Cancer exosomes induce tumor neo-neurogenesis potentiating tumor growth

Patients with densely innervated tumors do worse than those with less innervated cancers. We hypothesize that neural elements are acquired by a tumor-induced process, called neo-neurogenesis. Here, we use PC12 cells in a simple system to test this hypothesis. PC12 cells extend processes, called neurites, only when appropriately stimulated. Using this system, we show that patient tumors release vesicles (exosomes) which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumor cells compromised in exosome release grow slower and are less innervated than controls indicating a contribution of innervation to disease progression. We find that neo-neurogenesis is mediated in part by the axonal guidance molecule, EphrinB1, contained in exosomes. These findings support testing EphrinB1 blockers to inhibit tumor innervation and improve survival.