ABSTRACT. Background/Aims: Adiponectin is secreted from adipose tissue and is characterized by hyperinsulinemia,

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1 1841 Tissue and Serum Adiponectin Levels in Patients with Gastric Cancer: Are there any Correlations between Adiponectin Levels and Histopathological Variables? Mesut Seker 1, Ahmet Bilici 1, Derya Oztas Guler 2, Bala Basak Ustaalioğlu 1, Hülya Gozu 3, Fatih Yavuz Erkal 2, Berkant Sonmez 1, Mehmet Karaduman 3, Umut Kefeli 1, Emre Yildirim 1, Taflan Salepci 1 and Mahmut Gumus 1 1 Department of Medical Oncology, 2 Department of Internal Medicine, 3 Department of Endocrinology and Diabetes, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey Corresponding author: Mesut Seker, Altaycesme Mah, Sarıgul sok, Kuralkan Apt, A1 Blok, 4/18, Maltepe, Istanbul, Turkey Tel: , Fax: , drmesutseker@gmail.com ABSTRACT Background/Aims: Adiponectin is secreted from adipose tissue and is characterized by hyperinsulinemia, which is related with obesity. Adiponectin levels are significantly lower in gastric cancer patients than in healthy controls. The aim of this study was to investigate the relationship between adiponectin levels in serum, tumor tissue and normal tissue with some other insulin resistance parameters. Methodology: A total of 35 patients with gastric cancer who had undergone curative gastrectomy by standard lymph node dissection were enrolled in this study. Their serum adiponectin levels, tumor tissue and normal breast tissue adiponectin levels were compared. Results: The mean adiponectin levels of the tumor tissue, normal gastric tissue and serum were 48.6±2.9 (range, ), 48.3±4.2 (range, ) and 49.4±0.83 (range, ), respectively. There was no relationship between the adiponectin levels in serum, normal tissue and tumor tissue (p=0.08). There was an inverse relationship between normal tissue adiponectin levels and insulin levels (p=0.002, r=-0.5), but this association was not detected with adiponectin levels in tumor and serum (p>0.05). Conclusions: Relationships between adiponectin levels in serum, normal tissue and tumor tissue for gastric cancer patients were not found. The small sample size in this study may have influenced the results. However, we believe that our results constitute a first in evaluating the tissue adiponectin levels in gastric cancer tissue. KEY WORDS: Adiponectin; Insulin resistance; Gastric cancer. INTRODUCTION Obesity is a risk factor for the development of cardiovascular disorders and diabetes mellitus, which are closely related with angiogenesis. In addition, it has recently been shown that obesity is associated with an increased risk for several malignancies (1,2). In gastric cancer, obesity is documented to be especially associated with the development of adenocarcinoma in the cardiac region (3,4). This association is thought to be partly explained by the increased rate of gastroesophageal reflux disease as a result of increased intra-abdominal pressure (5-7). Nevertheless, the reflux theory cannot explain every aspect of the manifestation of gastric cancer and epidemiological studies have raised a hypothesis that adipose tissue might functionally lead to the development of gastric cancer. Adipocytokines, such as adiponectin and leptin, are secreted primarily by visceral adipose tissue (8,9). Adiponectin is a 247-amino acid adipocytokine Hepato-Gastroenterology 2011; 58: H.G.E. Update Medical Publishing S.A., Athens that has an increasingly important role in energy homeostasis and insulin sensitivity. It has been isolated during adipocyte differentiation of 3T3-L1 and 3T3-F442A fibroblasts and from large-scale sequencing of the human adipose cdna library (10). The negative correlations between plasma adiponectin levels and obesity (11), adiposity, waist to hip ratio (12), diabetic dyslipidemia (13), cardiovascular disease (14) and insulin resistance (12) have been reported in human cross-sectional studies. On the other hand, circulating adiponectin levels seem to be associated more with hyperinsulinemia and insulin resistance compared to obesity and body fat (12). The case-control studies showed that low plasma adiponectin was an independent risk factor for development of type 2 diabetes (15) but not for obesity (16). These findings suggest that adipocytokines contribute to the induction of carcinogenesis and tumor progression. Previous studies have indicated that serum adiponectin levels were decreased in patients with

