Prognostic significance of adiponectin levels in non-metastatic colorectal cancer.

Abstract

Circulating adiponectin levels are inversely correlated with the risk of colorectal cancer (CRC). This study was designed to evaluate the association between adiponectin levels and the clinicopathological variables of CRC and to analyze the possible prognostic value of adiponectin in predicting relapse-free survival.
Baseline adiponectin and serum tumor markers were analyzed in 60 patients with non-metastatic CRC followed-up from time of surgery for at least three years or until relapse.
The median adiponectin levels were lower in CRC patients (8.3 microg/ml) than controls (13.1 microg/ml, p <0.001). Moreover, median adiponectin concentration gradually decreased with increase in tumor stage. Low pre-surgical adiponectin levels were found in 52% of the relapsing patients compared to 26% (p=0.037) of the non-relapsing patients. Logistic regression analysis demonstrated that stage of disease (OR (odds ratio)=15.9, p<O.O1) and low adiponectin levels (OR=4.66, p<0.05) were independent predictors of recurrent disease.
Low serum adiponectin might represent an adjunctive tool in risk prediction for CRC recurrence.

Full text

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Abstract. Background: Circulating adiponectin levels are
inversely correlated with the risk of colorectal cancer (CRC).
This study was designed to evaluate the association between
adiponectin levels and the clinicopathological variables of CRC
and to analyze the possible prognostic value of adiponectin in
predicting relapse-free survival. Patients and Methods: Baseline
adiponectin and serum tumor markers were analyzed in 60
patients with non-metastatic CRC followed-up from time of
surgery for at least three years or until relapse. Results: The
median adiponectin levels were lower in CRC patients (8.3
Ìg/ml) than controls (13.1 Ìg/ml, p<0.001). Moreover, median
adiponectin concentration gradually decreased with increase in
tumor stage. Low pre-surgical adiponectin levels were found in
52% of the relapsing patients compared to 26% (p=0.037) of
the non-relapsing patients. Logistic regression analysis
demonstrated that stage of disease (OR (odds ratio)=15.9,
p<0.01) and low adiponectin levels (OR=4.66, p<0.05) were
independent predictors of recurrent disease. Conclusion: Low
serum adiponectin might represent an adjunctive tool in risk
prediction for CRC recurrence.
The associations between excess weight, obesity and cancer,
as well as the biological mechanisms contributing to these
associations, are an evolving and very active area of
research. It is generally accepted that endocrine dysfunction
of adipose tissue may represent one of the causal links
between obesity and cancer. Indeed, recent studies have
indicated that some adipokines may significantly influence
the growth and proliferation of tumor stroma and the
malignant cells within (1). Among them, adiponectin is
perhaps the most interesting and promising for the clinician,
since it has a profound protective effect on the pathogenesis
of obesity-related disorders (2).
Adiponectin is a 30-kDa protein hormone and cytokine
secreted mainly by adipocytes, structurally related to the
collagen superfamily and sharing homologies with collagens,
complement factors and tumor necrosis factor-· (TNF-·)
(3-6). Epidemiological studies have suggested that
circulating adiponectin levels are inversely correlated with
the risk of colorectal cancer (CRC) associated with obesity
and insulin resistance (7, 8). More recently, a case-control
study has demonstrated that men in the highest adiponectin
quintile had an approximately 60% reduced risk of
colorectal cancer compared to those in the lowest quintile,
the association being independent of body mass index
(BMI), waist circumference, waist-to-hip ratio and physical
activity (9). Moreover, decreased concentrations of plasma
adiponectin have been associated with the development of
colon adenomas in Japanese patients (10). In particular,
significant associations were found between decreased
adiponectin levels and the number or size of tumors and
histological progression from tubular to tubulovillous/villous
adenomas (10).
Several mechanisms have been proposed that may link
adiponectin to carcinogenesis, such as indirect effects
through altering hormone and cytokine levels or direct
effects through altering signal pathways involved in cell
growth and proliferation (11). Furthermore, experimental
483
Correspondence to: Patrizia Ferroni, MD, Department of Laboratory
Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Via
della Pisana 235, 00163, Rome, Italy. Tel: +39 (06) 66130425, Fax:
+39 (06) 66130407, e-mail: patrizia.ferroni@sanraffaele.it
Key Words: Adiponectin, colorectal cancer, prognosis.
ANTICANCER RESEARCH 27: 483-490 (2007)
Prognostic Significance of Adiponectin Levels
in Non-metastatic Colorectal Cancer
PATRIZIA FERRONI1, RAFFAELE PALMIROTTA1, ANTONELLA SPILA1, FRANCESCA MARTINI1,
VALERIA RAPARELLI2, EMANUELA FOSSILE3, SABRINA MARIOTTI3, GIROLAMO DEL MONTE3,
ORESTE BUONOMO4, MARIO ROSELLI3and FIORELLA GUADAGNI1
1Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS
San Raffaele Pisana, Via della Pisana 235, 00163 Rome;
2Department of Medical Therapy, University of Rome La Sapienza,
Viale del Policlinico 155, 00161 Rome;
3Medical Oncology, Department of Internal Medicine and
4Department of Surgery, University of Rome "Tor Vergata", Policlinico
Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
0250-7005/2007 $2.00+.40

