Int. J.

Cancer: 120, 1573–1578 (2007)

' 2006 Wiley-Liss, Inc.

Low adiponectin levels are associated with renal cell carcinoma:

A case-control study
Themistoklis N. Spyridopoulos1, Eleni Th. Petridou1,2*, Alkistis Skalkidou1,3, Nick Dessypris1, George P. Chrousos4,
Christos S. Mantzoros5 and the Obesity and Cancer Oncology Group6
1
Department of Hygiene and Epidemiology, Athens University Medical School, Goudi, Athens, Greece
2
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
3
Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
4 st
1 Department of Pediatrics, Athens University Medical School, Athens, Greece
5
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
6
Obesity and Cancer Oncology Group: Members of the Renal Cancer study: Aristeides Giannopoulos,
1st Department of Urology, University of Athens, ‘‘Laikon Hospital’’, Goudi, Athens, Greece;
Gerasimos Alivizatos, 2nd Department of Urology, University of Athens, ‘‘Sismanoglion Hospital’’,
Marousi, Athens, Greece; George Vassilakis, Department of Urology, General Hospital of Athens ‘‘G. Gennimatas’’,
Xolargos, Athens, Greece; Theodore Kalogeropoulos, Department of Urology, ‘‘Saint Savas’’ Anticancer Hospital,
Ampelokipoi, Athens, Greece

Adiponectin is a novel endogenous insulin sensitizer, secreted by nectin levels may mediate the effect of central or intra-abdominal
mature adipocytes. Circulating levels of adiponectin are inversely visceral obesity on RCC. To evaluate this hypothesis we have con-
associated with obesity and insulin resistance. Because obesity is a ducted a case-control study of 70 patients with RCC and 280
risk factor for renal cell carcinoma (RCC), we hypothesized that healthy controls.
low adiponectin levels are associated with RCC. To evaluate this
hypothesis, we conducted a case- control study of 70 patients with
histologically confirmed RCC and 280 healthy controls matched by Material and methods
gender, age and county of residence. Study subjects were inter- During a 32-month period (October 2002 to May 2005), 70
viewed and blood samples were collected during a 32-month period
in Athens, Greece. Serum adiponectin levels were statistically, sig- cases of histologically confirmed RCC were diagnosed, newly pre-
nificantly and inversely associated with RCC when compared with sented with signs and/or symptoms in 4 hospitals in Athens and
controls (OR 5 0.76, p 5 0.05) and this association remained prac- were recruited in the study by the study investigators. Seven cases
tically unchanged after controlling for BMI; the introduction of of transitional epithelium cancer and three with other renal malig-
waist to hip ratio along with adiponectin in the multiple logistic nancies that were diagnosed during the same period were not
regression analysis model rendered the association between adipo- included in the study, because these disease entities may have dif-
nectin and RCC risk insignificant, indicating that altered levels of ferent etiology and pathophysiology than RCC. Thirty cases
adiponectin may mediate the effect of central or intra-abdominal (42.9%) were Stage I, 17 (24.3%) Stage II, 15 (21.4%) Stage III
obesity on RCC. Prospective studies as well as studies exploring
underlying mechanisms are needed to fully explore the role of adi- and 8 (11.4%) Stage IV disease, whereas none of the cases
ponectin in predicting future risk of RCC in humans. included in the study had ever been previously diagnosed with any
' 2006 Wiley-Liss, Inc. other type of cancer.26 In addition to the overall tumor staging, we
used the TNM (Tumor-Node-Metastasis) system (updated version
1997) for a more detailed pathologic staging, the Fuhrman scale
Key words: adiponectin; renal cell carcinoma; intra-abdominal for tumor grading and we also classified tumors according to their
obesity histological subtype.27–29
For each one of these patients, 4 eligible controls matched for
Obesity, and more importantly central obesity, is closely associ- gender and of approximately the same age (65 years) and place of
ated with insulin resistance.1–3 Adiponectin, a 247 amino acid pro- residence were also enrolled consecutively in the study. Controls
tein with properties of an endogenous insulin sensitizer, was dis- had a negative self reported medical history for cancer, hepatic
covered in the mid-1990s4 and has been widely studied in relation disease, major hormonal or hematological disorders, asthma, auto-
to many disease entities associated with obesity and insulin resist- immune disease, HIV infection, advanced heart failure, chronic
ance.5,6 kidney failure, recent myocardial infarction, stroke, acute pancrea-
Adiponectin is produced and secreted exclusively by differenti- titis or bone fracture. Five potential controls refused or were
ated adipocytes. It is one of the most abundant serum proteins and unable to collaborate and were properly substituted for a total of
circulates in tightly associated trimers and higher order olig- 280 matched control subjects.
omers.4,7,8 Adiponectin decreases with increasing overall and central The study protocol was approved by the University of Athens
adiposity and increases with prolonged weight reduction4,9,10; thus, Medical School Ethics Committee and the study design and per-
it is currently thought that adiponectin represents a biochemical link formance were in accordance with the Helsinki Declaration of
between obesity, insulin resistance, and various other metabolic 1975. All participants provided written informed consent.
abnormalities associated with obesity.7,11 Consistently, interven-
tional studies have shown that adiponectin improves insulin sensi-
tivity12,13 and lipid profile,14 and suppresses inflammatory mecha- Grant sponsors: Athens University Medical School, Greece; Harvard
nisms involved in atherosclerosis.15 Finally, there is emerging Medical School, Boston
mechanistic and epidemiological evidence supporting a protective *Correspondence to: Department of Hygiene and Epidemiology,
role for adiponectin in obesity-associated malignancies.16–19 Athens University Medical School, 75 Mikras Asias Str, Goudi, Athens
11527, Greece. Fax: 130-210-7462105.. E-mail: epetrid@med.uoa.gr
Obesity is a known risk factor for renal cell carcinoma (RCC), Received 10 July 2006; Accepted after revision 20 November 2006
but the molecular pathways underlying this association remain to DOI 10.1002/ijc.22526
be elucidated.5,20–25 We have hypothesized that decreased adipo- Published online 4 January 2007 in Wiley InterScience (www.interscience.
wiley.com).

