Deciphering the Dialogue between Brain Tumors, Neurons, and Astrocytes.

Glioblastoma (GB) and brain metastases (BM) from peripheral tumors account for most cases of tumors in the central nervous system (CNS) while also being the deadliest. From a structural point of view, malignant brain tumors are classically characterized by hypercellularity of glioma and vascular endothelial cells. Given these atypical histologic features, GB and BM have long been considered as "foreign" entities with few to no connections to the brain parenchyma. The identification of intricate connections established between GB cells and the brain parenchyma paired with the ability of peripheral metastatic cells to form functional synapses with neurons challenged the concept of brain tumors disconnected from the CNS. Tumor cell integration to the CNS alters brain functionality in patients and accelerates cancer progression. Next-generation precision medicine should therefore attempt to disconnect brain cancer cells from the brain. This review encompasses recent discoveries on the mechanisms underlying these relationships and discusses the impact of these connections on tumor progression. It also summarizes the therapeutic opportunities of interrupting the dialogue between healthy and neoplastic brains.