Abstract LB-291: Central obesity drives oesophageal tumor cell growth through VEGF-mediated mechanisms

Abstract

Abstract Introduction: Obesity is a risk-factor for both esophageal/colorectal adenocarcinoma. Adipose tissue is an endocrine organ secreting numerous factors, including Vascular Endothelial Growth Factor (VEGF). VEGF was identified to be up-regulated in cancer cells by affymetrix-array following co-culture with human omental adipose tissue (OAT). An understanding of the mechanisms driving obesity-related disease is needed to uncover pathways and develop new targets for therapy. In this study, we aimed to investigate the effect of OAT-derived VEGF on tumor growth and the potential of bevacizumab to block this effect. Methods: Matched subcutaneous and omental adipose tissue, serum and tumor were harvested from oesophageal/colorectal cancer patients undergoing resective surgery. VEGF was quantified in adipose conditioned media (ACM) and serum by ELISA. Proliferation of esophageal (OE33, JH-ESO) and colorectal (HCT15, SW480) cells following culture with ACM was assessed by BrdU assay. The protective effect of ACM on chemotherapy (cisplatin and 5FU) induced death was assessed. The effect of bevacizumab in attenuating these effects was also examined. VEGF and VEGF receptor 2 (KDR) expression was assessed in tumor tissue by qPCR. In a 200-patient tissue microarray, VEGF and VEGFR expression was related to clinico-pathological parameters and obesity status. Results: ACM from omental adipose tissue of obese patients significantly (p<0.05) increased proliferation in oesophageal (313%) and colorectal (424%) adenocarcinoma cell lines relative to omental adipose tissue from non-obese cancer patients (180% and 157% respectively). Interestingly, this effect was not observed in ACM from matched subcutaneous depots indicating that omental adipose tissue is more pro-tumor and metabolically active. Omental ACM from obese patients contained significantly higher levels of VEGF (p<0.05). In our patient cohort, serum VEGF was significantly elevated in centrally obese relative to normal weight cancer patients (determined by CT). There was a significant (p<0.05) higher expression of VEGF and KDR expression in esophageal tumours from centrally obese patients. The expression of KDR was higher in the leading edge of tumors from patients classified as obese, and was associated with decreased survival and increased nodal involvement. ACM from omental adipose tissue protected against 5FU-induced cell death (P<0.01), an effect which could be blocked by treatment with bevacizumab. Conclusion: VEGF from OAT increased proliferation in oesophageal/colorectal cancer cells. VEGF and KDR expression in oesophageal cancer was higher in centrally obese patients. ACM protected against chemotherapy-induced death, an effect that was mediated through VEGF. These findings suggest anti-VEGF strategies are warrented in obesity-associated malignancies, alone or in combination with conventional chemotherapies. 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 LB-291. doi:10.1158/1538-7445.AM2011-LB-291