Publication of the International Union Against Cancer

1574 SPYRIDOPOULOS ET AL.

TABLE I – MEAN VALUES AND STANDARD DEVIATION (SD) OF ADIPONECTIN LEVELS AND SOMATOMETRIC VARIABLES
BY TUMOR STAGING AND CHARACTERISTICS AMONG 70 CASES WITH RENAL CELL CARCINOMA
Adiponectin BMI Waist to hip ratio Weight
Variable N
Mean SD Mean SD Mean SD Mean SD

Stage
I T1N0M0 30 10.04 4.70 28.19 3.64 97.50 13.76 80.03 13.33
II T2N0M0 17 8.86 3.13 28.46 3.12 105.26 9.09 80.00 10.68
III 15 8.75 2.19 26.44 2.39 99.58 14.98 73.47 6.58
T3aN0M0 8 8.84 2.08 26.81 2.56 104.95 16.27 76.00 7.50
T3bN0M0 3 7.81 1.26 27.40 2.51 91.88 19.30 73.33 2.89
T3bN1M0 4 9.25 3.17 25.00 1.79 94.61 3.45 68.50 3.87
IV 8 10.23 3.78 25.16 2.11 98.84 6.03 71.75 11.08
T1N0M1 1 10.24 – 27.55 – 101.00 – 75.00 –
T1N1M1 1 3.40 – 27.14 – 105.88 – 86.00 –
T2N1M1 1 10.64 – 24.90 – 100.00 – 78.00 –
T3bN2M1 1 15.60 – 21.88 – 94.44 – 56.00 –
T3cN2M1 1 11.18 – 22.83 – 95.24 – 57.00 –
T4N2M1 3 10.26 3.44 25.64 1.53 98.06 9.09 74.00 7.93
Grade
1 5 10.71 3.19 25.98 2.90 97.64 20.83 76.60 12.66
2 26 10.33 4.06 28.34 2.90 100.84 11.52 81.62 9.90
3 24 8.88 4.23 27.89 4.00 99.48 10.88 76.83 13.47
4 11 8.31 1.59 26.27 2.44 100.79 17.00 71.09 9.21
N.A.1 4 9.58 4.28 25.64 1.52 98.11 6.80 76.50 8.66
Histological type
Clear cell 52 9.64 3.74 27.51 3.46 99.64 11.63 77.79 12.12
Papillary 8 10.35 5.70 28.23 2.74 106.91 9.05 82.43 10.37
Chromophobe 6 7.12 2.28 26.18 2.12 100.54 25.46 70.20 4.63
Collecting duct 1 7.88 – 30.30 – 79.69 – 70.00 –
Unclassified 3 10.13 3.19 27.92 4.23 97.46 6.89 76.00 11.53
N.A.–not available.

