HIF-1α is essential for inflammation-associated colon carcinogenesis

Introduction: A substantial amount of cancer entities is driven by inflammation, e.g. liver and gastric cancer. Chronic inflammation might also represent a key factor in the pathogenesis of colorectal cancer (CRC), as evidenced by the inhibiting effect of anti-inflammatory drugs on CRC progression. Despite the intriguing interrelation of chronic inflammation and cancer, its molecular nature remains largely elusive. The transcription factor HIF-1α is upregulated in most human cancers and controls central pro-tumorigenic pathways such as glycolysis, angiogenesis and therapy resistance. To achieve a comprehensive characterization of HIF-1α, we have analyzed colitis-associated cancer in mice lacking HIF-1α specifically in intestinal epithelial or myeloid cells, respectively. Methods: Tissue-specific knockout (KO) of HIF-1α was achieved by the Cre-loxP-system. Colon tumors were generated by intraperitoneal injection of azoxymethan followed by three cycles of oral dextrane sodium sulphate. Results: Enterocyte-specific deletion of HIF-1α led to decreased tumor size, without affection of tumor incidence, at early (8 weeks), but not at later (12 weeks) time points after tumor initiation. Remarkably, the number of HIF-1α-positive tumor cells in Villin-Cre expressing mice increased over time until, at 12 weeks, no more difference between WT and enterocyte-specific KO tumors could be observed. We conclude from these data that in enterocyte-specific HIF-1α-KO mice a few remaining cells escaped recombination and can apparently participate in colon tumorigenesis due to accelerated proliferation. Deletion of HIF-1α in myeloid cells resulted in a significant decrease of both tumor incidence and tumor size independent of the time point. Furthermore, reduction of tumor formation in both conditional KO models was linked to decreased angiogenesis in HIF-1α-deficient tumors. Conclusions: In conclusion, specific inactivation of HIF-1α in both enterocytes and myeloid cells attenuates the course of colitis-associated cancer. The participation of HIF-1α-expressing (non-recombined) epithelial cells to tumor formation in enterocyte-specific HIF-1α-KO mice emphasizes a pivotal role for HIF-1α in colon carcinogenesis.