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evidence suggests that adiponectin is a direct angiogenesis
inhibitor that preferentially induces apoptosis in activated
endothelial cells in pathological neovascularization (12).
Previous studies have shown that circulating adiponectin
levels were decreased in patients with gastric cancer (13) and
the association of low adiponectin concentrations and CRC
risk has been previously reported (7-9). No data are
currently available on the distribution of adiponectin levels
in CRC patients not on their prognostic significance.
Therefore, the aim of the present study was to evaluate the
possible associations between adiponectin and the
clinicopathological variables of non-metastatic CRC patients
at the time of diagnosis of a primary tumor. Moreover, a
follow-up study was performed to analyze the possible
prognostic value of pre-surgical adiponectin levels in
predicting the disease-free survival of patients with CRC.
Patients and Methods
Patients. Sixty consecutive patients (31 males, 29 females, mean age
64±10 years) with histologically diagnosed non-metastatic primary
colorectal adenocarcinoma (Dukes’ stage A: n=7, stage B: n=34,
stage C: n=19), treated at the Department of Surgery of the
University of Rome "Tor Vergata", were enrolled into the study. All
patients underwent surgical resection with curative intent. The clinical
features of the CRC patients are summarized in Table I. As a control
group, in a 2:1 ratio, 30 subjects (13 males, 17 females; mean age
59±12, ranging from 37 to 80 years) were also evaluated. Diabetes
mellitus (fasting blood glucose level >115 mg/dL or treatment with
a hypoglycemic agent), body mass index >28, history of alcohol or
drug abuse, impaired liver (bilirubin level>1.5 mg/dl) or renal
(creatinine level>1.5 mg/dl) function and a Karnofsky performance
status lower than 90% were considered as exclusion criteria.
The patients were followed from the time of diagnosis of the
primary tumor for at least 3 years after surgery or until time of
recurrence (the median follow-up was 37 months, ranging from 3.9
to 69.1). All patients were generally reviewed at 3-month intervals
during the first 2 years after surgery. Thereafter, the interval between
visits increased to 6 or 12 months in relation to tumor stage. No
patient was lost at follow-up. The study was performed under the
appropriate institutional ethics approvals and in accordance with the
principles embodied in the Declaration of Helsinki. Informed
consent was obtained from each participating subject.
Sample collection and immunoassay. Blood samples from the CRC
patients were drawn during the week before surgery, or prior to
neoadjuvant chemotherapy and/or irradiation. After an overnight
fast and a rest of at least 20 minutes, blood was drawn from each
consenting subject by venipuncture of the antecubital vein using a
20G needle. Blood was allowed to clot and then centrifuged at
2000 g for 10 minutes at 4ÆC. Serum samples were aliquoted,
coded and stored at –80ÆC until the assays were performed.
Serum adiponectin levels were determined by a commercially
available enzyme immunoassay (BioVendor Laboratory Medicine,
Inc., Brno, Czech Republic) according to the manufacturer’s
instructions. Intra- and inter-assay co-efficients of variation were
below 5% and 10%, respectively. The minimum detectable dose
was 0.2 Ìg/ml.
Serum carcinoembryonic antigen (CEA) levels were measured
using a commercially available immunoassay (Abbott Labs,
Chicago, IL, USA). CA 72-4 and CA 19-9 levels were determined
using the CA 72-4 DDRIA and the CA 19-9 RIA Kits (both by
Fujirebio Diagnostics Inc., formerly Centocor Diagnostics,
Malvern, PA, USA). The cut-off limits chosen for sample
evaluation were 5 ng/ml, 6 U/ml and 37 U/ml for CEA, CA 72-4
and CA 19-9, respectively.
Measurements were ascertained while blinded to the sample
origin. All samples were assayed in duplicate and those showing
values above the standard curve were re-tested with appropriate
dilutions.
Statistical analysis. Differences between percentages were assessed
by chi-square test. Student’s unpaired t-test and Anova test were
used for the normally distributed variables. Appropriate non-
parametric tests (Mann-Whitney U-test and Kruskal-Wallis
ANOVA and median test) were employed for all the other
variables. Univariate and multivariate linear regression analyses
were performed to assess the possible associations between
adiponectin and the clinicopathological variables. Logistic
regression analysis was used to evaluate the odds ratios (OR) for
outcome (defined as recurrence) between high and low adiponectin
groups. Data are presented as percentages, mean±SD, or median
and interquartile ranges (IQR). Only p-values lower than 0.05 were
ANTICANCER RESEARCH 27: 483-490 (2007)
484
Table I. Clinical features of non-metastatic colorectal cancer patients.
Comparison between relapsing and NED (no evidence of disease).
VariableWhole
series
N=60
NED
N=35
p-value Relapsing
N=25
Age (years)Mean±SD 64±10
Range
N (%)
N (%)
63±9
36-80
18 (51)
NS64±11
36-80
13 (52)
36-80
31 (52)Males
Site of primary
tumor
Colon
Sigma
Rectum
Grading
1
2
3
Dukes’ stage
A
B
C
NS
NS
15 (25)
14 (23)
31 (52)
9 (26)
11 (31)
15 (43)
6 (24)
3 (12)
16 (64)
N (%) NS
7 (12)
37 (61)
16 (27)
5 (14)
21 (60)
9 (26)
2 (8)
16 (64)
7 (28)
N (%)0.004
7 (12)
34 (56)
19 (32)
7 (20)
22 (63)
6 (17)
0 (0)
12 (48)
13 (52)
Total 6035 25
Length of
follow-up
(Months)
Site of recurrence
Locoregional
Distant metastasis
Median
(range)
42.6
(30.9-69.1)
<0.001 14.6
(3.9-43.0)
N (%)
6 (25)
19 (75)

