Analysis of neuroglia and immune cells in the tumor microenvironment of breast cancer brain metastasis

Abstract

Breast cancer stands as the most prevalent cancer diagnosed worldwide, often leading to brain metastasis, a challenging complication characterized by high mortality rates and a grim prognosis. Understanding the intricate mechanisms governing breast cancer brain metastasis (BCBM) remains an ongoing challenge. The unique microenvironment in the brain fosters an ideal setting for the colonization of breast cancer cells. The tumor microenvironment (TME) in brain metastases plays a pivotal role in the initiation and progression of BCBM, shaping the landscape for targeted therapeutic interventions. Current research primarily concentrates on unraveling the complexities of the TME in BCBM, with a particular emphasis on neuroglia and immune cells, such as microglia, monocyte-derived macrophages (MDMs), astrocytes and T cells. This comprehensive review delves deeply into these elements within the TME of BCBM, shedding light on their interplay, mechanisms, and potential as therapeutic targets to combat BCBM.

Keywords: Breast cancer; brain metastasis; immune cells; neuroglia; tumor microenvironment.

Figure 1.

The tumor microenvironment of breast cancer brain metastasis consists of neuroglia and immune cells. (A) Activation of the wnt signaling pathway by microglia promotes breast cancer cell invasion and colonization into brain tissue. Microglia promote breast cancer cell adhesion to brain capillaries through the lnc-BM/JAK2/STAT3/ICAM1 signaling pathway. (B) MDMs release TNFα, TGFβ1 and EGF, promoting cancer cell migration and invasion. Through the lnc-BM/JAK2/STAT3/ICAM1 signaling pathway, MDMs facilitate breast cancer cell adhesion to brain capillaries. MDMs-induced invasion is related to the release of T-MV. (C) Astrocytes contribute to BCBM by involving Notch signaling in CSCs. They confer growth advantages to brain metastatic cancer cells, enhance chemotherapy resistance by activating STAT1 and nf-κB pathways. Astrocytes increase the production of BDNF, favoring breast cancer cell survival in the brain. Astrocytes accelerate the migration rate of cancer cells in the BBB and enhance the invasiveness of cancer cells by secreting chemokines. TGF-β2 secreted by astrocytes may disrupt vascular endothelial junctions or confer anoikis resistance in tumors. Astrocytes increase BTB permeability via S1P3 signaling. Additionally, astrocytes secrete MMP-2 and MMP-9, enhancing cancer cell invasion and migration. CSCs contact with astrocytes activates the PCDH7-PLCβ-Ca²⁺ signaling pathway, facilitating breast cancer cell colonization in the brain. Astrocytes up-regulate the expression of cancer cell survival genes (GSTA5, BCL2L1, TWIST1) by activating AKT and MAPK signaling pathways, and the extent of upregulation positively correlates with increased chemotherapy resistance. Elevated IL-6 levels and endothelin-dependent signaling contribute to astrocyte-induced chemoresistance. (D) Overexpression of Arg2 in T cells suppressed tumor adaptive immune response. Breast cancer cells pass the BBB is associated with GBP1. The figure was generated by Adobe Illustrator.