Each case and the 4 matched controls were interviewed by one To further explore the possible effect of obesity we run an addi-
of 4 trained interviewers. The interview lasted about 30 min and tional analysis restricted to obese (BMI  30 kg/m2) patients and
information pertaining to socio-demographic, anthropometric, controls (n 5 25 and 87, respectively). Using unconditional logis-
lifestyle and medical history variables was obtained. Anthropo- tic regression the risk (OR) for RCC in relation to adiponectin was
metric variables were measured by specially trained health profes- calculated with and without adjustment for the pre-defined poten-
sionals (height, with subjects wearing no shoes; waist and hip cir- tial cofounders, as well as for age and gender. The SAS statistical
cumference, with subjects wearing no clothes) as previously package was used in all analyses and the level of statistical signifi-
described.16,18,30 In addition, blood samples were taken from all cance was set at 0.05.32
cases and controls (no later than 9 a.m.) for hormonal measure-
ments and for the determination of fasting glucose levels. Results
All coded samples, blinded as to case control status, were cen-
trifuged and stored at 270°C, prior to being air shipped with dry In Table I data concerning somatometric variables and adipo-
ice to the Beth Israel Deaconess Medical Center, in Boston USA. nectin levels of the 70 RCC patients are presented tabulated by tu-
Serum adiponectin levels were measured in 1 batch by trained mor stage, grade and histological subtype. No statistically signifi-
technicians utilizing a radioimmunoassay procedure with a sensi- cant association of adiponectin with any of the studied variables
tivity of 2 ng/ml and intra-assay coefficient of variation of <10%, was observed. Nevertheless, it was noticed that mean serum levels
as previously described.16–18 Average preservation time was simi- of adiponectin were decreasing with increasing tumor grade.
lar for cases and controls, although adiponectin levels do not sys- In Table II we present data on demographic and lifestyle varia-
tematically change with storage time.31 bles as well as presence of diabetes for the 70 patients with RCC
To investigate how adiponectin levels and the somatometric vari- and the 280 gender-age- and residence matched controls. These
ables correlate with tumor characteristics, we performed analysis of data serve mostly descriptive purposes and are not directly inter-
mean values of adiponectin, weight, Body Mass Index (BMI) and pretable because of mutual confounding. However, they reveal
Waist to Hip Ratio (WHR) by tumor stage, grade and histological most of the established risk characteristics of RCC. Thus, patients
subtype. For the case control statistical analyses, representative val- with RCC were statistically significantly less educated (p 5 0.02),
ues (mean, SD, percentiles) of the anthropometric variables and se- they smoked and drank coffee more frequently, they had more fre-
rum adiponectin levels were calculated. We, subsequently, eval- quently positive history of diabetes mellitus and had more pro-
uated the correlation of serum adiponectin with the somatometric nounced weight loss during the 2 months prior to presentation
variables to identify possible predictors of adiponectin levels among when compared with their respective controls. Controls, on the
healthy individuals. To study the association of adiponectin with other hand, appeared to consume alcohol on a more regular basis.
RCC, we modeled the data through multiple conditional logistic Both total abstinence, but also over-consumption of alcohol, was
regression analysis using case control as the outcome variable and positively associated with RCC in comparison to drinking 1 alco-
adiponectin (in increments of 1 standard deviation of the hormone holic drink per day.
among controls), as well as a series of possible confounders as pre- Table III shows representative values of somatometric variables
dictor variables. Potential confounders considered in the study were and serum adiponectin levels by case-control status. Mean values
