Supportive roles of microglia in breast cancer brain metastases

Abstract

Abstract Background Lung, breast, melanoma, colorectal or renal carcinoma cells frequently metastasize to the central nervous system (CNS) and the frequency of CNS metastases increases with a prolonged survival of cancer patients. New anti-cancer therapies frequently fail to reduce metastatic burden. Tumor-associated macrophages act as pro-tumorigenic cells facilitating tissue remodeling, invasion and metastasis. The CNS is equipped in resident macrophages, including microglia, perivascular, meningeal and choroid plexus macrophages, that may interact with metastatic cancer cells and create a permissive niche in the CNS. The literature review shows accumulation of activated microglia in different cancer metastases. Methods We evaluated systematically the abundance and morphology of microglia and other macrophages on tissue microarrays and sections from breast cancer metastases using immunohistochemistry. Searching for a potential attractant of microglia, we evaluated the expression of Osteopontin (OPN) on sections from breast cancer metastases and the protein levels in six human breast cancer cell lines. The responses of microglial cultures to breast cancer MDA-MB-231 cells were characterized. Invasion of breast cancer cells in co-cultures with microglial cells was evaluated using a Matrigel assay. Results We found activated, amoeboid microglia in tissues surrounding breast cancer CNS metastases. OPN was expressed mainly by metastatic breast cancer cells and its high expression was also noted in CNS metastases from different cancers. Invasiveness of MDA-MB-231 cells co-cultured with murine or human microglial cells was significantly increased. OPN was produced by human breast cancer cells, but not by non-transformed cells. Its expression was blocked by minocycline, a clinically used antibiotic. Conclusion Our study shows that metastatic cancer cells may employ microglia to facilitate colonization of brain parenchyma. OPN production is elevated in cultured breast cancer cells and CNS breast cancer metastases. OPN can mediate interactions between microglia and metastatic cancer cells. Minocycline interferes with those interactions and may impair creating a metastatic niche and cancer progression. Legal entity responsible for the study Nencki Institute of Experimental Biology. Funding Foundation for Polish Science Team Tech Core Facility: Development of comprehensive diagnostics and personalized therapy in neuro-oncology. Disclosure All authors have declared no conflicts of interest.