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Clinical Cancer Research Vol. 11, 466-472, January 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

Plasma Adiponectin and Gastric Cancer

Makoto Ishikawa1, Joji Kitayama1, Shinsuke Kazama2, Takeyuki Hiramatsu2, Kenji Hatano1 and Hirokazu Nagawa1

1 Department of Surgery, Division of Surgical Oncology, University of Tokyo, Bunkyo-ku, Tokyo, Japan and 2 Department of Surgery, Yaizu Municipal Hospital, Yaizu-City, Shizuoka, Japan

Requests for reprints: Makoto Ishikawa, Department of Surgical Oncology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-3815-5411, ext. 33246; Fax: 81-3-3811-6822; E-mail: makoto-ishi{at}umin.ac.jp.


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Recently, increased body weight has been associated with an increased risk of cancers at multiple specific sites, including gastric cancer. Adiponectin is a peptide hormone secreted by adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Moreover, the circulating level of adiponectin has been reported to be inversely related to body mass index.

Methods: Fasting plasma levels of adiponectin were determined in 75 patients with gastric cancer and 52 healthy controls using an ELISA. In these patients, we analyzed the association between plasma adiponectin level and gastric cancer risk as well as various clinicopathologic characteristics.

Results: Plasma adiponectin level was significantly lower in patients with gastric cancer than in healthy controls (9.1 ± 6.2 versus 13.3 ± 9.4 ng/mL, P < 0.01) and showed a significant modest inverse relation with the gastric cancer (odds ratio, 0.92; 95% confidence interval, 0.85-0.97; adjusted odds ratio, 0.89; 95% confidence interval, 0.84-0.95], although body mass index was not different. In addition, adiponectin level was extremely low in patients with upper gastric cancers (upper, 5.5 ± 4.1 ng/mL; middle, 9.7 ± 6.4 ng/mL; lower, 10.7 ± 4.1 ng/mL; P = 0.012). Furthermore, adiponectin level tended to decrease as the tumor stage increased (stage I, 9.9 ± 6.9 ng/mL; stage II, 8.7 ± 5.5 ng/mL; stage III, 8.6 ± 4.1 ng/mL; stage IV, 5.2 ± 6.2 ng/mL; P = 0.34). Interestingly, in 32 patients with undifferentiated cancer, serum adiponectin showed a negative correlation with pathologic findings such as tumor size, depth of invasion, as well as tumor stage (P < 0.05), but no correlation in the remaining 43 patients with differentiated cancer.

Conclusions: Our results suggest that a low plasma adiponectin level is associated with an increased risk for gastric cancer and raise the possibility that adiponectin has a potential role in the progression of gastric cancer, especially in undifferentiated type cancers in the upper stomach.

Key Words: gastric cancer • plasma adiponectin • obesity


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adipose tissue produces various growth factors and hormones including angiotensinogen, plasminogen activator inhibitor 1, acylation-stimulating protein, interleukin 6, tumor necrosis factor {alpha} (TNF-{alpha}), resistin, and leptin (1). Adiponectin is a peptide hormone secreted exclusively by adipose tissue and acts as an antiatherogenic hormone through the inhibition of proliferation of vascular smooth muscle cells and endothelial cells (2, 3). The hormone is also related to the pathogenesis of diabetes through the modulation of glucose and fatty acid metabolism and insulin sensitivity in various stromal and epithelial cells (4–6). The circulating level of adiponectin has been reported to be inversely related to body mass index (BMI;ref. 7–9) and to be reduced in conditions of insulin resistance and hyperinsulinemia such as visceral obesity and type 2 diabetes (6).

Obesity is a risk factor for the development of cardiovascular disorders and diabetes, which are closely linked to angiogenesis. In addition, increased body weight has recently been shown to be associated with increased death rates for cancers at multiple specific sites (10). Consistently, there have been many studies showing a positive association between adiposity and increased risk of cancer of the endometrium, kidney, colon, and gallbladder in women, and breast cancer in postmenopausal women (11–16).

