Interrupting Neuron—Tumor Interactions to Overcome Treatment Resistance

SIMPLE SUMMARY: Solid cancers take advantage of the surrounding tissue to stimulate their own growth, to promote their spread, and to escape anticancer immune responses and treatments. Neurons are an important newly identified target for tumors because they can provide all of these benefits and are found throughout the body. Neurons communicate using chemical signals, many of which can be recognized and leveraged by tumor cells. Tumors, in turn, manipulate neurons by sending local signals that drive the growth of neurons into the body of the tumor. In tandem with local signaling, tumors transmit protein and RNA messengers within extracellular vesicles that travel through the bloodstream and other bodily fluids. This long-range tumor signaling is a growing area of research that allows for new diagnostic and therapeutic approaches. Ongoing clinical trials will uncover methods of disrupting tumor–neuron communication for the benefit of patients. ABSTRACT: Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.