@article{a716ef92b36b48489dffd986127ab698,
title = "Adrenergic nerves activate an angio-metabolic switch in prostate cancer",
abstract = "Nerves closely associate with blood vessels and help to pattern the vasculature during development. Recent work suggests that newly formed nerve fibers may regulate the tumor microenvironment, but their exact functions are unclear. Studying mouse models of prostate cancer, we show that endothelial b-adrenergic receptor signaling via adrenergic nerve-derived noradrenaline in the prostate stroma is critical for activation of an angiogenic switch that fuels exponential tumor growth. Mechanistically, this occurs through alteration of endothelial cellmetabolism. Endothelial cells typically rely on aerobic glycolysis for angiogenesis.We found that the loss of endothelial Adrb2, the gene encoding the b2-adrenergic receptor, leads to inhibition of angiogenesis through enhancement of endothelial oxidative phosphorylation. Codeletion of Adrb2 and Cox10, a gene encoding a cytochrome IVoxidase assembly factor, prevented the metabolic shift induced by Adrb2 deletion and rescued prostate cancer progression. This cross-talk between nerves and endothelial metabolism could potentially be targeted as an anticancer therapy.",
author = "Zahalka, {Ali H.} and Anna Arnal-Estap{\'e} and Maria Maryanovich and Fumio Nakahara and Cruz, {Cristian D.} and Finley, {Lydia W.S.} and Frenette, {Paul S.}",
note = "Funding Information: We thank G. Karsenty, R. H. Adams, and J. W. Pollard for Adrb2fl/fl, Cdh5-CreERT2, and Csf1r-iCre mice, respectively, and M. Ginsberg (Angiocrine Bioscience) for primary mouse prostate endothelial cells. We also thank C. Prophete, P. Ciero, S. Pierce, J. F. Reidhaar-Olson, P. Guo, X. L. Du, M. Hanoun, L. Tesfa, Y. Qiu, and I. L. Kurland for advice and technical support; A. Beck for assistance with pathology; A. Zahalka for assistance programming in R; and L. Schwartz, S. K. Libutti, H. Pierce, S. Murillo, T. Mizoguchi, and S. Pinho for critical advice. We are grateful for grant support from the NIH (HL097700, DK056638, and HL069438 to P.S.F.) and the New York State Department of Health (C029154 and C030318GG to P.S.F.). A.H.Z. received the Junior Investigator Neuroscience Research Award from the Albert Einstein College of Medicine and was supported by grant F30CA203446 from the National Cancer Institute and NIH training grants T32 NS007098 and GM007288. M.M. is a New York Stem Cell Foundation Druckenmiller Fellow and was supported by the European Molecular Biology Organization (EMBO) European Commission FP7 (Marie Curie Actions, EMBOCOFUND2012, GA-2012-600394, ALTF 447-2014). F.N. was supported by a Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science. This work was also supported by NIH shared equipment grant 1S10OD019961 and NIH Diabetes and Research Training Center grant P60DK020541.",
year = "2017",
month = oct,
day = "20",
doi = "10.1126/science.aah5072",
language = "English (US)",
volume = "358",
pages = "321--326",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6361",
}