Macrophages orchestrate breast cancer early dissemination and metastasis.

Abstract

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.

• Authors: Nina Linde, Maria Casanova-Acebes, Maria Soledad Sosa, Arthur Mortha, Adeeb Rahman, Eduardo Farias, Kathryn Harper, Ethan Tardio, Ivan Reyes Torres, Joan Jones, John Condeelis, Miriam Merad, Julio A Aguirre-Ghiso
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 21 (01 02 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29295986 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Erbb2 protein, mouse
• Receptor, ErbB-2

Topics

• Animals
• Breast Neoplasms (pathology)
• Disease Progression
• Female
• Macrophages (pathology)
• Mice
• Neoplasm Metastasis
• RAW 264.7 Cells
• Receptor, ErbB-2 (genetics)
• Wnt Signaling Pathway