Japanese Journal of Clinical Oncology Advance Access published online on February 1, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym158
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© The Authors (2008). Published by Oxford University Press. All rights reserved
Decreased Serum Adiponectin Levels in Patients with Metastatic Renal Cell Carcinoma
Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan
For reprints and all correspondence: Akio Horiguchi, Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail: impreza{at}cb3.so-net.ne.jp
Received September 11, 2007; accepted October 31, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Low levels of serum adiponectin are associated with increased risk and aggressiveness of obesity-related cancer. The purpose of the study reported here was to investigate the association between serum adiponectin levels and clinicopathological parameters of renal cell carcinoma.
Methods: Preoperative serum total and high-molecular-weight (HMW) adiponectin levels were measured in 118 patients with renal cell carcinoma, and their association with clinicopathological parameters was analysed.
Results: There were no statistically significant associations between total adiponectin and HMW adiponectin and pathological stage, regional lymph node involvement, histological grade, histological type (clear cell carcinoma versus other types) or presence of venous invasion. Total and HMW adiponectin levels in patients with metastasis, however, were significantly lower than in patients without metastasis (P = 0.044 for total adiponectin and P = 0.041 for HMW adiponectin). Low total and HMW adiponectin levels were significantly associated with metastasis in patients with a normal BMI (<25 kg/m2) (P = 0.034 for total adiponectin and P = 0.028 for HMW adiponectin) but not in overweight and obese patients (P = 0.652 for total adiponectin and P = 0.489 for HMW adiponectin). Multivariate logistic regression analysis showed that total adiponectin level was an independent predictor of metastasis of renal cell carcinoma in all patients (P = 0.024, 95% CI = 1.031–1.560) and in patients with a normal BMI (P = 0.040, 95% CI = 1.043–6.534).
Conclusions: Serum total and HMW adiponectin levels were decreased in patients with metastatic renal cell carcinoma. Adiponectin might be a molecular link between obesity and the progression of renal cell carcinoma.
Key Words: adiponectin • obesity • metabolic syndrome • kidney cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The prevalence of obesity has increased dramatically in recent years and become a serious problem (1). Obesity is a significant risk factor not only for the development of cardiovascular disorder and diabetes but also for carcinogenesis (2–7). Between 2 and 3% of all adult cancers are renal cell carcinoma and obesity is a well-known risk factor for the development of renal cell carcinoma (6). The mechanism underlying this relationship remains to be elucidated.
Adipose tissue has been shown to be not only a site of energy storage but also an important endocrine organ that produces a variety of cytokines (8). One of them, adiponectin, has recently been identified as an insulin sensitizer (8). Adiponectin has a variety of functions including anti-atherogenic, anti-diabetogenic and anti-inflammatory actions protecting against the development of obesity-related disorders such as cardiovascular disease and diabetes (8). Adiponectin exists in the circulation in a wide range of multimer complexes and combines via its collagen domain to create three major oligomeric forms: a low-molecular-weight (LMW) trimer, a middle-molecular-weight (MMW) hexamer and high-molecular-weight (HMW) 12- to 18-mer adiponectins that are the most active forms of the protein (9). Serum adiponectin levels are reduced in obese humans, particularly those with visceral obesity, and are inversely correlated with insulin resistance (8).
Adiponectin has emerged as a possible link between obesity and cancer. It has been suggested that decreased levels of serum adiponectin are associated with an increased risk for obesity-related cancers such as colon, breast, endometrial and prostate cancer (2,3,5,7). Furthermore, serum adiponectin in patients with gastric cancer has been found to be inversely correlated with pathological findings such as tumor size, depth of invasion and tumor stage in patients with gastric cancer (10). Because renal cell carcinoma is a well-known obesity-related cancer, we thought that adiponectin might play an important role in the development or progression of renal cell carcinoma. The purposes of the study reported here were to evaluate serum levels of total adiponectin and HMW adiponectin in patients with renal cell carcinoma and to investigate the association between these levels and clinicopathological parameters.
