New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
School of Electrical Engineering and Computer Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Clin Cancer Res. 2018 Nov 1;24(21):5407-5421. doi: 10.1158/1078-0432.CCR-18-0125. Epub 2018 Jun 29.
M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network. Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database. Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data. Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the "henchmen" for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. .
M2 型 TAMs 越来越被认为是促进转移的关键因素。许多细胞类型通过基于细胞因子的复杂通讯网络来指示单核细胞分化为 M2 TAMs。阐明该网络中的关键途径可以为抑制转移提供新的靶点。在这项研究中，我们专注于癌细胞、CAF 和单核细胞作为该网络中的主要节点。单核细胞与受癌症刺激的 CAF 共培养用于研究向 M2 样 TAMs 的分化。细胞因子阵列分析用于发现分化的 CAF 衍生调节剂。这些调节剂在原代 CAF 和骨髓来源的单核细胞中得到验证。使用共移植 CAF 建立了同源、同基因结肠癌细胞模型，以观察对肿瘤生长和转移的影响。为了确认与临床证据的相关性，使用 Oncomine 数据库进行了荟萃分析。我们的共培养研究表明，IL6 和 GM-CSF 是癌细胞激活的 CAF 释放的关键信号，它们共同诱导单核细胞分化为 M2 样 TAMs。在同源、同基因结肠癌细胞小鼠模型中，共移植的 CAF 升高了 IL6 和 GM-CSF 水平、TAM 浸润和转移。联合使用 IL6 和 GM-CSF 阻断可显著逆转这些病理效应。通过对临床数据的荟萃分析观察到 GM-CSF 和 IL6 表达与疾病进程之间的正相关。我们的研究表明，IL6 和 GM-CSF 在转移中的作用需要重新评估，并暗示 CAF 是癌细胞产生免疫抑制肿瘤生态位的“帮凶”。GM-CSF 和 IL6 的双重靶向是抑制转移的一种很有前途的新方法。