2 1842 Hepato-Gastroenterology 58 (2011) M Seker, A Bilici, DO Guler, et al. breast or endometrial cancer (17-19). Similarly, they showed that plasma adiponectin levels were significantly lower in gastric cancer patients than in healthy controls (5,20). Recently, and in contrast to other trials (21), we showed that there was no difference in serum adiponectin levels among gastric cancer patients and the control group. The aim of the present study was to investigate the nature of the relationship between adiponectin levels in serum, tumor tissue and normal tissue with some other insulin resistance parameters, such as glucose, insulin, body mass index (BMI), C- peptid, the homeostasis model assessment (HOMA) and lipid levels in gastric cancer patients. In addition, the correlation of adiponectin levels with histopathological parameters was also evaluated. METHODOLOGY A total of 35 patients with gastric cancer who had undergone curative gastrectomy by standard lymph node dissection, at the Department of Medical Oncology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, were enrolled in this study. Clinical information was obtained from the patients charts and included age, gender, resection type, tumor location, histopathology, tumor stage, tumor size, histological grade, the depth of tumor invasion, lymphatic vessel invasion, vascular invasion and perineural invasion. Tumor localization was classified as fundus, corpus, antrum and all of the stomach. Normal gastric tissues, which were obtained from the same patient with gastric cancer, were used as the controls. Blood samples were collected from the antecubital vein before the operation, followed by 12 hour fasting to evaluate plasma adiponectin, c-peptide, insulin, glucose, HbA1c and lipid values. Samples for plasma adiponectin level measurement were centrifuged at 3000rpm for 10 minutes in order to separate the serum and they were then stored in dry tubes at -70 C according to manufacturer recommendations until the study initiation day. Tumor tissues and normal gastric tissues of the patients were collected as fast as possible and maintained at -70 C until the study. On the study day frozen tissue samples were homogenized in homogenized buffer (50mM HEPES, 0.2% Triton X-100, 1mM EDTA and 0.1mM PMSF, ph7.4) at 13500rpm in Ultraturrax T25 (Janke & Kunkel, IKA Labortechnic, Staufen, Germany) according to the procedure described by Karaduman et al. Serum samples were melted at room temperature on the day of homogenization. Whole adiponectin samples (tissue and serum) were studied with the Assaymax Human Adiponectin (Acrp30) Elisa Kit (ASSAYPRO, MO, USA) and they were transferred to a blank ELISA plate. Informed consents and approval were taken from patients and the ethics committee of the hospital. Other laboratory tests, except for adiponectin, were studied in biochemistry and microbiology laboratories of the hospital. The BMI of the patients was calculated by using the Quetelet index (Quetelet index=weight (kg)/height (m²)). Measuring tape was used for waists and hips of patients. Following this the adiponectin levels of plasma, tumor tissue and normal tissue were analysed and the results were compared with other parameters. Statistical analysis Statistical analyses were performed using SPSS 13.0 software (SPSS Inc., Chicago, IL, USA). A confidence interval of 95% and mean±sd (standard deviation) was used for continuous variables. Normality of the data was calculated using the Kolmogorov-Smirnov test. Normal distribution parameters were compared using the Student s t-test. The Kruskal-Wallis H test was used for distributed data that did not assume normal distribution. For the correlation between adiponectin levels, insulin sensitivity parameters and clinicopathological parameters of the patients, Pearson and Spearman correlation analyses were used. A p value of 0.05 was considered as statistically significant. RESULTS Twenty-four women (68.6%) and eleven men (31.4%) were enrolled in the study. The mean age of the patients was 53 years, (range, 41-85). The mean BMI was calculated as 24.4±4.2kg/m² (range, 16-36). Based on the biochemical results of the patients, the mean glucose, insulin, c-peptide, HbA1c, LDL cholesterol, HDL cholesterol, total cholesterol and triglyceride levels were 97.7±14.4mg/dL (range, ), 6.6±3.4µU/mL (range, ), 2.3±0.9ng/mL (range, ), 5.3±0.4% (range, ), 101.2±30.8mg/dL (range, ), 39±9.5mg/ dl (range, 20-68) 161.7±36.7mg/dL (range, ) and 107.6±36mg/dL (range, ), respectively. Demographics and biochemical results of the patients are summarized in Table 1. TABLE 1 Demographics and Biochemical Results of the Patients Parameters Mean (range or %) Age 61.7 (41-85) Gender Female 24 (68.6%) Male 11 (31.4%) BMI (kg/m²) 24.4±4.2 (16-36) Glucose (mg/dl) 97.7± 14.4 (76-134) Insulin (uu/ml) 6.6±3.4 (0.5-15) C-peptide (ng/ml) 2.3±0.9 ( ) LDL (mg/dl) 101.2±30.8 (42-178) HDL (mg/dl) 39±9.5 (20-68) T. cholesterol (mg/dl) 161.7±36.7 (88-244) Triglyseride (mg/dl) 107.6±36 ( ) HbA1c (%) 5.3±0.4 ( ) T.cholesterol: Total cholesterol, HDL: High-density lipoprotein, LDL: Low-density lipoprotein, HbA1c: Haemoglobin A1c.

