Reciprocal interactions between glioma and tissue-resident cells fueling tumor progression

Gliomas are the most frequent primary brain tumor and are essentially incurable. While nondiffuse gliomas are circumscribed, diffuse gliomas display an aggressive behavior characterized by tumor cell migration over large distances into the brain parenchyma, thereby precluding curative surgical resection. Almost all diffuse gliomas progress and recur as higher grades and become resistant to standard-of-care treatments. It is being increasingly recognized that glioma cells establish functional interactions with cells residing in the tumor microenvironment. Of these, tumor-associated microglia and macrophages (TAMs) play critical roles in immunosuppression through modulation of the extracellular matrix, and the secretion of molecules such as cytokines, neurotrophic factors, and micro-RNAs (miRNAs). Conversely, glioma cell signals influence cell states and drive the metabolic reprogramming of TAMs. Similarly, emergent evidence indicates that neuronal activity influences glioma by released factors and by establishing functional synapses with glioma cells to promote tumor growth and invasion. Glioma cells also affect local neuronal activities and maintain connections through microtube gap junctions to amplify local effects. Here, we discuss the molecular mechanisms underlying bidirectional interactions between glioma cells and TAMs, as well as between glioma cells and neurons. A better understanding of these cellular cross talks is crucial for the development of novel therapeutic strategies for diffuse gliomas.