Epithelial Hypoxia-Inducible Factor 2a Facilitates the Progression of Colon Tumors through Recruiting Neutrophils

Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2a in colon tumors; however, the function of epithelial HIF-2a as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2a was essential in tumor growth. Concurrently, epithelial disruption of HIF-2a significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2a-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2a signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2a-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2a-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2a-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2a is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer. Overall design: Comparing gene expression profiles of colon tissues from Hif2a (+/+; n=9) and Hif2a (LSL; n=9) mice