Abstract 3402: Ephrin B2 and Dll-4 mediated co-dependence of tumor and endothelial progenitor cells in human hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is a highly vascularized tumor, which preferentially recruits new blood vessels from the hepatic artery to fuel its growth, through mechanisms not well understood. Here, we examined the intercellular cross-talk of HepG2 (human HCC) and endothelial progenitor cells (EPC) in transwell co-cultures to mimic initial tumor parenchyma and stroma interactions. We present evidence showing that, in culture, HepG2 cells secrete factors to induce an ‘activated’ EPC phenotype, namely, an increase in survival, growth, proliferation and migration rates. EPC cells showed a significant increase in growth (∼40%) and survival (∼80%) when co-cultured with HepG2 cells. Simultaneously, activated EPCs improved the viability of HepG2 cells. A major mediator of intercellular crosstalk are the secreted microvesicles called exosomes. Exosomes constitute a set of distinct nanovesicles (30-100 nm), endosomal in origin, constitutively secreted by many cells. They are involved in intercellular communication by transferring proteins and RNA from one cell to another. Intercellular crosstalk between these HepG2 cells and EPCs cells lead to qualitative and quantitative changes in the exosomal cargo secreted by the respective cells. The exosomal cargo constituting various proteins and genetic material have been demonstrated to be involved in processes which promote remodeling of extracellular matrix (ECM), biological adhesion and pathways modulating developmental processes and progression of inflammation, leading to cancer growth and development. In other work with glioma cell-derived exosomes has shown the presence of Ephrin A and B receptors which suggests a prominent role of secreted exosomes in stimulating and guiding tumor angiogenesis, a hallmark characteristic of glioblastoma multiforme (GBM). Additionally, our results with co-cultures of tumor and endothelial cells show that angiogenesis signaling in EPC appears to be induced by HepG2 cells via elevated endothelial Ephrin B2 and DLL-4 expression. Overall, our results demonstrate the co-dependence of HCC and EPC intercellular crosstalk, likely accomplished via secreted exosomes, in the initial stages of HCC establishment and stimulation of angiogenesis and development, thus a promising target for new clinical strategies. Citation Format: Rajshekhar A. Kore, Meenakshi Upreti, Azemat Jamshidi-Parsian, Rudd P.M. Dings, Issam Makhoul, Robert J. Griffin. Ephrin B2 and Dll-4 mediated co-dependence of tumor and endothelial progenitor cells in human hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3402.