Sex influences on tumor innervation

Peripheral solid malignancies are infiltrated by nerves. Using syngeneic cell lines, we set out to define whether sex influences tumor innervation in oral cancers and melanoma. Tumors grew significantly slower in females and were significantly more innervated than in males. In oral cancer, tumor-infiltrating nerves connect to a pre-existing neural circuit that enters the brain and impacts behavior. Thus, we evaluated the impact of sex on this circuit and assessed the behavioral consequences. We found no differences in the timing or extent of behavioral declines between oral tumor-bearing males and females. Moreover, in untreated mice, metastasis did not differ by sex. Treatment of oral tumors with cisplatin and radiation slowed tumor growth in male and female mice but significantly increased tumor innervation with females harboring the greatest innervation density. Treated females also harbored significantly increased metastases in their lungs compared to treated males. Treatment improved tumor-associated behavioral changes. While the tumor-brain circuit did not differ between males and females, the activation status of neurons and glia in projection areas significantly increased on the ipsilateral side. This heightened activation was attenuated following cisplatin/radiation treatment. These studies indicate that peripheral malignancies activate neurons and glia in central nervous system (CNS) projection areas, and that standard-of-care therapy attenuates this, which correlates with improved behavior. These findings emphasize that sex influences peripheral tumor-infiltrating nerves and brain function (via the tumor-brain circuit) and suggest that severing or silencing this circuit could improve patient outcomes.