3 Adiponectin Levels in Patients with Gastric Cancer Hepato-Gastroenterology 58 (2011) 1843 Twenty-two (62.9%) patients underwent total gastrectomy and thirteen (37.1%) patients underwent subtotal gastrectomy. Based on the macroscopical appearance of tumor tissue, 1 patient (2.9%) was classified as polypoid, 13 (37.1%) as ulcerovegetan and 21 (60%) as ulceroinfiltrative. Tumors were located in the upper stomach in 5 (14.3%) patients, in the middle stomach in 10 (28.6%) patients, in the lower stomach in 17 (48.6%) patients and in the entire stomach in 3 (8.5%) patients. Concerning the depth of invasion, 1 patient had T0 (2.9%), 1 (2.9%) patient had T1, 9 (25.7%) patients had T2, 22 (62.8%) patients had T3 and 2 (5.8%) patients had T4 tumors. While tumors of 24 (68.6%) patients were poorly differentiated, tumors of the remaining 11 (31.4%) patients were moderately differentiated, however, there were no well-differentiated tumors. Vascular invasion was detected in 29 (82.9%) tumors, perineural invasion and lymphatic vessel invasion were found to be positive in 86% and 92% of patients, respectively. Peritoneal involvement was histopathologically confirmed in only 5 (14.3%) patients, so the majority of patients (n=30, 85.7%) had no peritoneal involvement. Pathological staging revealed that 3 (8.6%) patients had stage I disease, 9 (25.7%) patients had stage II disease, 18 (51.4%) patients had stage III disease and 5 (14.3%) patients had stage IV disease. Clinicopathological features of the patients are shown in Table 2. The mean adiponectin levels in the tumor tissue, normal gastric tissue and serum were 48.6±2.9ng/ ml (range, ), 48.3±4.2ng/mL (range, ) and 49.4±0.83ng/mL (range, ), respectively (Figure 1). There was no relationship between the adiponectin levels of serum, normal tissue and tumor tissue (p=0.08). A correlation between tumor tissue adiponectin and cholesterol levels was found (p=0.04, r=0.344). There were positive correlations between serum cholesterol and serum adiponectin, and normal tissue adiponectin levels (p=0.26, r=0.197 and p=0.27, r=0.192, respectively) but these relationships were not significant. There was an inverse relationship between normal tissue adiponectin levels and insulin level (p=0.002, r=-0.5), but this association was not detected with adiponectin levels of tumor and serum (p>0.05). Serum adiponectin levels were significantly associated with tumor localization (p=0.03, r=0.358). However, an inverse correlation between serum adiponectin levels and perineural invasion was found (p=0.02, r=-0.384). In the subgroup analysis, adiponectin levels of the serum, normal and tumor tissue in women were not different compared with those of male patients (p>0.05). No relationships were detected among tumor stage, grade, nodal status, lymphatic vessel invasion and vascular invasion and the levels of serum, normal and tumor tissue adiponectin (p>0.05). There was a negative correlation between insulin level and normal tissue adiponectin level (p=0.002, TABLE 2 Clinicopathological Features of the Patients with Gastric Cancer (n=35) Type of surgery n (%) Total gastrectomy 22 (62.9) Subtotal gastrectomy 13 (37.1) Tumor localization Upper stomach 5 (14.3) Middle stomach 10 (28.6) Low stomach 17 (48.6) Entire stomach 3 (8.5) Macroscopic appearance Polypoid 1 (2.9) Ulcerovegetan 13 (37.1) Ulceroinfiltrative 21 (60) Depth of invasion T0 1 (2.9) T1 1 (2.9) T2 9 (25.7) T3 22 (62.8) T4 2 (5.8) Tumor differentiation Poor differentiated 24 (68.6) Moderately differentiated 11 (31.4) Well differentiated 0 (0) Vascular invasion Present 29 (82.9) Absent 6 (17.1) Perineural invasion Present 30 (85.7) Absent 5 (14.3) Lymphatic vessel invasion Present 32 (91.4) Absent 3 (8.6) Peritoneal invasion Present 5 (14.3) Absent 30 (85.7) Clinical stage I 3 (8.6) II 9 (25.7) III 18 (51.4) IV 5 (14.3) r= 0.496). An inverse relationship between normal tissue adiponectin and BMI was found (p=0.039, r= 0.351). On the other hand, relationships were not detected between serum adiponectin level and BMI, and tumor tissue adiponectin level and BMI in this study (p=0.290, r=0.184 and p=0.797, r=0.045, respectively).

