Colorectal adenocarcinoma is a leading cause of death worldwide, and immune infiltration in colorectal tumors has been recognized recently as an important pathophysiologic event. In this context, tumor-associated macrophages (TAM) have been related to chemoresistance to 5-fluorouracil (5-FU), the first-line chemotherapeutic agent used in treating colorectal cancers. Nevertheless, the details of this chemoresistance mechanism are still poorly elucidated. In the current study, we report that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to macrophage-induced chemoresistance to 5-FU via inactivation of the drug. Hypoxia-induced macrophage DPD expression was controlled by HIF2α. TAMs constituted the main contributors to DPD activity in human colorectal primary or secondary tumors, while cancer cells did not express significant levels of DPD. In addition, contrary to humans, macrophages in mice do not express DPD. Together, these findings shed light on the role of TAMs in promoting chemoresistance in colorectal cancers and identify potential new therapeutic targets. Significance: Hypoxia induces HIF2α-mediated overexpression of dihydropyrimidine dehydrogenase in TAMs, leading to chemoresistance to 5-FU in colon cancers.

中文翻译：

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缺氧驱动巨噬细胞中二氢嘧啶脱氢酶的表达并赋予结直肠癌化疗耐药性

结直肠腺癌是全世界死亡的主要原因，结直肠肿瘤中的免疫浸润最近被认为是重要的病理生理事件。在这种情况下，肿瘤相关巨噬细胞 (TAM) 与 5-氟尿嘧啶 (5-FU) 的化学耐药性有关，5-氟尿嘧啶 (5-FU) 是用于治疗结直肠癌的一线化疗药物。然而，这种化学抗性机制的细节仍未得到很好的阐明。在当前的研究中，我们报告巨噬细胞在缺氧条件下特异性过度表达二氢嘧啶脱氢酶 (DPD)，导致巨噬细胞通过药物失活诱导对 5-FU 的化学耐药性。缺氧诱导的巨噬细胞 DPD 表达受 HIF2α 控制。TAM 是人类结直肠原发性或继发性肿瘤中 DPD 活性的主要贡献者，而癌细胞不表达显着水平的 DPD。此外，与人类相反，小鼠的巨噬细胞不表达 DPD。总之，这些发现揭示了 TAM 在促进结直肠癌化学耐药性方面的作用，并确定了潜在的新治疗靶点。意义：缺氧诱导 TAM 中 HIF2α 介导的二氢嘧啶脱氢酶过表达，导致结肠癌对 5-FU 产生化学耐药性。