Deleting Adrb2, encoding the β2-adrenergic receptor, in tumor endothelial cells suppresses angiogenesis.
Major finding: Deleting Adrb2, encoding the β2-adrenergic receptor, in tumor endothelial cells suppresses angiogenesis.
Mechanism: Adrb2 loss in endothelial cells enhances oxidative phosphorylation to inhibit angiogenesis.
Impact: The cross-talk between nerves and endothelial metabolism promotes tumor angiogenesis in prostate cancer.
During development, growing blood vessels closely associate with peripheral nerves to regulate vascular patterning. Nerve fibers may play a similar role in the tumor microenvironment, where the “angiogenic switch” facilitates the transition to a highly vascularized growing tumor. However, the exact function of nerves in the tumor microenvironment and angiogenesis is unclear. To investigate the role of adrenergic nerves in early tumorigenesis, Zahalka and colleagues generated prostate cancer xenografts with the β-adrenergic receptors (βAdR) Adrb2 and Adrb3 knocked out (βAdRKO). βAdRKO xenografts exhibited no substantial tumor growth, compared with wild-type grafts that grew rapidly. The βAdRKO tumor growth was arrested at day 18, and pathologic examination revealed that βAdRKO tumors had reduced tumor vessel density, indicating that the loss of adrenergic signaling may suppress angiogenesis. In the Hi-Myc spontaneous autochthonous prostate cancer mouse model, low-grade preneoplastic lesions progress to high-grade malignant tumors, adenocarcinoma, and invasive carcinoma. This progression was associated with an increased physical association between nerves and blood vessels and an increase in the levels of the β-adrenergic neurotransmitter noradrenaline. Deletion of Adrb2 in endothelial cells in the low-grade lesions suppressed the progression to high-grade tumors and was associated with reduced vessel density, migration, and branching, altogether suggesting that adrenergic nerves target endothelial cells in the tumor microenvironment to promote early angiogenic progression mediated by endothelial Adrb2. Adrb2 loss inhibited angiogenesis by enhancing oxidative phosphorylation in endothelial cells, which typically rely on aerobic glycolysis for angiogenesis. Further, codeletion of Cox10 with Adr2 prevented the switch to oxidative phosphorylation, thereby promoting angiogenesis and cancer progression. In addition to demonstrating a cross-talk between nerves and endothelial metabolism, these findings suggest the possibility for cotargeting angiogenesis and neural signals or endothelial cells to potentially prevent resistance to antiangiogenic agents.
Zahalka AH, Arnal-Estapé A, Maryanovich M, Nakahara F, Cruz CD, Finley LW, et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 2017;358:321–6.
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