4 1844 Hepato-Gastroenterology 58 (2011) M Seker, A Bilici, DO Guler, et al. FIGURE 1 Mean adiponectin levels in the serum, tumor tissue and normal tissue. DISCUSSION To the best of our knowledge this is the first study to have simultaneously investigated adiponectin levels in normal and tumor tissue and also in plasma of patients with gastric cancer. Our results showed that there was no correlation between adiponectin levels of serum, normal tissue and tumor tissue. Three case-control studies have been reported regarding serum adiponectin levels in gastric cancer patients up until now (5,20,21). In these studies, adiponectin was only examined in blood samples. In the first trial, including 75 gastric cancer patients and 52 healthy controls, carried out by Ishikawa et al., plasma adiponectin levels were significantly lower in patients than in healthy controls (5). In addition, the authors showed that there was a significantly modest inverse relationship between plasma adiponectin levels and gastric cancer, although BMI was not significantly different. They concluded that a low plasma adiponectin level was associated with an increased risk of gastric cancer. The second trial was recently reported by Nakajima et al. In their trial, the levels of BMI, adiponectin, leptin, resistin, visfatin and C-peptide in blood samples at diagnosis were measured in 156 gastric cancer patients and 156 age- and gendermatched controls (20). They indicated that plasma adiponectin, C-peptide and BMI levels were significantly lower, and resistin and visfatin levels were significantly higher in the patients in a multivariate analysis. The inverse correlation between BMI and adiponectin levels was comparatively strong in the controls, but was weak in patients. Moreover, the authors compared plasma adiponectin levels in 38 patients with stage I gastric cancer with the controls in a subgroup analysis and they found that the serum adiponectin level tended to decrease in patients. The BMI level was not found to be different between the two groups (20). In this trial an inverse relationship between normal tissue adiponectin levels and BMI was found (p=0.039, r=-0.351). On the other hand, there was no relationship between serum adiponectin levels and BMI or tumor tissue adiponectin levels and BMI (p=0.290, r=0.184 and p=0.797, r=0.045, respectively). The expression of adipocytokines in human adipose tissue and the corresponding circulating concentrations are under the influence of the body fat mass. In six of the seven adipocytokines, plasma levels are positively correlated with BMI and are elevated in obesity; the exception is adiponectin, for which the correlation is a negative one (21). In the current study, we found a positive correlation between serum adiponectin and BMI, but it was not statistically significant. The nutritional status of patients with cancer might also affect the serum adiponectin level. However, in the study by Ishikawa et al., there were no significant associations between preoperative albumin, total protein, total cholesterol, triglyceride and cholinesterase with adiponectin levels (5). In this study a significant relationship was found between tumor tissue adiponectin and cholesterol levels (p=0.04, r=0.344). There were positive correlations between cholesterol and serum adiponectin, and normal tissue adiponectin, (p=0.26, r=0.197 and p=0.27, r=0.192, respectively) but these relationships were not significant. Therefore, the difference between plasma and normal gastric tissue adiponectin levels was not attributable to nutritional status. In contrast to the promotional effects of leptin, TNF-alpha and IL-6 on insulin resistance, adiponectin is emerging as having a protective role in the maintenance of insulin sensitivity. Plasma adiponectin concentration is inversely correlated with fasting plasma insulin. Adiponectin increases the sensitivity of the tissues to insulin and hypoadiponectinaemia is associated with insulin