Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications

• Published in: Oncotarget 2015-11, Vol.6 (36), p.39140-39150
• Main Authors: Khan, Mohammad Aslam, Srivastava, Sanjeev K, Bhardwaj, Arun, Singh, Seema, Arora, Sumit, Zubair, Haseeb, Carter, James E, Singh, Ajay P
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Research Paper; Signal Transduction; Survival Analysis; Tumor Microenvironment
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3784

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 desmoplasiatic reaction in a preclinical model resulted in increased microvessel-density and intratumoral drug concentration, leading to improved therapeutic response. This approach, however, failed to generate a favorable response in clinical trial. In that regard, we have previously demonstrated a role of gemcitabine-induced CXCR4 signaling as a counter-defense mechanism, which also promoted invasiveness of pancreatic cancer (PC) cells. Here, we investigated the effect of gemcitabine on endothelial cell phenotype. Gemcitabine-treatment of human-umbilical-vein-endothelial-cells (HUVECs) did not promote the growth of HUVECs; however, it was induced when treated with conditioned media from gemcitabine-treated (Gem-CM) PC cells due to increased cell-cycle progression and apoptotic-resistance. Moreover, treatment of HUVECs with Gem-CM resulted in capillary-like structure (CLS) formation and promoted their ability to migrate and invade through extracellular-matrix. Gemcitabine-treatment of PC cells induced expression of various growth factors/cytokines, including IL-8, which exhibited greatest upregulation. Further, IL-8 depletion in Gem-CM diminished its potency to promote angiogenic phenotypes. Together, these findings suggest an indirect effect of gemcitabine on angiogenesis, which, in light of our previous observations, may hold important clinical significance.