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PATIENTS AND METHODS |
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Patients
The subjects in this study were 118 consecutive patients, 82 men and 36 women from 36 to 81 year old (median age = 64), who were newly diagnosed and underwent surgical treatment for renal cell carcinoma at the National Defense Medical College between February 1995 and November 2006. Patients who had any previous history of malignancy were excluded from this study. We estimated BMI at the time of operation by dividing the patient's weight in kilograms by the square of the patient's height in meters (11). BMIs ranged from 16.43 to 40.76 (mean 23.19) in males and from 14.84 to 35.34 (mean 22.81) in females. There were 87 patients of normal weight (BMI < 25) and 31 patients who were overweight or obese (BMI
25). The follow-up intervals, from the date of operation to the last recorded follow-up, ranged from 2 to 113 months (mean = 26.4 months). All tumor tissues were evaluated for pathological staging and histological grading according to the TNM classification. The study protocol was approved by the National Defense Medical College Ethical Committee and informed consents were obtained from all participants.
Measurement of Serum Adiponectin Levels
Blood samples were obtained in the morning on the day of operation after overnight fasting. After serum separation, serum samples were stored at –70°C until they were analysed. Serum total adiponectin levels were measured by using a sandwich ELISA kit for human adiponectin (Otsuka Pharmaceutical Co. LTD., Tokyo, Japan), and serum HMW adiponectin levels were measured by using a kit for the HMW forms of human adiponectin (FUJIREBIO Co. LTD., Tokyo, Japan). Plasma fasting glucose, insulin, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) levels were measured using the same samples used to measure adiponectin levels. Insulin resistance was calculated by the Homeostatic Model Approach-Insulin Resistance (HOMA-IR) methods as follows: HOMA-IR = fasting plasma insulin (microunits/ml) x fasting plasma glucose (mg/dl)/405 (3).
Statistical Analysis
All statistical analyses were performed by using the StatView 5.0 software system for Windows (SAS Institute, Cary, NC, USA). Data are presented as means and standard errors (SE). The Spearman correlation test was used to evaluate the relations between continuous data, the Mann–Whitney U test was used to compare the serum levels of total and HMW adiponectin in different groups, univariate and multivariate logistic regression analysis was used to assess independent predictors of metastasis, and the log-rank test was used for univariate survival comparison. P-values <0.05 were considered to indicate statistical significance.
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RESULTS |
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We first assessed the relations between serum adiponectin levels and obesity-related parameters in patients with renal cell carcinoma. Total adiponectin levels ranged from 2.70 to 40.50 µg/ml (mean 9.91 µg/ml), and HMW adiponectin levels ranged from 0.80 to 28.2 µg/ml (mean 6.26 µg/ml). Total adiponectin levels were inversely correlated with BMI (r = 0.085, P = 0.0002, Fig. 1A), fasting glucose (r = 0.0063, P = 0.0059), TG (r = 0.091, P = 0.0009) and HOMA-IR (r = 0.015, P = 0.0009) and were positively correlated with HDL-C (r = 0.077, P = 0.024) and age (r = 0.036, P = 0.039). Serum levels of HMW adiponectin, which has a more important role in insulin sensitivity and in protecting against diabetes, were also inversely correlated with BMI (r = 0.080, P = 0.0003, Fig. 1B), fasting glucose (r = 0.049, P = 0.016), TG (r = 0.089, P = 0.001) and HOMA-IR (r = 0.013, P = 0.0008) and were positively correlated with HDL-C (r = 0.032, P = 0.039) and age (r = 0.052, P = 0.0127).
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Data concerning BMI and total and HMW adiponectin levels are listed in Table 1 against various pathological parameters. BMI was not significantly associated with any pathological parameters. The mean BMI of patients with metastasis (M0) disease tended to be higher than that of patients without metastasis (M1) disease, but this difference was not statistically significant (P = 0.072). There were no statistically significant associations between total adiponectin and sex, pathological T stage, regional lymph node involvement, histological grade, histological type (clear cell carcinoma versus other types) or venous invasion. Nor was there a statistically significant association between HMW adiponectin and any of these pathological parameters (Table 1). Total and HMW adiponectin levels in patients with M1 disease, however, were significantly lower than those in patients with M0 disease (P = 0.044 for total adiponectin and P = 0.041 for HMW adiponectin, Table 1 and Fig. 2). We further analysed the impact of total adiponectin and HMW adiponectin on cancer-specific survival and progression-free survival by using various cut-off values but did not find any significant difference.
