Sue Wang

Obesity potentiates the growth and dissemination of pancreatic cancer

BACKGROUND Obesity is an independent risk factor for pancreatic cancer development and progression, although the mechanisms underlying this association are completely unknown. The aim of the current study was to investigate the influence of obesity on pancreatic cancer growth using a novel in vivo model. METHODS Lean (C57BL/6 J) and obese (Lep(Db) and Lep(Ob)) mice were inoculated with murine pancreatic cancer cells (PAN02), and studied after 5 weeks of tumor growth. Tumor histology was evaluated by hematoxylin and eosin staining, cellular proliferation was assessed by 5-bromodeoxyuridine, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Serum adiponectin, leptin, and insulin levels were assayed. RESULTS Obese mice developed larger tumors, and a significantly greater number of mice developed metastases; mortality was also greater in obese mice. Tumor apoptosis did not differ among strains, but tumors from both obese strains had greater proliferation relative to those growing in lean animals. Serum adiponectin concentration correlated negatively and serum insulin concentration correlated positively with tumor proliferation. Intratumoral adipocyte mass in tumors from both obese strains was significantly greater than that in tumors of lean mice. CONCLUSION Data from this novel in vivo model suggest that the altered adipokine milieu and insulin resistance observed in obesity may lead directly to changes in tumor microenvironment, thereby promoting pancreatic cancer growth and dissemination.

Abstract 510: Do adipocytes in the tumor microenvironment influence the growth of pancreatic cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: Pancreatic cancer develops more frequently and progresses more rapidly in obesity. The mechanisms influencing this association are incompletely understood. Using our murine model of pancreatic cancer in diet-induced obesity, we hypothesized that changes in the immune profile and tumor microenvironment may contribute to accelerated pancreatic cancer growth in obesity. Methods: Thirty male C57BL/6J mice were studied. At 5 weeks of age, 20 mice were fed high fat diet (60% fat; HFD) and 10 were fed low fat (10% fat) diet. At 19 weeks of age all mice were inoculated in the flank with 2.5 x105 Pan02 murine pancreatic cancer cells. After 5 weeks of tumor growth, spleens and tumors were collected, splenic flow cytometry evaluated lymphocyte population, proliferation was determined by PCNA staining, and tumor infiltrating lymphocytes (TIL), both B and T, were scored by immunohistochemistry. Intratumoral adipocyte volume was assessed by H&E staining. Studentss t-test and Pearsons correlation were applied where appropriate. P value <0.05 was accepted as statistically significant. Results: Mice were segregated into overweight (OW – heavier than the mean body weight of the HFD mice – 35.5g, n=15) and lean (<35.5g, n=14). OW mice were significantly heavier (37.3±0.2g vs. 33.9±0.3g, p<0.001). Tumors were twice as large in OW mice as in lean mice (1.23±0.2g vs. 0.6±0.1g; p=0.001). The peripheral lymphocyte profile was similar in both OW and lean animals (T cells: 51.2±2.5% vs. 49.2±2.3%, p=0.59; B cells: 32.9±1.0% vs. 32.0±1.9%, p=0.73). TIL were observed in similar numbers in both OW and lean groups (T cell: 1.31±0.18 vs. 1.54±0.16, p=0.35; B cell: 0.63±0.08 vs. 0.91±0.15, p=0.33). Tumor proliferation as measured by PCNA was similar in both groups (139±18 OW vs. 143±14 lean, p=0.85). Interestingly, adipocyte volume was significantly greater in the OW tumor microenvironment than in the lean tumors (3.7%±0.7 vs. 2.2%±0.3, p<0.05). Conclusions: These results demonstrate that: 1) tumor weight was significantly greater in OW mice; 2) peripheral and tumor infiltrating lymphocyte profile was similar in OW and lean animals; and 3) adipocyte volume was significantly greater in the tumor microenvironment of OW mice. We conclude that obesity accelerates the growth of pancreatic cancer, and adipocytes in the tumor microenvironment may directly influence tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 510. doi:10.1158/1538-7445.AM2011-510

M1759 Does Adiponectin Upregulation Attenuate the Severity of Acute Pancreatitis in Obesity

Introduction Obesity is an independent risk factor for severe acute pancreatitis, though the mechanisms underlying this association are unknown. The powerful anti-inflammatory adipokine adiponectin is decreased in obesity. We recently showed that the severity of pancreatitis in obese mice is inversely related to circulating adiponectin levels, and therefore hypothesized that adiponectin upregulation would attenuate the severity of pancreatitis in obese mice.