The paracrine effects of tumor cells on endothelial cells and macrophages in brain metastases with different primary sites.

BACKGROUND: Brain metastases (BrMs) represent the most common intracranial tumors, which occur at a significantly higher incidence than primary brain neoplasms. Although some studies addressed the modulation of endothelial cells (ECs) and macrophages in lung and breast BrMs, it is still unclear how these cells are modulated in other BrM types. METHODS: Tumor cells (TCs) were isolated from human melanoma, lung and gastrointestinal (GI) BrM tissues, using individual patient isolates (n=2 per tissue origin) as the primary unit of inference. The paracrine effects of BrM-TCs on ECs and macrophages were examined in ex vivo models using BrM-TC-derived supernatants, HUVEC ECs, and peripheral blood monocytes isolated from healthy donors. The functional implications of the macrophages stimulated with BrM-TCs were investigated on autologous T-cells, focusing on T-cell proliferation. RESULTS: None of the BrM-TCs had a direct effect on the ECs regarding MMP release, migration, proliferation and tubulogenesis. Interestingly, lung and GI but not melanoma BrM-TCs polarized macrophages into an M2-like phenotype, characterized by enhanced MMP9 release, increased Arg1 and CD206 expression, as well as elevated IL-6, IL-8, IL-10, and VEGF levels. Moreover, macrophages polarized by lung and GI but not melanoma BrM-TCs inhibited the proliferation of CD8 and CD4 T-cells. CONCLUSION: These findings indicate that lung and GI but not melanoma BrM-TCs polarize macrophages towards a tumor-promoting, M2-like phenotype. Although the direct effects of BrM-TCs on ECs remain to be further elucidated, our results highlight the need for further comparative studies on BrMs, with particular focus on their histological origins.