Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Abstract

Colon adenocarcinoma is characterized by an infiltration of tumor-associated macrophages (TAMs). TAMs are associated with a chemoresistance to 5-Fluorouracil (5-FU), but the mechanisms involved are still poorly understood. In the present study, we found that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to a macrophage-induced chemoresistance to 5-FU by inactivation of the drug. Macrophage DPD expression in hypoxia is translationally controlled by the cap-dependent protein synthesis complex eIF4FHypoxic, which includes HIF-2. We discovered that TAMs constitute the main contributors to DPD activity in human colorectal primary or secondary tumors where cancer cells do not express significant levels of DPD. Together, these findings shed light on the role of TAMs in forming chemoresistance in colorectal cancers and offer the identification of new therapeutic targets. Additionally, we report that, contrary to what is found in humans, macrophages in mice do not express DPD.