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regarded as statistically significant. All calculations were made
using computer software packages (EGRET Cytel Software Co.,
Cambridge, MA, Statistica, StatSoft Inc., Tulsa, OK, USA).
Results
The median serum adiponectin levels were lower in the
CRC patients (8.3 (5.5-9.4) Ìg/ml) than in the control
subjects (13.1 (12.2-15.6) Ìg/ml, p<0.0001). Moreover, as
shown in Figure 1, the median adiponectin concentration
gradually decreased with increase in tumor stage (Stage A:
8.9 (8.2-9.7) Ìg/ml; Stage B: 8.5 (5.8-9.3) Ìg/ml; Stage C: 6.2
(4.8-9.5) Ìg/ml), although the difference within stages did
not reach the level of significance.
Serum adiponectin was then categorized into low
(<6.4 Ìg/ml) or high (≥6.4 mg/ml) according to a cut-off
value calculated from the mean –2SD of the values observed
in the control subjects (14.2±3.9 Ìg/ml). The associations
between adiponectin and the clinicopathological variables
were analyzed after categorization. As shown in Table II, no
significant correlation was observed between the serum
adiponectin level and the site of the primary tumor or grading.
In the male patients, 18 (58%) out of 31 showed low
adiponectin levels compared to four (14%) out of 29 of the
female patients (p<0.001). More interestingly, low
adiponectin levels were found in approximately 35% and 53%
of the patients with stage B and C of disease, whereas all the
stage A patients had high serum adiponectin levels (Table II).
To assess the possible determinants of adiponectin among
the clinical and laboratory features of CRC, a multiple
regression analysis was performed in which adjustments were
made for the following variables: age, sex, site of primary
tumor, grading, serosal and lymph node involvement, Dukes’
stage, CEA, CA 19-9 and CA 72-4 tumor markers. As shown
Ferroni et al: Adiponectin in Colorectal Cancer
485
Figure 1. Box-plot analysis of serum adiponectin levels in 60 non-metastatic CRC patients stratified on the basis of the stage of disease and 30 control
subjects. Data are presented as median values (solid lines), interquartile range (columns) and non-outlier (whiskers) ranges. Closed circles indicate
outliers. Mann-Whitney test of single stages CRC compared to control subjects.

