Role of the neural niche in brain metastatic cancer

Abstract

Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer.

Figure 1. Interactions between metastatic cells and the brain milieu

1) Astrocytes release cytokines that facilitate colonization by stimulating growth of tumor cells (50). 2) Brain metastates release BMP-2 which increase astrocytic density by differentiating NSCs toward astrocytic lineage (36). 3) Neurons release GABA neurotransmitters that shuttle through their respective transporters to serve as metabolic substrates (37). 4) Possibly, abundant neurotrophins in the brain’s extracellular space are captured by their cognate receptors on metastatic cells (unpublished). CTC= circulating tumor cells, NSC= neural stem cells.