Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
Cancer Res. 2017 Mar 1;77(5):1083-1096. doi: 10.1158/0008-5472.CAN-16-0598. Epub 2017 Jan 12.
Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγtILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. .
癌细胞往往首先转移到肿瘤引流的淋巴结，但介导癌细胞侵入淋巴管的机制仍知之甚少。在这里，我们表明，在人类乳腺肿瘤微环境（TME）中，增加的 RORγt 组 3 固有淋巴细胞（ILC3）的存在与淋巴结转移的可能性增加相关。在乳腺癌的临床前小鼠模型中，CCL21 介导的 ILC3 向肿瘤的募集刺激了 TME 基质细胞产生 CXCL13，进而促进了 ILC3-基质相互作用和癌细胞运动因子 RANKL 的产生。耗尽 ILC3 或中和 CCL21、CXCL13 或 RANKL 足以减少淋巴结转移。我们的研究结果确立了 RORγtILC3 通过调节 TME 中癌细胞局部趋化因子环境在促进淋巴转移中的作用。