BMI at the time of diagnosis and 2 months before the time of diag- of height, weight, BMI and hip circumference were not signifi-
nosis (in 2 kg/m2 increments), WHR (in 5% increments), education, cantly different between cases and controls (p-values 0.30, 0.72,
smoking, coffee alcohol consumption, diabetes mellitus status (self 0.69 and 0.55, respectively). Cases had more pronounced weight
reported history of diabetes mellitus or fasting glucose level higher loss than controls (mean values 21.0 and 0.1 kg, respectively).
than 125 mg/dl) and weight change during the last 2 months. Mean values of waist circumference and WHR were higher among
 ADIPONECTIN AND RENAL CELL CARCINOMA 1575
cases than among controls (p-values 0.003 and 0.0001 respec- higher among controls, when compared with those of patients
tively), indicating more pronounced intra-abdominal obesity (p 5 0.06). Finally, no differences of mean values of adiponectin
among cases. Conversely, mean serum levels of adiponectin were serum levels were observed between localized (9.62 lg/ml) and
metastatic cases (9.26 lg/ml).
TABLE II – DISTRIBUTION OF 70 CASES OF RENAL CELL CARCINOMA We then examined associations between serum adiponectin and
AND 280 AGE- AND GENDER-MATCHED CONTROLS BY DEMOGRAPHIC,
LIFE STYLE VARIABLES AND DIABETES MELLITUS STATUS somatometric variables as well as age among healthy controls and
the Pearson correlation coefficients are presented in Table IV.
Cases Controls
Variable p-value Adiponectin was negatively correlated with obesity, especially
N % N % central obesity. Again, these results may not be directly interpreta-
Age Matched ble because of the possibility of mutual confounding.
Variable Subsequently, multiple logistic regression analyses were per-
<50 years 11 15.7 57 20.3 formed and the odds ratio for RCC for each increment of adipo-
50–59 16 22.9 59 21.1 nectin, corresponding to 1 standard deviation among controls were
60–69 17 24.3 51 18.2 determined (Table V). The odds ratios were derived from 5 differ-
70–79 23 32.8 103 36.8 ent models. The crude odds ratio for adiponectin (Model 1) was
801 3 4.3 10 3.6
Gender Matched 0.76 (p-value 5 0.05). The statistically significant inverse associa-
Variable tion between serum adiponectin and RCC remained essentially
Male 42 60.0 168 60.0 unchanged (OR 5 0.75, p-value 5 0.05) after controlling for BMI
Female 28 40.0 112 40.0 at the time of diagnosis (Model 2) and for BMI 2 months before
Education 0.02* diagnosis (data not shown), namely in both instances they were
<6 years 11 15.7 33 11.8 not found to be significantly associated with the risk of RCC. Fur-
6–8 32 45.7 85 30.4 ther adjustment for the potential confounders from Table II,
9–11 12 17.2 54 19.3 including BMI, education, coffee consumption, smoking, alcohol
12 4 5.7 60 21.4 and weight change during the last 2 months (Model 4) did not
121 11 15.7 48 17.1
Coffee consumption 0.07** essentially alter the inverse association with adiponectin (OR 5
Yes 65 92.9 239 85.4 0.77, p-value 5 0.08); the associations of the other variables with
No 5 7.1 41 14.6 RCC in this model were in agreement with those initially pre-
Smoking 0.52** sented in Table II. More specifically, the risk for RCC is reduced
Yes or ex-smoker 43 61.4 160 57.1 as education level is increasing. The absence of alcohol consump-
No 27 38.6 120 42.9 tion or the increased consumption was positive related with the
Alcohol consumption 0.001*** RCC in relation to drinking 1 alcoholic drink per day. Recent
0 (glass/month) 23 32.9 49 17.5 weight loss was significantly related with RCC risk whereas coffee
1–31 (glasses/month) 25 35.7 172 61.4
321 22 31.4 59 21.1 consumption, smoking and BMI were not found to be associated
Diabetes mellitus 0.01*** with RCC risk. When WHR was included along with adiponectin
Yes 21 30.0 45 16.1 (Model 3), however, the association of adiponectin with RCC
No 49 70.0 235 83.9 became statistically non-significant (OR 5 0.84, p-value 5 0.26)
and was further attenuated when all studied potential confounding
*p-value derived from Chi-square for trend;–**p-value derived from variables were mutually adjusted in Model 5 (OR 5 0.89, p-value
Fisher’s Exact test;–***p-value derived from Chi-square for contrast.

