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HIF1α promotes tumor chemoresistance via recruiting GDF15-producing TAMs in colorectal cancer
Experimental Cell Research ( IF 3.7 ) Pub Date : 2020-11-23 , DOI: 10.1016/j.yexcr.2020.112394
Hongtu Zheng , Shan Yu , Congcong Zhu , Tianan Guo , Fangqi Liu , Ye Xu

Chemoresistance is a tremendous challenge to efficacy of systemic chemotherapy which is the preferred treatment for the advanced CRC patients. More tumor-associated macrophages (TAMs) are recruited into the CRC tumor under chemotherapy, which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we present that activated HIF1α signaling in CRC cells under chemotherapy drives the expression of HMGB1to promotes macrophage infiltration and in turn chemoresistance development. Chemotherapeutic treatment with 5-FU leads to increased recruitment of macrophages into tumors, which display tumor-protective alternative activation. Mechanistically, tumor HIF1α signaling activated by chemo-induced ROS drives the transcription of HMGB1 to promote more macrophage infiltration into CRC tumor. Furthermore, high levels of GDF15 produced by TAMs impair the chemosensitity of tumor cells via enhancing fatty acids β-oxidation. Together, our current study reveals a new insight into the cross-talking between tumor cells and immune cells, and provides novel drug targets for clinic treatments for CRC.



中文翻译:

HIF1α通过募集生产GDF15的TAMs促进结直肠癌的肿瘤化学耐药性

化学抗性是全身化疗疗效的巨大挑战,全身化疗是晚期CRC患者的首选治疗方法。在化学疗法下,更多的肿瘤相关巨噬细胞(TAM)被募集到CRC肿瘤中,这与化学抗药性的发展高度相关,但潜在的分子机制尚不清楚。在这里,我们提出在化疗下CRC细胞中激活的HIF1α信号驱动HMGB1的表达来促进巨噬细胞浸润,进而促进化学抗性的发展。用5-FU进行化学治疗会导致巨噬细胞募集到肿瘤中,从而显示出肿瘤保护性替代激活。从机制上讲,由化学诱导的ROS激活的肿瘤HIF1α信号驱动HMGB1的转录,从而促进更多的巨噬细胞浸润到CRC肿瘤中。此外,由TAM产生的高水平的GDF15通过增强脂肪酸β-氧化而损害肿瘤细胞的化学敏感性。总之,我们当前的研究揭示了对肿瘤细胞与免疫细胞之间相互作用的新见解,并为CRC的临床治疗提供了新的药物靶标。

更新日期:2020-12-16
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