Previous studies have shown that circulating adiponectin is decreased in patients with breast or endometrial cancer (17–20). In gastric cancer, it is well known that the frequency of adenocarcinoma in the cardia is positively related to obesity, and the reason is considered to be increased gastroesophageal reflux (21–24). Even in gastric cancers including noncardia adenocarcinoma, several studies have reported an inverse association between a diet low in fruits and vegetables and the risk of gastric cancer (25–30). In this study, we therefore evaluated plasma adiponectin levels in patients with gastric cancer by ELISA assay, and delineated the possible role of this adipokine in the development and spread of gastric cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Plasma adiponectin concentration was examined in 75 patients with gastric cancer (cases) who were treated by curative gastrectomy with standard lymph node dissection at the First Department of Surgery, Tokyo University Hospital, Tokyo, and the Yaizu Municipal Hospital, Shizuoka, during 2003 to 2004. All the resected primary tumors and regional lymph nodes were histologically examined by H&E staining according to the Japanese Classification of Gastric Carcinoma (31). Tumors were histologically classified into two types based on the predominant features: differentiated type (well and moderately differentiated adenocarcinoma) and undifferentiated type (poorly differentiated adenocarcinoma and signet ring cell carcinoma). In addition, we examined several discrete histologic parameters, including lymphatic invasion, venous invasion, and lymph node metastasis.

A fasting morning blood sample was obtained for adiponectin assay after admission. Samples were also obtained from 52 controls who participated in the gastric cancer screening program at the affiliated institutes in Tokyo and Shizuoka and were confirmed as free from gastric cancer by physical examination and upper gastrointestinal examination during 2003 to 2004. These control patients also showed no abnormality in routine blood tests, urine and stool occult blood tests, chest X-ray examination, and abdominal ultrasonography, and thus were considered to be free of malignancy. In each patient, written informed consent was obtained, and the final response rate of cases was 99% (75 of 76) and that of controls was estimated to be 50%.

Weight and height was obtained by medical staff. BMI was calculated as weight in kilograms divided by height in square meters. All data were measured by medical staff. The serum was immediately separated by centrifugation and stored at –80°C until use. Plasma adiponectin levels were determined using an adiponectin ELISA kit (Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan; ref. 32). Adiponectin standards were prepared using recombinant human adiponectin, with a sensitivity of 0.47 ng/mL and intra-assay and interassay coefficients of variation of 4.32% and 9.82%, respectively. All statistical calculations were carried out using StatView-J 5.0 statistical software (SAS Institute, Cary, NC). The relationship between the plasma adiponectin level and various clinicopathologic characteristics of gastric cancer was evaluated by Student's exact tests, Fisher's exact tests, and Spearman rank test. To study the association of adiponectin level with gastric cancer, odds ratio (OR) was examined using multiple logistic regression analysis, including age, sex, and BMI as predictive valuables. Differences with a P value ≤ 0.05 were considered to be statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Plasma Adiponectin Was Reduced in Patients with Gastric Cancer
As shown in Table 1, no significant differences were observed in age, sex, and BMI between patients and controls. However, plasma adiponectin level was 9.1 ± 6.2 ng/mL in patients with gastric cancer, which was significantly lower than that in healthy controls (13.3 ± 9.4 ng/mL; P < 0.01). Moreover, as shown in Fig. 1, adiponectin concentration gradually decreased with increase in tumor stage (stage I, 9.9 ± 6.92 ng/mL; stage II, 8.7 ± 5.52 ng/mL; stage III, 8.6 ± 4.12 ng/mL; stage IV, 5.2 ± 6.2 ng/mL; P = 0.34). In contrast, BMI tended to be decreased in advanced stages, although the difference was not statistically significant.


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  		Table 1 Clinical characteristics of cases and controls

 


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  		Fig. 1 Plasma adinopectin concentration in healthy controls and patients with different stages of gastric cancer.

 
Low Plasma Adiponectin Was a Risk Factor for Gastric Cancer
Next, we did multiple logistic regression analysis to compute ORs and 95% confidence intervals (CI) for gastric cancer for a 1 SD increment of adiponectin (Table 2). The crude OR of low plasma adiponectin was 0.92 (P < 0.05) and the adjusted OR was reduced to 0.89 if the potential confounding variables in Table 1 were included (P < 0.005). Thus, plasma adiponectin level showed a significant modest inverse relation with the development of gastric cancer, suggesting the possibility that low circulating adiponectin level could be a new risk factor for gastric cancer.