TABLE III – REPRESENTATIVE VALUES OF SOMATOMETRIC VARIABLES AND ADIPONECTIN LEVELS BY CASE-CONTROL STATUS*
Variable N Min value 25% Median 75% Max value Standard deviation Mean p-value t-test

Height (cm)
Cases 70 148 164 167.5 170 187 7.66 167.8 0.30
Controls 280 145 160 167 173 190 9.35 166.6
Weight (kg)
Cases 70 47 70 76.5 85 105 11.58 77.7 0.72
Controls 280 46 68 77 85 154 14.17 77.1
Weight change(kg): last 2 months
Cases 70 220 22 0 0 10 3.75 21.0 0.02
Controls 280 212 0 0 0 8 2.18 0.1
BMI (kg/m2)
Cases 70 21.5 25.5 27.0 29.4 36.3 3.28 27.5 0.69
Controls 280 18.0 25.0 27.3 30.0 45.7 4.37 27.7
Waist circumference (cm)
Cases 70 62 96 105 113 141 16.26 103.8 0.003
Controls 280 60 90 98 106 148 13.02 97.5
Hip circumference (cm)
Cases 70 60 98 104.5 110 135 11.26 104.0 0.55
Controls 280 68 98.5 104 110 154 10.83 104.8
Waist/Hip ratio (%)
Cases 70 70.4 91.9 97.2 107.9 140.0 12.56 100.0 0.0001
Controls 280 64.8 87.6 93.7 99.0 138.2 10.21 93.2
Adiponectin (lg/ml)
Cases 70 2.3 7.2 9.0 11.7 22.8 3.80 9.50 0.06
Controls 280 0.4 8.2 10.0 12.6 22.5 3.29 10.34
*
p-value derived from t-tests, comparing means between cases of renal cell carcinoma and controls.
1576 SPYRIDOPOULOS ET AL.

TABLE IV – PEARSON CORRELATION COEFFICIENTS (p-VALUES) BETWEEN AGE, SOMATOMETRIC VARIABLES

AND ADIPONECTIN LEVELS AMONG THE 280 CONTROLS
Variable Height Weight BMI Waist circum. Hip circum. Waist to hip ratio Adipo-nectin

Age 20.24 (0.0001) 20.04 (0.47) 0.15 (0.01) 0.23 (0.0001) 0.07 (0.22) 0.24 (0.0001) 20.01 (0.80)
Height 0.55 (0.0001) 20.10 (0.11) 0.23 (0.0001) 0.01 (0.95) 0.27 (0.0001) 20.28 (0.0001)
Weight 0.78 (0.0001) 0.71 (0.0001) 0.54 (0.0001) 0.38 (0.0001) 20.30 (0.0001)
BMI 0.73 (0.0001) 0.68 (0.0001) 0.26 (0.0001) 20.15 (0.008)
Waist 0.62 (0.0001) 0.65 (0.0001) 20.24 (0.0001)
circumference
Hip 20.18 (0.0001) 0.00 (0.99)
circumference
Waist to hip ratio 20.30 (0.0001)

TABLE V – CONDITIONAL LOGISTIC REGRESSION-DERIVED ODD RATIOS (ORs) AND 95% CONFIDENCE INTERVALS (95% CIs)
FOR RENAL CELL CARCINOMA BY DEMOGRAPHIC AND LIFE STYLE VARIABLES, DIABETES MELLITUS STATUS,
WEIGHT CHANGE IN THE LAST 2 MONTHS AND ADIPONECTIN
Variable Category or increment ORs1 (95% CIs) ORs2 (95% CIs) ORs3 (95% CIs) ORs4 (95% CIs) ORs5 (95% CIs)
p-value p-value p-value p-value p-value

Adiponectin 1 SD among controls 0.76 (0.57–1.00) 0.75 (0.56–0.99) 0.84 (0.62–1.13) 0.77 (0.57–1.03) 0.89 (0.64–1.22)
0.05 0.05 0.26 0.08 0.46
BMI 2 kg/m2 0.96 (0.78–1.17) 0.95 (0.76–1.19) 0.84 (0.66–1.07)
0.66 0.63 0.17
Waist/Hip ratio 5% more 1.89 (1.39–2.55) 2.09 (1.45–3.00)
0.0001 0.0001
Education 1 level more 0.71 (0.54–0.92) 0.72 (0.54–0.96)
0.01 0.03
Coffee yes vs. rare or not 2.26 (0.78–6.56) 2.37 (0.77–7.29)
consumption 0.13 0.13
Smoking yes or 1.19 (0.64–2.22) 1.17 (0.60–2.31)
ex-smoker vs. no 0.58 0.64
Alcohol 0 vs. 1–31 2.71 (1.30–5.65) 3.20 (1.46–7.01)
glasses/month 0.01 0.004
321 vs. 1–31 2.26 (1.13–4.52) 2.52 (1.20–5.31)
glasses/month 0.02 0.01
Diabetes mellitus no vs. yes 1.56 (0.78–3.12)
0.21
Weight change: 1 kg more 0.86 (0.77–0.96) 0.88 (0.78–1.00)
last 2 months 0.01 0.04
1
Model 1: Unadjusted odds ratio for Adiponectin.–2Model 2: Odds ratio for mutually adjusted Adiponectin and BMI.–3Model 3: Odds ratio
for mutually adjusted Adiponectin and waist to hip ratio.–4Model 4: Odds ratio for mutually adjusted Adiponectin, BMI, education, coffee con-
sumption, smoking, alcohol and weight change during the last 2 months.–5Model 5: Odds ratio for mutually adjusted Adiponectin, BMI, waist
to hip ratio, education, coffee consumption, smoking, alcohol, diabetes mellitus status and weight change during the last 2 months.

