The naïve view of tumors as isolated islands of rogue cells has given way to a deeper understanding of cancer as being closer to a foreign organ. This "organ" contains immunologic, vascular, and neural connections to its host that provide not only mechanisms for disease progression but also opportunities for therapeutic intervention. The presence of nerves within tumor tissues has long been appreciated. However, a mechanistic understanding of how tumors recruit nerves has been slower to emerge. Tumor release of neurotrophic factors and axonal guidance molecules likely directs axons toward the tumor bed. Newly emerging data support a contribution of tumor-released exosomes in the induction of axonogenesis toward the tumor. Exosomes, small membrane-bound vesicles that carry a complex cargo (DNA, RNA, miRNA, lipids, and proteins), protect their cargo from the low pH of the tumor microenvironment. They also represent an efficient means of local and distal communication between the tumor and potentially innervating nerves. Likely, a combination of neurotrophins, guidance molecules, and exosomes work in concert to promote tumor innervation. As such, defining the critical components driving tumor innervation will identify new targets for intervention. Moreover, with a deepening understanding, tumor innervation may emerge as a new hallmark of cancer.
©2019 American Association for Cancer Research.