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  		Table 2 Multiple logistic regression-derived adjusted OR and 95% CI for gastric cancer for a change in adiponectin of 1 SD in controls

 
Plasma Adiponectin and Clinicopathologic Characteristics of Tumors
The median value of plasma adiponectin level was 8.0 ng/m. Therefore, the patients were divided into low (n = 34) and high (n = 41) groups by the cutoff value of 8.0, and the clinicopathologic characteristics were compared between the two groups (Table 3). No significant difference was observed in age, depth of tumor invasion, histologic type, venous invasion, lymphatic invasion, lymph node metastasis, and tumor stage between the two groups. In male patients, 29 (56.9%) of 51 showed low adiponectin levels, whereas 5 (23.8%) of 21 female patients were categorized in the low group. More interestingly, when the stomach was anatomically divided into three portions (upper, middle, and lower parts; ref. 31), adiponectin levels in patients with upper gastric cancer were lower than those in patients with cancers in the middle or lower part (Table 3; Fig. 2). However, BMI did not significantly differ according to tumor location, suggesting that the reduced adiponectin levels were not attributable to the patients' physique. Among these 75 patients, 1 and 3 cases had hematogenous metastasis and peritoneal dissemination at surgery, respectively. All 4 cases were categorized in the low-adiponectin-level group.


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  		Table 3 Relationship between plasma adiponectin level and clinical and pathologic characteristics of gastric cancers

 


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  		Fig. 2 Plasma adinopectin concentration in each part of the stomach.

 
Plasma Adiponectin Had an Inverse Relation with Tumor stage in Undifferentiated Carcinoma but Not in Differentiated Carcinoma
Next, we separately evaluated the clinicopathologic features in tumors with differentiated or undifferentiated histologic type, because they show considerably different biological characteristics (Table 4). The mean adiponectin level was 9.1 ± 6.6 and 8.9 ± 5.4 ng/mL in patients with differentiated and undifferentiated carcinoma, respectively (P = 0.89). As shown in Table 3, adiponectin level was correlated with BMI only in differentiated type (P < 0.05). On the contrary, in undifferentiated type, adiponectin was not correlated with BMI but was correlated with some progression-related factors. Tumor size was significantly larger in the low group (70.9 ± 48.2 mm) than in the high group (39.1 ± 27.7 mm; P < 0.05). In addition, the percentage of patients in the low-adiponectin group increased with increase in the depth of invasion and tumor stage (P < 0.05) and positive lymphatic invasion (P < 0.05). Venous invasion and lymph node metastasis also tended to be more frequent in the low group than in the high group, although the difference was not statistically significant.


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  		Table 4 Relationship between plasma adiponectin level and clinical and pathologic characteristics of patients with differentiated or undifferentiated gastric cancer

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results clearly indicate that plasma adiponectin levels were significantly decreased in patients with gastric cancer as compared with controls, and that low circulating adiponectin is another risk factor for gastric cancer. In fact, BMI was not statistically significantly different between cases and controls, providing a new insight into the association between this adipokine and the development of gastric cancer. Nutritional status in patients with cancer might also affect the serum adiponectin level. However, none of preoperative albumin, total protein, total cholesterol, triglyceride, and cholinesterase showed a significant association with adiponectin level in our series (data not shown). This indicates that the difference in plasma adiponectin level was not attributable to the nutritional status.

Maeda et al. reported that the expression and secretion of adiponectin by adipocytes were significantly reduced by TNF-{alpha} in a dose- and time-dependent manner via its promoter activity (33). Other reports have shown that the expression of adiponectin mRNA was reduced in the adipose tissue of insulin-resistant obese humans and rodents, in which TNF-{alpha} production was increased (34, 35). Because cancer development is often associated with inflammatory processes, these findings suggest that local production of TNF-{alpha} might be partially responsible for the relation between adiponectin and carcinogenesis.

