Abstract 5083: Adipocytes promote pancreatic cancer cell proliferation and progression

Abstract

Abstract Pancreatic cancer (PC) is a devastating disease with an extremely low survival rate. By the year 2030, this disease is projected to be the second deadliest cancer, bypassing breast, prostate and colorectal cancer-related fatalities. While population-based epidemiological studies have reported that obesity and a higher BMI (body mass index) not only increase the risk of developing PC but also promote tumor aggressiveness, and reduce overall patient survival, how obesity may influence pancreatic tumor progression and aggressiveness is not well understood. We hypothesize that the increased local presence of mature adipocytes (in obesity) within the pancreatic microenvironment markedly enhances the tumorigenic functions of pancreatic tumors and tumor-associated stroma, thereby accelerating tumor growth and progression. In this study, we used mature adipocytes and pancreatic cancer (PC) and pancreatic stellate (PSC) cell lines and a variety of in vitro functional assays including migration, proliferation, gemcitabine chemoresistance and development of a fibrotic phenotype, to determine whether local interactions between adipocytes and tumor cells promote PC growth and to identify the underlying mechanism/s. In cell migration assays, both PCs (MiaPaca-2, AsPC-1 and BxPC-3) and PSCs (HImPSC) migrated at significantly higher rates towards adipocyte conditioned medium (ACM) compared to serum-free or normal human fibroblast conditioned medium. The ACM-mediated stimulation of migration was dose-dependent and adipocyte-specific. ACM pretreatment of PC cells as well as PSCs resulted in a significant increase in proliferation rates. Given that the development of chemoresistance is a critical challenge in PC therapy, we next investigated the effects of adipocytes on PC cell gemcitabine toxicity. Pretreatment with ACM resulted in 50-70% increased cell viability for PC and PSC's in the presence of gemcitabine. Extensive fibrosis is a hallmark of pancreatic tumors and both PC and PSCs contribute to excessive ECM production in the PC microenvironment. Compared to cells treated with full medium, ACM-treated PSC and PC cells significantly upregulated their expression of fibronectin and Collagen VI. Taken together, our results indicate that secreted factor/s present in ACM promote cell migration, proliferation, gemcitabine resistance and induce a fibrotic phenotype in PC and PSC. Current efforts in our laboratory are focused on identifying the adipocyte-secreted factor/s that may mediate these effects. Our findings will establish a direct causal role for obesity in pancreatic cancer progression and identify molecular determinants that may drive this process, thereby delineating important pathways in the obesity-pancreatic cancer axis that may be therapeutically targeted in the future. [Supported by: The Advanced Medical Foundation] Citation Format: Roopali Roy, Marsha A. Moses. Adipocytes promote pancreatic cancer cell proliferation and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2015-5083