Tumor Tissue Is Innervated

The microenvironment of a solid tumor represents a highly complex ecosystem, composed of tumor and nontumor cells, blood and lymphatic vessels, and extracellular matrix. In this environment, tumor cells interact with immune cells, fibroblasts, adipocytes, endothelial, and other cells of the tumor tissue. These interactions are mediated by a spectrum of molecules, from cytokines to growth factors to miRNA molecules, which are released either alone or within extracellular vesicles (Guo and Gil 2022; Galappaththi et al. 2023). Another important component of the tumor microenvironment is the neural cell processes, axons as well as the neurons themselves (Fig. 4.1) (Silverman et al. 2021; de Visser and Joyce 2023), with neurotransmitters and neuromodulators being released from synaptic endings in the tumor microenvironment. In addition, neurons can also release neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that promote tumor cell survival and proliferation. On the other hand, nonneuronal cells of the tumor microenvironment synthesize and release nerve growth factors, axon guidance molecules, and miRNAs, which promote the survival of local neurons and navigate the ingrowth of new nerve fibers into the tumor. Thus, highly complex neurotumor interactions take place in the microenvironment, which may determine the progression of cancer and the efficacy of antitumor therapies (Hunt et al. 2020; Arese et al. 2022).