Hypoxia, Neutrophils, and the Colon Tumor Inflammatory Response

Abstract

In 1863, Rudolf Virchow proposed that tumors arise from sites of chronic inflammation. This concept was largely ignored throughout the majority of the next century as the genetic basis of cancer was explored. However, it has become well appreciated that inflammation and cancer are intimately linked. For example, chronic inflammation of the intestine in the form of Inflammatory Bowel Disease (IBD) predisposes to the development of colon cancer. Although the vast majority of colon tumors do not arise from sites of chronic inflammation, sporadic colon tumors elicit an inflammatory response that is essential for tumor growth, progression, and evasion of anti-tumor immunity. Hypoxia is a well-characterized feature of nearly all solid tumors and promotes stabilization of the hypoxia inducible transcription factors (HIF-1α and HIF-2α) with known roles in modulating tumor-associated inflammation. We have previously reported that intestinal epithelial HIF-2α is an important driver of the acute inflammatory response in colitis. The present work describes a novel axis by which intestinal epithelial HIF-2α serves as a critical link between inflammation and cancer of the colon. Mechanistically, our work shows a crucial role for intestinal epithelial HIF-2α in regulation of the immune microenvironment of colon tumors through recruitment of intra-tumoral neutrophils. Neutrophils are granulocytic myeloid cells of the innate immune system that are the first responders to sites of infection to limit microbes. Neutrophils are highly infiltrated in nearly all solid tumors including colon cancer. We showed that neutrophil influx was due to direct HIF-2α-dependent regulation of the potent neutrophil chemokine CXCL1. These data identify a novel role for HIF-2α in modulation of the tumor immune microenvironment of inflammation-driven colon tumors and suggest therapeutic potential. Our data suggested an important role for neutrophils in the maintenance of colon tumors. However, the importance of neutrophils in the initiation of colon tumorigenesis is largely unknown. Using mice with constitutive genetic depletion of neutrophils, the present work demonstrates an essential role for neutrophils in restricting colon tumor growth and progression in both inflammation-driven and sporadic colon tumor models. Neutrophil depletion correlated with robust expansion of colon-tumor associated microbiota and tumor-associated B-cells, both of which had important roles in neutrophil-deficient colon tumorigenesis. Together, our data suggest divergent roles for neutrophils in the initiation and maintenance of colon tumors. The work presented in this thesis also shows an important role for the transcription factor, myc-associated zinc finger (MAZ) in colitis and colon cancer. MAZ is an inflammation induced transcription factor that has a previously identified role as a HIF-2α transcriptional cofactor. We show that MAZ is highly active in human colitis and colon cancer. The present work delineates a critical function for MAZ in the inflammatory progression of colitis and colon cancer through regulation of oncogenic STAT3 signaling. Collectively, these studies shed new light onto the inflammatory progression of colon cancer and propose potential therapeutic targets.