Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Exp Cell Res. 2021 Sep 1;406(1):112734. doi: 10.1016/j.yexcr.2021.112734. Epub 2021 Jul 13.
Chemotherapy is the preferred clinical treatment for advanced stage gastric cancer (GC) patients, of which efficacy could be markedly impaired due to the development of chemoresistance. Alternatively activated or M2-type tumor associated macrophages (TAMs) are recruited under chemotherapy and are highly implicated in the chemoresistance development, but underlying molecular mechanism for TAM activation is largely unknown. Here, we present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent manner. Mechanistically, cisplatin-induced HIF1α signaling activation directly drive the transcription of LIF, which promotes the resistance of gastric tumors to chemo drug. Further study revealed that tumor cell-derived LIF stimulates macrophages into tumor-supporting M2-type phenotype via activating STAT3 signaling pathway. Therapeutically, blocking LIF efficiently elevates chemo sensitivity of tumor cells and further represses the growth rates of tumors under chemotherapy. Therefore, our study reveals a novel insight in understanding the cross talking between tumor cells and immune cells and provides new therapeutic targets for gastric cancer.
化疗是晚期胃癌 (GC) 患者的首选临床治疗方法，但由于化疗耐药性的发展，其疗效会显著降低。在化疗过程中，被募集的肿瘤相关巨噬细胞（TAMs）呈现出一种替代激活或 M2 型表型，它们在化疗耐药性发展中高度相关，但 TAM 激活的潜在分子机制在很大程度上仍是未知的。在这里，我们提出肿瘤衍生的白血病抑制因子 (LIF) 被化疗药物诱导，以 TAM 依赖的方式抑制胃肿瘤细胞的化疗敏感性。从机制上讲，顺铂诱导的 HIF1α 信号激活直接驱动 LIF 的转录，从而促进胃肿瘤对化疗药物的耐药性。进一步的研究表明，肿瘤细胞衍生的 LIF 通过激活 STAT3 信号通路刺激巨噬细胞向肿瘤支持的 M2 型表型转化。治疗上，阻断 LIF 能有效提高肿瘤细胞的化疗敏感性，并进一步抑制化疗下肿瘤的生长速度。因此，我们的研究揭示了肿瘤细胞和免疫细胞之间相互作用的新见解，并为胃癌提供了新的治疗靶点。
