Abstract
Abstract Pancreatic tumor microenvironment (TME) is characterized by poor tumor vasculature and extensive desmoplasia that together contribute to poor response to chemotherapy. It was recently shown that targeting of TME to inhibit desmoplastic reaction in a mouse model of pancreatic cancer resulted in increased microvessel density and intratumoral drug concentration, leading to improved therapeutic response. This approach; however, failed to generate a favorable response in a clinical trial. In that regard, we have previously demonstrated that gemcitabine-treatment of pancreatic cancer cells induces CXCR4 expression in a counter-defense mechanism and promotes pancreatic tumor cell invasiveness. The goal of present study was to examine the effect of chemotherapy on endothelial cell growth and migration. Pancreatic cancer cells were treated with gemcitabine or vehicle for 8 h and subsequently incubated in fresh low serum-containing media for next 48 h. Conditioned media was collected from vehicle- (V-CM) and gemcitabine-treated (Gem-CM) pancreatic cancer cells and used for the treatment of human umbilical vein endothelial cells (HUVEC). The data demonstrated stimulatory effects of Gem-CM on endothelial cell proliferation, migration, invasion and capillary-like structure (CLS) formation. Expression analysis of vehicle- and gemcitabine-treated pancreatic cancer cells and their conditioned-media revealed an upregulation of CXCL8/IL8, which is a known regulator of angiogenesis. Currently, we are investigating whether IL8 mediates the effect of Gem-CM on endothelial cells. Together, our findings suggest that gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells, which, in light of our previous observations, may hold important clinical and translational significance. Citation Format: Mohammad Aslam Khan, Sanjeev K. Srivastava, Arun Bhardwaj, Seema Singh, James E. Carter, Ajay P. Singh. Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications. [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 4182. doi:10.1158/1538-7445.AM2015-4182
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