Macrophages orchestrate breast cancer early dissemination and metastasis

作者：Linde, Nina; Casanova-Acebes, Maria; Sosa, Maria Soledad; Mortha, Arthur; Rahman, Adeeb; Farias, Eduardo; Harper, Kathryn; Tardio, Ethan; Torres, Ivan Reyes; Jones, Joan; Condeelis, John; Merad, Miriam; Aguirre-Ghiso, Julio A.^*

来源：Nature Communications, 2018, 9(1): 21.

DOI：10.1038/s41467-017-02481-5

• CARCINOMA IN-SITU
• COLONY-STIMULATING FACTOR
• DISSEMINATED TUMOR-CELLS
• MAMMARY-GLAND
• BONE-MARROW
• PHENOTYPIC HETEROGENEITY
• EXPRESSION
• MIGRATION
• RADIOTHERAPY
• ACTIVATION

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.

• 出版日期2018-1-2