Fig. 2.

Cross talk of the brain tumor microenvironment with BC cells. a Autocrine and paracrine role of miR-122 in the development of the pre-metastatic niche via regulating glucose metabolism in cancer cells. MiR-122 downregulates the expression of pyruvate kinase isozymes, PKM2, and glucose transporter 1 (GLUT1), and decreases ATP levels in BC cells. MiR-122 reduces glucose consumption in stromal cells and allows more glucose to be accessible to cancer cells, hence facilitating the formation of the metastatic niche and cancer cell growth [74]. b CXCL12 or CCL2 secreted by astrocytes increases the level of miR-345 via CXCR4, which negatively regulates the expression of KISS1 and promotes invasion and survival in the brain [72]. c MiR-19a mediates the suppression of PTEN in cancer cells secreted by activated astrocytes. Reactive astrocytes secrete interleukins and chemokines, such as CCL2 and CXCL12/SDF1. Reduced expression of PTEN leads to enhanced CCL2-mediated recruitment of IBA1⁺ myeloid cells, and thereby establishment of the brain metastasis (BM) [42]. miR-26a is present in astrocytes and released by astrocytes through exosomes, or it can be secreted by HUVEC cells, but its role in brain niche formation is not clear [70, 71]. d Microglia release cytokines and interleukins that support cancer cells to invade and colonize the parenchyma. In cancer microglia, it can transform from the immunogenic phenotype (M1) to immunosuppressive phenotype and miRNA can modulate microglial polarization. MiR-124, miR-155, and miR-689 are associated with the M1 phenotype, whereas MiR-711 and miR-145 are strongly associated with M2 polarization [128, 129]. Loss of XIST, a long noncoding RNA in tumor cells, causes local immune suppression by converting the microglia to the M2 phenotype through the transport of exosomal miR-503 from the tumor cells [41]