Linde Nina, Casanova-Acebes Maria, Sosa Maria Soledad, Mortha Arthur, Rahman Adeeb, Farias Eduardo, Harper Kathryn, Tardio Ethan, Reyes Torres Ivan, Jones Joan, Condeelis John, Merad Miriam, Aguirre-Ghiso Julio A
Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Nat Commun. 2018 Jan 2;9(1):21. doi: 10.1038/s41467-017-02481-5.
Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2 breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206/Tie2 macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2 early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.
乳腺癌极早期阶段的癌细胞播散机制尚不清楚。在此，我们在HER2乳腺癌小鼠模型中发现，先前描述的早期进化癌细胞亚群在早期播散过程中需要巨噬细胞。在癌前阶段特异性清除巨噬细胞可减少早期播散，并导致癌症进展终末期转移负担减轻。从机制上讲，我们发现，在癌前病变中，癌细胞和髓样细胞产生的CCL2吸引CD206/Tie2巨噬细胞，并诱导Wnt-1上调，进而下调HER2早期癌细胞中的E-钙黏蛋白连接。我们还在癌前病变中观察到含有巨噬细胞的转移结构肿瘤微环境，其可作为血管内渗的入口。这些数据支持巨噬细胞在早期播散中起因果作用，而早期播散在癌症进展后期对长期转移发展有很大影响。对人体标本的初步分析显示，导管原位癌中有上皮内巨噬细胞和E-钙黏蛋白连接缺失，支持其潜在的临床相关性。