resistance. Furthermore, a causal relationship between adiponectin and the sensitivity of target tissues to insulin was indicated by the observation that a reduction in the plasma adiponectin level preceded the loss of insulin sensitivity. The degree of hypoadiponectinaemia is more closely related to the severity of insulin resistance than it is to the BMI (22). In this study there was a negative correlation between insulin level and normal tissue adiponectin level (p=0.002, r=-0.496). There were also positive correlations between serum adiponectin and insulin and tumor tissue adiponectin and insulin, but these correlations were not statistically significant (p=0.723 and p=0.396, respectively). Recently, we investigated the relationship between serum adiponectin levels, demographic features and histopathological variables in gastric cancer patients (23). Forty consecutive patients with gastric cancer who had undergone curative gastrectomy with standard lymph node dissection and forty-three healthy controls were analyzed. The serum levels of glucose, insulin, C-peptide, HbA1c and adiponectin were measured in both groups. In this study, we indicated that there were

5 Adiponectin Levels in Patients with Gastric Cancer Hepato-Gastroenterology 58 (2011) 1845 no differences in terms of adiponectin, C-peptide and HOMA-R levels in both groups. There was no correlation between the levels of adiponectin, BMI, insulin and c-peptide in the patient group. The adiponectin levels of women were significantly lower than those of male patients. No relationships were detected between tumor stage, tumor localization, nodal status, lymphatic and vascular invasion, and the levels of serum adiponectin. Interestingly, a positive correlation was found between tumor grade and plasma adiponectin levels. In contrast to other trials (5,20), our results (23) suggested that plasma adiponectin levels were similar in both gastric cancer patients and the controls. In addition, no correlation was found between adiponectin levels and demographic features or histopathological variables of patients. But, in undifferentiated tumors plasma adiponectin levels were significantly high compared with well-differentiated tumors (23). In case-control studies, a significant decrease in adiponectin levels has been previously documented in patients with breast, endometrial, prostate and colon cancers and myelodysplastic syndrome, in addition to gastric cancer (5,24,25). Karaduman et al. showed that tissue adiponectin levels were significantly high in breast cancer patients and this was associated with an increased risk of breast cancer (26). Recently, we compared adiponectin levels in plasma, breast tissue with tumor and normal breast REFERENCES Calle EE, Rodriguez C, Walker-Thurmond K, et al.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: Bergstrom A, Pisani P, Tenet V, et al.: Overweight as an avoidable cause of cancer in Europe. 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6 1846 Hepato-Gastroenterology 58 (2011) M Seker, A Bilici, DO Guler, et al Seker M, Bilici A, Sonmez B, Ustaalioğlu BB, Gumus M, Gozu H, Sargin M, Orcun A, Gezen C, Eser M, Bildik N, Salepci T: The association of serum adiponectin levels with histopathological variables in gastric cancer patients. Med Oncol 2010; 27: Wei EK, Giovannucci E, Fuchs CS, et al.: Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst 2005; 97: Dalamaga M, Karmaniolas K, Nikolaidou A, et al.: Adiponectin and resistin are associated with risk for myelodysplastic syndrome, independently from the insulin- like growth factor-i (IGF- I) system. Eur J Cancer 2008; 44: Karaduman M, Bilici A, Ozet A, Sengul A, Musabak U, Alomeroglu M: Tissue levels of adiponectin in breast cancer patients. Med Oncol 2007; 24(4): Sonmez B, Seker M, Bilici A, Yavuz Erkal F, Oven Ustalioglu BB, Gumus M, Ozturk Guler D, Karaduman M, Gezen C, Eser M, Bildik N, Salepci T: Is there any correlation among adiponectin levels in serum, tumor tissue and normal tissue of the same patients with breast cancer? J BUON. 2011; 16: