Hypoxic cancer–associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling

Kugeratski, F. G. et al. (2019) Hypoxic cancer–associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science Signaling, 12(567), eaan8247. (doi: 10.1126/scisignal.aan8247) (PMID:30723174) (PMCID:PMC6794160)

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Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry–based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors. Hypoxia induced pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Among those, the uncharacterized protein NCBP2-AS2 that we renamed HIAR (hypoxia-induced angiogenesis regulator) was the protein most increased in abundance in hypoxic CAFs. Silencing of HIAR abrogated the pro-angiogenic and pro-migratory function of hypoxic CAFs by decreasing secretion of the pro-angiogenic factor VEGFA and consequently reducing VEGF/VEGFR downstream signaling in the endothelial cells. Our study has identified a regulator of angiogenesis and provides a map of hypoxia-induced molecular alterations in mammary CAFs.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK [CRUK Beatson Institute A17196 (to F.G.K., S.J.A., L.J.N., S.L., D.M.B., A.J., and E.K.M.); CRUK Glasgow Centre A18076 and Stand Up to Cancer campaign for Cancer Research UK A12935 (to S.Z.), A19257 (to S.I.), A15673 (to L.M.M.), and A21139 (to L.M.M., J.R.P.K., and O.J.S.); and CRUK Science Committee Programme Award A24388 (to O.J.S.)] and ERC Starting Grant ColonCan agreement 311301 (to J.R.P.K.). M.M. and J.S. were funded by FWO (G0D1717N) and Stichting tegen Kanker.
Keywords:Cell biology, biochemistry, molecular biology.
Glasgow Author(s) Enlighten ID:Juin, Dr Amelie and Kugeratski, Fernanda Grande and Lilla, Dr Sergio and Markert, Dr Elke and Machesky, Professor Laura and Zanivan, Professor Sara and Ismail, Dr Shehab and Bryant, Dr David and Sansom, Professor Owen
Authors: Kugeratski, F. G., Atkinson, S. J., Neilson, L. J., Lilla, S., Knight, J. R.P., Serneels, J., Juin, A., Ismail, S., Bryant, D. M., Markert, E. K., Machesky, L. M., Mazzone, M., Sansom, O. J., and Zanivan, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Science Signaling
Publisher:American Association for the Advancement of Science (AAAS)
ISSN (Online):1937-9145
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Science Signaling 12(567):eaan8247
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076Institute of Cancer Sciences