“Research Article”
Received September 12, 2016; Accepted January 30, 2017; Published February 25, 2017
http://dx.doi.org/10.18081/2333-5106/017-45-60
Vincent Xu; An Yan; Jing Luan; Liang Chen; Betty Li; Nan Zhang
Abstract
The aim of this study was to investigate the role of tumor cell HIF-1α as the main actor in the colon cancer tumor microenvironment by development and characterization of tumor cell clones with enforced expression or knockdown of HIF-1α in two different murine colon adenocarcinoma cell lines CT26 and MC-38. It was shown that tumor cell intrinsic hypoxic response promotes aberrant angiogenesis in a colon cancer-specific manner, through a complex interaction with the TRAF6 pathway, required for colorectal cancer development. The expression of Hypoxia-Inducible Factor-1α (HIF-1α) in colon adenocarcinomas from patients and its association with tumor vascularization and accumulation of nitrosative stress marker 3-nitrotyrosine was evaluated. A tight relationship was found between the expression of HIF-1α and aberrant tumor angiogenesis in human colorectal cancer. Furthermore, the modulation of HIF-1α either by overexpression or knockdown in murine colon adenocarcinoma cells confirmed its role in the promotion of aberrant tumor angiogenesis. The investigation showed that the tumor cell response to hypoxia is critical for the development of colon cancer in mice, mediated by aberrant angiogenesis, nitrosative stress accumulation and secretion of Cyr61, a multifunctional CCN protein involved in angiogenesis. The interaction between the tumor cell hypoxic response and the TRAF6 pathway is a key mechanism of colon cancer-tumor microenvironment cross-talk.
Keywords: HIF-1; VEGF; Notch-1; colorectal; Angiogenesis
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