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Because it has been suggested that the direction of association of adiponectin and cancer aggressiveness depend on the extent of adiposity (4), we further examined the data as stratified by the BMI categories of normal weight (BMI < 25, n = 87) and overweight and obesity (BMI
25, n = 31). In neither category total or HMW adiponectin level was significantly associated with pathological T stage, lymph node metastasis, histological grade, histological type or venous invasion. Low levels of total and HMW adiponectin were more strongly associated with metastatic disease in normal-weight patients than they were in all patients (P = 0.034 for total adiponectin and P = 0.028 for HMW adiponectin, Table 2). In overweight and obese patients, on the other hand, there was no significant association between total or HMW adiponectin levels and the presence of metastasis (Table 2).
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We further used logistic regression analysis to evaluate the significance of various clinicopathological parameters including gender, age, BMI, blood pressure, HOMA-IR, HDL-C, TG, total adiponectin, CRP level, pathological T stage, regional lymph node involvement, histological grade and venous invasion as predictors of renal cell carcinoma metastasis. Univariate analysis revealed that in the group comprising all 118 patients, HDL-C (P = 0.022, OR = 1.056, 95% CI = 1.008–1.107), total adiponectin (P = 0.044, OR = 1.174, 95% CI = 1.005–1.372), CRP (P = 0.001, OR = 1.270, 95% CI = 1.103–1.464), pathological T stage (T3–4, P < 0.0001, OR = 14.935, 95% CI = 4.237–52.632), regional lymph node metastasis (
N1, P = 0.027, OR = 6.172, 95% CI = 1.233–31.250), histological grade (Grade 3, P = 0.004, OR = 5.263, 95% CI = 1.462–18.651) and venous invasion (positive, P = 0.0013, OR = 12.668, 95% CI = 2.695–58.824) were significantly associated with distant metastasis. Multivariate analysis revealed that in the group comprising all 118 patients total adiponectin, CRP and pathological T stage were significant predictors of metastasis (Table 3). On the other hand, in patients with normal weight, BMI (P = 0.032, OR = 1.332, 95% CI = 1.025–1.730), total adiponectin (P = 0.033, OR = 1.213, 95% CI = 1.015–1.448), CRP (P = 0.0004, OR = 1.483, 95% CI = 1.195–1.845), pathological T stage (T3–4, P = 0.0004, OR = 11.627, 95% CI = 2.985–45.454), histological grade (Grade 3, P = 0.005, OR = 5.681, 95% CI = 1.531–23.256) and venous invasion (positive, P = 0.003, OR = 10.640, 95% CI = 2.160–52.632) were significantly associated with distant metastasis on univariate analysis. On multivariate analysis, total adiponectin and CRP, but not pathological T stage, were significant predictors of metastasis in patients with normal weight (Table 3).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Recent studies have revealed that adipose tissue is an important endocrine organ producing various adipocytokines (8). The most prominent are leptin and adiponectin, both of which are strongly correlated with obesity (12). We previously investigated the association of serum leptin and various clinicopathological parameters in patients with renal cell carcinoma and found that increased serum leptin levels were significantly associated with venous invasion in tumor specimens and with shortened progression-free survival, together suggesting that adipocytokines play an important role in the progression of renal cell carcinoma (11). In the present study, we therefore investigated the association of the other prominent adipocytokine, adiponectin and pathological parameters of renal cell carcinoma.