Recently, Mueller et al. reported that many fat-specific cytokines including adiponectin were significantly up-regulated in mice that acquired long-term protective immunity by immunization with Helicobacter felis with cholera toxin as a mucosal adjuvant (36). Because it is well known that Helicobactor pylori infection is strongly related to the development of gastric cancer (37–41), it is reasonable that low adiponectin in the mucosa facilitates H. pylori infection, which may be involved in the development of gastric cancer.

It has been reported that diets with a high glycemic load are directly related to gastric cancer risk (42). In obese people, a decreased level of adiponectin is often associated with an increased serum insulin level, and insulin has been shown to act as a cancer-promoting agent in both in vitro and animal studies (43, 44), possibly through increased activity of insulin-like growth factor I (IGF-I; ref. 45). IGF-I inhibits apoptosis, increases production of vascular endothelial growth factor (45), and has been linked to increased mitogenesis in gastric cancer cell lines (46, 47). In fact, higher levels of IGF-I have been found in patients with gastric cancer compared with healthy controls (48). This is consistent with the results of early studies on the risk of prostate (49–51), breast (52, 53), colorectal (54), pancreas (55), and lung (56) cancer. These findings strongly suggest that low adiponectin level together with high IGF-I level can promote the carcinogenesis of gastric cancer.

Recently, it has been shown that adiponectin potently inhibits endothelial cell proliferation and migration and induces a cascade of activation of caspases-8, -9, and -3, which leads to cell death (57). This suggests another possibility that adiponectin has a positive role in preventing pathologic angiogenesis and thus, a reduced adiponectin level facilitates the development of gastric cancer.

Some studies have shown that the risk for adenocarcinoma of the gastric cardia was higher in obese people than in normal counterparts. It has been generally accepted that obesity is one of the main risk factors for adenocarcinoma of the gastric cardia (23, 58–60), possibly through the increased rate of gastroesophageal reflux disease as a result of increased intra-abdominal pressure (60–65). Our study also showed a strong correlation between adiponectin level and the development of upper gastric cancer. However, the reflux theory cannot explain every aspect of the manifestation of gastric cardia adenocarcinoma, because BMI did not show a difference among patients with different tumor locations. Analysis of the real molecular mechanisms of this adipokine in tumor development is an attractive research target.

Another important finding of this study is that the stage was inversely related to the plasma adiponectin level in undifferentiated gastric cancer. On the other hand, this tendency was not observed in patients with differentiated gastric cancer. This was a clear contrast between the two groups and thus may reflect a biological difference between differentiated and undifferentiated gastric cancer. However, such a correlation between adiponectin level and tumor stage has never been described in previous reports on breast and endometrial cancer (17–20), and thus far, this is the first report to suggest the possible role of adiponectin in tumor progression. Our finding suggests the possibility that adiponectin may prevent invasion or metastasis, and that a decrease in this adipokine creates favorable circumstances for tumor spread, at least in undifferentiated gastric cancer. The effects of adiponectin on these cancer cells are currently under investigation.

Another possibility is that low adiponectin levels resulted from the increased volume of cancer cells. As mentioned previously, TNF-{alpha} can inhibit the production of adiponectin by fat cells (33–35). Because many cancer cells produce various inflammatory cytokines and the level of circulating TNF-{alpha} is increased in the cachexic stage (66), TNF-{alpha} produced by gastric cancer cells would suppress the production of adiponectin in adipose tissue, which may reduce the adiponectin level in patients with cachexia. In our series, most of the patients with stage IV gastric cancer showed an extremely low adiponectin level even if they did not show apparent cachexia. This suggests that this adipokine may play possible roles in the progression of various clinical symptoms observed in cachexic patients.

In conclusion, we found a significant association between a low plasma adiponectin level and an increased risk for gastric cancer, raising the possibility that adiponectin has a potential role in the progression of gastric cancer, especially in undifferentiated type cancer in the upper stomach. The close interaction between cancer cells and adipocytes is an intriguing issue in tumor biology.


   FOOTNOTES
 
Grant support: NIH grants RO1AG21418, RO1CA1018447, and T32DK07790, Veterans Affairs Research Enhancement Award Program, and Merit Review grants.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/15/04; revised 9/30/04; accepted 10/ 6/04.


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 DISCUSSION
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