Salting the Soil: Targeting the Microenvironment of Brain Metastases

Paget's "seed and soil" hypothesis of metastatic spread has acted as a foundation of the field for over a century, with continued evolution as mechanisms of the process have been elucidated. The central nervous system (CNS) presents a unique soil through this lens, relatively isolated from peripheral circulation and immune surveillance with distinct cellular and structural composition. Research in primary and metastatic brain tumors has demonstrated that this tumor microenvironment (TME) plays an essential role in the growth of CNS tumors. In each case, the cancerous cells develop complex and bidirectional relationships that reorganize the local TME and reprogram the CNS cells, including endothelial cells, pericytes, astrocytes, microglia, infiltrating monocytes, and lymphocytes. These interactions create a structurally and immunologically permissive TME with malignant processes promoting positive feedback loops and systemic consequences. Strategies to interrupt interactions with the native CNS components, on "salting the soil," to create an inhospitable environment are promising in the preclinical setting. This review aims to examine the general and specific pathways thus far investigated in brain metastases and related work in glioma to identify targetable mechanisms that may have general application across the spectrum of intracranial tumors.