Fig. 1

Brain metastases occur when cancer cells migrate from their primary site commonly lung, breast, colon, kidney, and melanoma to the brain. Circulating tumor cells (CTCs) or disseminated cancer cells are continuously shed from the tumor that survives in the bloodstream and can seed secondary tumors. The CTCs can house at metastatic sites and go dormant, which can eventually come out of the dormancy triggered by various mechanisms. (A) Brain stroma has plasmin that converts the astrocytic FasL into paracrine death signal for the metastatic cancer cells and inhibits L1CAM, needed for vascular co-option and metastatic outgrowth. In brain metastasis, anti-plasminogen activator (PA) serpins inhibit the plasmin (via inhibiting plasminogen activator) that guards the cells against FasL attack and activates the L1CAM that helps in vascular co-option of the brain metastatic cells. (B) STAT3 was found to label a subpopulation of astrocytes that were reactive and required for BrM. Brain metastatic cells had upregulated cytokines like MIF, TGF-α, and EGF that induced the STAT3 activation via phosphorylation leading to astrospheres formation that was capable of suppressing CD8⁺ T-cells. Reactive astrocytes also induce MIF to activate the MIF-CD74 axis to promote the outgrowth in BrM. (C) Cathepsin S proteolytically cleaves the junctional adhesion molecules, JAM-B in blood-brain barrier and helps in the transmigration of brain metastatic cells. Cathepsin S is elevated in primary tumors as well as in the macrophages of the stroma in TME