Contributions of autonomic nerves to exocrine malignancies: A focus on adrenergic signals in prostate cancer progression

Abstract

Just as autonomic nerves pattern exocrine gland development, malignancies arising from these glands (including pancreatic, breast, and prostate) co-opt neural programs to promote their growth and progression. Animal models of exocrine tumorigenesis in combination with clinical data suggest that adrenergic nerves promote exocrine malignancies through beta-adrenergic signaling in the tumor microenvironment. Since nerves closely associate with blood vessels, patterning the vasculature during development, we explored the contributions of adrenergic nerves and signals to the endothelium in prostate cancer. Here, we show that loss of beta-adrenergic receptor signaling in the prostate stroma inhibits tumor growth by altering endothelial metabolism, turning off the angiogenic switch that enables exponential tumor growth. While endothelial cells rely on anaerobic glycolysis for vessel formation, loss of endothelial Adrb2 (the gene encoding the beta2-adrenergic receptor) inhibits angiogenesis by shifting metabolism to oxidative phosphorylation. Co-deletion of Adrb2 and Cox10, a cytochrome IV oxidase assembly factor, prevented this metabolic shift and rescued angiogenesis and cancer progression. These results thus suggest that adrenergic nerves mediate a pro-angiogenic switch during the early stages of prostate carcinogenesis, and abrogation of beta-adrenergic signaling inhibits the angiometabolic switch and delays cancer progression. Since exocrine glands such as the pancreas and breast may exhibit a similar developmental and malignant dependency on adrenergic signals, targeting the cross-talk between nerves and endothelial metabolism may serve as a novel anti-cancer therapeutic strategy.