to more active hormones, ie, estradiol (E2) and testosterone (T). Altered
concentrations of adiponectin, insulin, IGF-1 and sex hormones alter cellular proliferation and inhibit apoptosis. FFA, free fatty acid.
ADIPONECTIN AND CANCER
by guest on June 8, 2013
adiponectin administration has been shown to increase whole-
body insulin sensitivity through increased insulin-induced ty-
rosine phosphorylation of the insulin receptor in rodents (61).
correlated with an insulin-resistant state (103).
been shown to inhibit the growth of macrophage precursors and
and tumor necrosis factor-? production (82, 104). In addition,
intercellular adhesion molecule-1 and circulating vascular cell
adhesion molecule-1 (105, 106), inhibits interleukin (IL)-6 and
factor ?B by adiponectin might explain some of these effects (6,
108). Whether these antiinflammatory effects of adiponectin
play a role in carcinogenesis remains to be elucidated.
Regulation of angiogenesis
of adiponectin to alter neovascularization, possibly because of
differences in the cell types used as well as differences in the
microenvironments between in vivo versus in vitro studies, as
recently reviewed elsewhere (98).
CONCLUDING REMARKS AND FUTURE DIRECTIONS
supports a role of low adiponectin concentrations in obesity-
associated malignancies. Adiponectin’s ability to increase insu-
lin sensitivity in conjunction with its antiproliferative properties
has rendered this novel adipokine a promising potential future
diagnostic and therapeutic tool.
Further investigations to address a potential role of adiponec-
to fully elucidate the mechanisms underlying the effects of adi-
ponectin, are warranted. These may include 1) studies of the
expression and activation of adiponectin receptors and studies
that fully describe adiponectin signaling in vitro; 2) in vivo an-
imal studies that directly assess adiponectin’s anticarcinogenic
anti-tumor effects of adiponectin in addition to high-fat diet-
obesity; and 3) observational studies in humans designed to
the development of reliable laboratory techniques (eg, enzyme-
linked immunosorbent assays) for measuring total, HMW, and
LMW adiponectin. Large prospective studies assessing the var-
ious forms of adiponectin as diagnostic and prognostic markers
in several malignancies are clearly needed.
adiponectin receptor, or development of adiponectin receptors
agonists, as well as administration of human recombinant adi-
ponectin should be considered in the context of potentially en-
hancing our pharmacologic armamentarium for treating malig-
nancies in the not so distant future.
The contributions of the authors were as follows—DB, CJW, and AKN:
wrote the original draft and conducted the research, and CSM: edited and
revised the article. None of the authors had any conflicts of interest to
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