5 0.46). In Model 5, WHR index was associated with increased for other lifestyle characteristics, including educational level, smok-
RCC risk and the impact of the other variables, that were also ing, coffee, alcohol consumption, diabetes mellitus status and recent
included in Model 4, remained practically the same, and whereas weight change does not materially alter the observed association,
diabetes was not statistical significantly associated with RCC risk. suggesting little confounding effect from these factors. Conversely,
Introducing adiponectin as a categorical variable in these models the association between adiponectin levels and RCC risk becomes
yielded similar results, whereas the exclusion of coffee consump- statistically non-significant after adjusting for indicators of central
tion or the introduction of smoking as a categorical variable in 3 obesity including WHR. This somatometic index is significantly
levels (never smoking, ex-smoker, current smoker) or in 4 levels positively associated with RCC risk and negatively with adiponec-
based on the number of cigarettes (0, 1–19, 20–39, 401) in Mod- tin levels. Since the introduction of WHR in multivariate models
els 4 and 5 did not alter the initial results (data not shown). Con- attenuated the significance of the association of adiponectin with
cerning the possible effect of obesity, the results from the stratified RCC risk, we propose that decreased circulating adiponectin levels
analysis (restricted to obese patients and controls) were practically may mediate the effect of central or intra-abdominal visceral obe-
the same with those of the total study group. The OR for adiponec- sity on RCC. Finally, the analysis of mean values of adiponectin
tin in the univariate model (Model 1) was 0.65 (CI 5 0.39–1.07) levels and weight, BMI, WHR by tumor stage, grade and histologi-
and for the corresponding Models 4 and 5 were 0.71 (CI 5 0.38– cal subtype did not reveal any statistically significant difference;
1.35) and 0.66 (CI 5 0.33–1.36), respectively. The introduction of however, a trend of decreasing serum adiponectin levels with
WHR in both Models 4 and 5 decreased the effect of adiponectin increasing tumor grade was observed in our study. Further studies
in relation to RCC, indicating that altered adiponectin levels may of a larger size should be conducted in the future to compare these
mediate the effect of central or intra-abdominal obesity on RCC. variables between metastatic and non-metastatic RCC patients.
Overweight and obese subjects have a 1.5- to 3-fold higher risk
Discussion for RCC when compared with subjects of normal weight.21 Most
studies have reported a dose-response relationship of RCC with
This case-control study shows, for the first time, that serum adi- increasing weight or BMI, which is more pronounced among
ponectin levels are significantly and inversely associated with the females.22 Adiposity is also related with hypertension and diabe-
risk of RCC. The association between adiponectin levels and RCC tes, disorders clearly associated with insulin resistance, which are
risk persists after adjustment for BMI, whereas further adjustment also considered to be risk factors for RCC.23–25 The molecular
 ADIPONECTIN AND RENAL CELL CARCINOMA 1577
46,47
pathways linking obesity, especially central obesity, with RCC liferation and apoptosis, and also through suppression of the
remain to be fully elucidated, although several mechanisms have transcription factor STAT3,48 which may also regulate cell prolif-
been proposed to date. Obesity leads to increased levels of several eration, differentiation, survival and apoptosis.49
hormones including insulin as well as activation of the insulin-like Our study has several strengths, but also limitations. The size
growth factor 1 pathway, which may promote carcinogenesis.23 of the study sample is fairly large given that RCC is a relatively
Obesity may also increase the risk for RCC by increasing the cir- rare type of cancer. The exclusion of cases with cancer of the re-
culating levels of estrogens.23,33 Importantly, visceral obesity is nal pelvis, a histological type of kidney cancer distinct from
related to elevated insulin levels and insulin resistance, more RCC, prevents bias from potential inclusion of renal cancer cases
closely than overall obesity.34 with different underlying pathophysiology. We utilized state-of-
Adiponectin, a novel endogenous insulin sensitizer, is inversely the-art methodology and assays were performed blindly in 1
associated with overall and visceral obesity, as well as insulin re- batch minimizing variability. Although random misclassification
sistance.13,34–36 Of note, central obesity expressed by WHR, is remains a possibility, this could have merely attenuated the sta-