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in Table III, Dukes’ stage of disease and male gender were
both independent predictors for low adiponectin levels (R2
for the entire model=0.28, p<0.001).
Clinical information on post-operative follow-up was
available from all the CRC patients. Over a median follow-
up period of 37 months, 35 (58%) out of the 60 patients
remained free of disease, while 25 (42%) patients
experienced relapsing disease (Table I). No differences were
observed in age, sex, site of primary tumor or grading
between patients with and without recurrence (Table I). Pre-
surgical adiponectin levels were below the cutoff in
approximately 52% of the relapsing patients compared to
26% (p=0.037) of the patients who remained free of disease.
A multiple logistic regression analysis was performed to
compute the odds ratios (ORs) and 95% confidence
intervals (CI) for recurrent disease. As shown in Table IV,
both Dukes’ stage of disease (OR=15.9, p<0.01) and low
adiponectin levels (OR=4.66, p<0.05) were independent
predictors of recurrent disease. Figure 2A demonstrates the
Kaplan-Meier disease-free survival curves for non-metastatic
CRC patients with low (below the cut-off value) or high
(above the cut-off value) adiponectin levels. As shown, low
pre-surgical adiponectin levels were associated with an
increased recurrence rate compared to patients with high
levels of this adipokine (Log-rank statistic=2.11, p=0.035).
Similar results were obtained when only Dukes’ stage B
CRC patients were included in the analysis (Log-rank
statistic=1.94, p=0.053) (Figure 2B).
Discussion
The results obtained in this study indicate for the first time
that serum adiponectin levels are significantly decreased in
patients with non-metastatic CRC compared to control
subjects, and that low circulating adiponectin might
represent a risk factor for recurrent disease. It is currently
recognized that nutritional status in patients with cancer
might also affect adiponectin levels (14). However, the pre-
surgical albumin, total protein, total cholesterol and
triglyceride levels were not altered in the recruited patients
(data not shown). Furthermore, patients with metastatic
disease were excluded from the study to avoid any
confounding variable linked to the presence of cancer
cachexia, in which weight loss is significantly associated to
increased adiponectin concentrations (14). All these
considerations suggest that in this study the differences
observed in serum adiponectin levels were not attributable
to the nutritional status.
One important finding of our study is the correlation of
low adiponectin levels with the increasing stage of disease,
which is in agreement with the currently accepted
hypothesis that adiponectin may exert protective actions
through its anti-proliferative and anti-angiogenic effects (11,
12). Another possibility is that the low adiponectin levels
might result from the increased tumor burden, which is in
agreement with the finding that expression and secretion of
adiponectin were significantly reduced by TNF-· in a dose-
and time-dependent manner via its promoter activity (15).
Indeed, many tumors, including CRC, produce various
inflammatory cytokines and the levels of TNF-· have been
shown to be associated with advanced stage of CRC (16).
On the other hand, adiponectin has also been shown to
inhibit the production of TNF-· in macrophages and its
action in endothelial cells, suggesting that low adiponectin
levels could potentially lead to carcinogenesis by changing
the influence of TNF-· on tumor cell proliferation (11).
Thus, the issue of whether adiponectin changes are directly
linked to cancer development or whether they simply
correlate with metabolic dysfunction is still open to
question.
Although the findings obtained in this study do not allow
us to draw any conclusion on the mechanisms responsible
for the relationship between adiponectin and cancer
progression, the association found with tumor stage and,
most importantly, the predictive value of low adiponectin
levels with respect to disease-free survival suggest that this
ANTICANCER RESEARCH 27: 483-490 (2007)
486
Table II. Association between clinicopathological variables and serum
adiponectin levels in non-metastatic colorectal cancer patients.
Serum adiponectin levels*
VariableN <6.39 Ìg/ml ≥6.39 Ìg/ml p-value
Gender
Male
Female
Site of primary tumor
Colon
Sigma
Rectum
Grading
1
2
3
Serosal involvement
No
Yes
Lymph node involvement
N0
N+
Dukes’ stage
A
B
C
31
29
18 (58.1)
4 (13.8)
13 (41.9)
25 (86.2)<0.001
15
14
31
4 (26.7)
6 (38.7)
12 (42.9)
11 (73.3)
8 (61.3)
19 (57.1)0.63
73 (42.9)
12 (32.4)
7 (43.8)
4 (57.1)
25 (67.6)
9 (56.2)
37
16 0.69
43
17
13 (30.2)
9 (52.9)
30 (69.8)
8 (47.1) 0.10
41
19
12 (29.3)
10 (52.6)
29 (70.7)
9 (47.4) 0.08
70 (0.0)
12 (35.3)
10 (52.6)
7 (100)
22 (64.7)
9 (47.4)
34
19 0.05
*Categorized according to a cut-off value calculated from the mean
value – 2SD of the values observed in the control subjects. Numbers in
parentheses represent percentages.