Previous studies have shown that serum adiponectin levels are decreased in patients with various types of cancer (2,3,5,7) and are inversely correlated with tumor aggressiveness in patients with gastric and prostate cancer (3,10). Spyridopoulos et al. (13) have recently reported that low adiponectin levels are significantly associated with the risk of renal cell carcinoma as well as other types of cancer. These investigators also assessed the association of adiponectin levels and pathological parameters in 70 renal cell carcinoma patients, including 8 with metastasis, and found that decreased serum adiponectin levels tended to be associated with higher tumor grades but did not find adiponectin levels to differ between M0 and M1 patients (13). In the present study, we found low serum adiponectin levels to be significantly associated with the presence of metastatic disease but not with tumor grade. Moreover, total adiponectin level was an independent predictor of metastasis in our overall patient population as well as in the patients with a normal BMI. Spyridopoulos et al. (13) measured serum adiponectin levels in 70 European patients whose average BMI was 27.5 kg/m2, and 25 of them (35.7%) were obese (BMI 30). We, on the other hand, measured serum adiponectin levels in 118 Japanese patients whose average BMI was 23.1 kg/m2 and only 5 of them (4.2%) were obese. The contradicting results with regard to the effects of serum adiponectin on pathological parameters might be due to the difference of race or to the different distributions of BMI values. When we further analysed the impact of serum adiponectin separately in patients with normal and above-normal BMIs, we found adiponectin to be significantly associated with metastasis in patients with a normal BMI but not in those with an above-normal BMI. Our data suggest that the association of adiponectin and metastasis depends on the extent of adiposity.
Adiponectin occurs in several isoforms, and distinct isoforms have different biological activities (8,9). HMW adiponectin level has been shown to be a better biomarker for insulin resistance and diabetes than total adiponectin level is (9). In addition to its function as an insulin sensitizer and anti-diabetes agent, adiponectin has a variety of anti-tumor functions (14–16). It has been shown to be an inhibitor of angiogenesis and to be associated with impaired growth of murine fibrosarcoma xenograft tumors due to decreased angiogenesis (14). Moreover, adiponectin directly suppresses the growth of prostate and breast cancer cells via inhibition of STAT3 and ERKs signaling pathways (15–17). Interestingly, Bub et al. (15) have reported that HMW adiponectin has more potent antitumor activity against DU145 prostate cancer cells than LMW adiponectin does. Therefore, we presumed that HMW adiponectin might be a better parameter than total adiponectin. We evaluated for the first time the impact of HMW adiponectin on clinicopathological parameters but found that HMW adiponectin level does not provide any information that total adiponectin does not.
Although obesity is a widely accepted risk factor for the development of renal cell carcinoma, it remains unclear whether obesity is associated with its aggressiveness and with survival. Increased body weight has recently been shown to be associated with increased death rates for cancers at multiple sites (18), but several studies have suggested that in patients with renal cell carcinoma a higher BMI is associated with better clinicopathological features such as a better prognosis and a lower likelihood of distant metastasis (19,20). Our results showed that M0 patients tend to have a higher BMI than M1 patients do, although the difference between these two groups of patients does not reach statistical significant (P = 0.072, Table 1). This might suggest that M1 patients had suffered some degree of cancer-induced cachexia and had lost weight. Interestingly, our results showed that M0 patients tend to have a greater BMI and higher serum adiponectin levels than M1 patients do, which is inconsistent with the inverse association between BMI and serum adiponectin level. Although high adiponectin levels are found in patients with weight loss due to anorexia nervosa, Wolf et al. (21) found no significant elevation of adiponectin levels in patients suffering from cancer-induced cachexia. One possible explanation for this discrepancy might be that cancer-induced cachexia, unlike starvation or other cachectic states, is often characterized by preferential loss of skeletal muscle rather than adipose tissue (21). Because serum adiponectin levels are determined predominantly by adipose tissue, especially by visceral fat components (12), an index combining BMI with the distribution of adipose tissue might provide better prognostic information in cases of renal cell carcinoma.
One limitation of our study is that we could not assess the distribution of adipose tissue. Spyridopoulos et al. (13) reported that the waist-to-hip ratios of patients with renal cell carcinoma are significantly higher than those of controls. Further studies should see if the progression of renal cell carcinoma can be better predicted by parameters combining adiponectin levels with the visceral fat area. Another limitation of our study is that we did not take into consideration the effects of the antihypertensive and/or antihyperlipidemic drugs that about half of the patients had taken regularly. Recent studies have reported that angiotensin II receptor blockers and HMG-CoA reductase inhibitors significantly increased serum adiponectin levels in Japanese patients (22,23). Despite these limitations, we think our results are important and that adiponectin could link obesity and the progression of renal cell carcinoma.
Conflict of interest statement None declared.
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