much more closely associated with decreased production of adipo- tistical significance of our findings. To eliminate any selection
nectin as well as development of insulin resistance than BMI.37 bias the main confounding factors, such as the educational level
More specifically, central fat distribution is an important, inde- and alternatively the profession (data not shown) have been con-
pendent negative predictor of adiponectin and accumulating data trolled for in the analysis. The educational level of the control
suggests that adiponectin may represent an important link between group was similar with that of the general population of the study
central obesity and the development of insulin resistance or diabe- area indicating that no major bias is likely to have been intro-
tes later in life.37–39 The negative association of adiponectin with duced in the selection of the controls. One may suggest that the
HOMA-IR (Homeostatic Model Approach-Insulin Resistance) results of this study may be biased due to the retrospective nature
index, fasting insulin and glucose levels remains significant after of case-control studies. Given however, the low incidence of
adjusting for fat mass, but becomes non-significant after adjusting RCC and the time needed to collect a sizeable group of eligible
for markers of central adiposity such as WHR or Waist Circumfer- cases, we applied this study design, which is appropriate for rare
ence, suggesting that the relation between central obesity and insu- diseases. Inherent with the study design issue is that case- control
lin resistance may be mediated, at least in part, by adiponectin.37,40 studies lack the time sequence criterion for causality; since prior
Adiponectin may also play an important role in several malig- prospective studies have also demonstrated an inverse association
nancies associated with obesity and insulin resistance, independ- between adiponectin and colon cancer, the data on RCC need to
ently of other established risk factors for cancer.16–19 Specifically, be further confirmed by cohort studies, which can prove causality
adiponectin levels are inversely associated with risk for endome- i.e. clinical prospective trials. Despite its limitations, this is the
trial,17,18 breast,16 prostate,19 gastric cancer41 as well as leuke- first study that investigated the association of adiponectin with
mia.30 In addition to these prior case- control studies,16–19 we have RCC.
found, utilizing a prospective cohort study design that men in the Our findings support the hypothesis that low adiponectin levels
highest quintile of adiponectin levels have an 60% reduced risk are significantly associated with RCC and may mediate the effect
for colorectal cancer compared with those in the lowest quintile.31 of central or visceral adiposity on the pathogenesis of RCC. Fur-
Data from the present case-control study are consistent with those ther prospective studies that incorporate the time criterion for cau-
previous studies and extend their findings by demonstrating that sality, as well as studies exploring underlying mechanisms, should
low adiponectin levels are also associated with another obesity be undertaken to confirm and expand the findings of this study.
related malignancy, i.e. RCC. Further studies for the elucidation of the molecular mechanisms
There is accumulating experimental evidence supporting the underlying the effects of adiponectin on the pathogenesis of RCC
protective role of adiponectin in the development of several types are also warranted.
of cancer, as recently reviewed elsewhere.42 In brief, increasing
levels of adiponectin improve insulin resistance and thus decrease Acknowledgements
circulating levels of insulin and insulin like growth factors
in vivo.37,43 In vitro treatment of acute myelomonocytic leukemia We thank Drs. T. Kakkavas, K. Livadas, S. Papadoukakis, A.
cell lines with adiponectin suppresses the growth of myelomono- Zarogiannos, I. Liakatas, G. Papadopoulos and A. Paschalis for
cyte cells, induces apoptosis and down-regulates Bcl-2 gene their long-standing commitment to the study as well as S. Giala-
expression.44 Adiponectin is also a direct inhibitor of angiogenesis mas, T. Katsifotis and A. Pagonis, students of the Athens Univer-
through activation of caspases in endothelial cells in vivo and sity Medical School for their valuable contribution to the study.
in vitro.45 Finally, adiponectin may act on tumor cells directly This work was supported by a pilot feasibility grant to C.S.M.
through activation of c-jun NH2-terminal kinase, a member of from Harvard Medical School, Boston. C.S.M. is a Bessel Award
mammalian MAPK family involved in the regulation of cell pro- recipient of the Humboldt Foundation.

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