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adipokine might represent an adjunctive tool in risk
prediction for CRC recurrence. It is worth noticing that of
the 25 patients who had recurrent disease, 52% had low
pre-surgical adiponectin levels compared to approximately
26% of the patients who remained free of disease, thus,
making low adiponectin levels a strong predictor of
recurrence in the overall population (OR=4.66, p<0.05)
independently of tumor stage.
Ferroni et al: Adiponectin in Colorectal Cancer
487
Table III. Multiple regression analysis of the variables associated with low adiponectin levels in non-metastatic colorectal cancer patients.
Entire model
Dependent variable Explanatory variableStandardized regression co-efficient Standard error
p-value
Adiponectin
Male gender
Age
Site
Grade
Dukes’ stage
CA199
CEA
CA 72-4
0.422074
0.001226
0.002214
0.011046
–0.220367
–0.003509
0.003313
–0.005525
0.120303
0.005808
0.090649
0.096394
0.094725
0.002506
0.002262
0.016270
0.000951
0.833664
0.980610
0.909219
0.024009
0.167467
0.149162
0.735562
Forward stepwise method
Male gender
Dukes’ stage
0.430824
–0.222684
0.107373
0.085555
0.000177
0.011764
*Categorized according to a cut-off value calculated from the mean value – 2SD of the values observed in the control subjects.
Table IV. Logistic regression analysis of relapse-free survival in non-metastatic colorectal cancer patients.
Recurrence
VariableN Yes NoOR 95% CI
p-value
Gender
Female
Male
Site
Colon
Sigma
Rectum
Dukes’ stage
A
B
C
Adiponectin
*Low
High
CEA
Negative
Positive
CA 19-9
Negative
Positive
29
31
12 (41)
13 (42)
17 (59)
18 (58)2.21 0.47-10.42 0.316
15
14
31
6 (40)
3 (21)
16 (52)
9 (60)
11 (79)
15 (48) 1.030.43-2.440.950
7 0 (0)
12 (35)
13 (68)
7 (100)
22 (65)
6 (32)
34
1915.9 1.98-127.9< 0.01
22
38
13 (59)
12 (32)
9 (41)
26 (68)4.660.95-22.9 < 0.05
45
15
16 (36)
9 (60)
29 (64)
6 (40)2.01 0.38-10.50.408
5220 (38)
5 (63)
32 (62)
3 (37)82.49 0.33-18.8 0.376
CA 72-4
Negative
Positive
51 21 (41)
4 (44)
30 (59)
5 (56)9 0.640.10-3.890.625
Numbers in parenthesis represent percentages.
*Below (low) and above (high) the mean – 2SD of the control subjects.

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ANTICANCER RESEARCH 27: 483-490 (2007)
488
Figure 2. Kaplan-Meier Analysis of relapse-free survival time of non-metastatic CRC patients. Comparison between patients with low (solid line) and high
(dotted line) adiponectin levels (cut-off 6.39 Ìg/ml, mean –2SD of controls). A: overall population (n=60) (Log-rank statistic=2.11, p=0.035); B:
patients with Dukes’ stage B disease (n=34) (Log-rank statistic=1.94, p=0.053).

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One limitation of this study was that detailed information
on anthropometric measures was not available to the
investigators. Despite this limitation, this is the first study, to
our knowledge, on adiponectin levels in CRC and supports
the hypothesis that this adipokine may have an independent
prognostic role in predicting relapsing disease. While this
hypothesis requires detailed experimental evaluation before
its ultimate significance can be determined; it is hoped that
new studies will be undertaken to fully elucidate the
mechanisms underlying the adiponectin effects and to better
understand its significance in disease progression, as well as
its contribution as a prognostic factor for CRC. Nonetheless,
our results suggest that the determination of serum
adiponectin levels might represent a prognostic parameter in
the management of patients with CRC, and may help in the
choice of more aggressive treatment and/or more strict
follow-up procedures in a subset of patients who are at high
risk of recurrence.
Acknowledgements
The authors wish to thank Isabella Lucci for her excellent technical
assistance.
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Received October 6, 2006
Revised November 24, 2006
Accepted November 27, 2006
Ferroni et al: Adiponectin in Colorectal Cancer
489