Abstract
A paracrine interaction between epidermal growth factor (EGF)-secreting tumor-associated macrophages (TAMs) and colony-stimulating factor 1 (CSF-1)-secreting breast carcinoma cells promotes invasion and metastasis. Here, we show that mice deficient in the hematopoietic-cell-specific Wiskott-Aldrich syndrome protein (WASp) are unable to support TAM-dependent carcinoma cell invasion and metastasis in both orthotopic and transgenic models of mammary tumorigenesis. Motility and invasion defects of tumor cells were recapitulated ex vivo upon coculture with WASp(-/-) macrophages. Mechanistically, WASp is required for macrophages to migrate toward CSF-1-producing carcinoma cells, as well as for the release of EGF through metalloprotease-dependent shedding of EGF from the cell surface of macrophages. Our findings suggest that WASp acts to support both the migration of TAMs and the production of EGF, which in concert promote breast tumor metastasis.
Highlights
Cancer progression is a complex multi-step process consisting of neoplastic cell transformation, tumor growth, invasion and metastasis
Macrophage Wiskott-Aldrich Syndrome protein (WASp) is required for breast carcinoma cell interaction in vitro
To test whether WASp plays a role in the epidermal growth factor (EGF)/colony stimulating factor-1 (CSF-1) paracrine interaction, bone marrow derived macrophages (BMMs) from WASp+/+ or WASp−/− mice were co-cultured with
Summary
Cancer progression is a complex multi-step process consisting of neoplastic cell transformation, tumor growth, invasion and metastasis. While metastasis is the major cause of cancer deaths, it remains poorly characterized (Valastyan and Weinberg, 2011). Malignant dissemination is not an exclusively cancer cell-autonomous process; other constituents of the tumor microenvironment, such as inflammatory cells, heavily influence cancer progression (Hanahan and Coussens, 2012). Clinical studies on invasive breast cancer demonstrate tumor associated macrophage (TAM) density correlates with poor prognosis (Qian and Pollard, 2010). TAMs promote angiogenesis, extracellular matrix proteolysis, and enhance tumor cell invasion and dissemination (Joyce and Pollard, 2009). The authors declare no conflict of interest
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