The HIF-prolyl hydroxylases have distinct and non-redundant biological roles in the pathogenesis of colitis-associated cancer

Abstract

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaption to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared to WT mice. In Phd3 -/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages (TAMs) in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin ( Ereg) in macrophages, and (iii) augmented signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic ( Vav:Cre-Phd2f/f) but not in intestinal epithelial cells ( Villin:Cre-Phd2f/f) increased CAC growth. In conclusion, the three different PHD isoenzymes have distinct and non-redundant, either promoting (PHD1), diminishing (PHD2), or neutral effects (PHD3) on CAC growth. KBK received funding from the German Cancer Aid. MJS. received funding from the German Research Foundation (DFG; STR 1570/1-1) and the Braun Foundation (Braun®; BBST-D-18-00018). MSch received funding from the German Federal Ministry of Education and Research (BMBF; 031L0084). JMH received funding from the Heidelberg Stiftung Chirurgie. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.