Research ArticleCancer

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

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Science Signaling  05 Feb 2019:
Vol. 12, Issue 567, eaan8247
DOI: 10.1126/scisignal.aan8247

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The secret(ing) life of the tumor stroma

The hypoxia that develops in solid tumors leads to the formation of a dysfunctional vasculature that enables cancer cell survival and also prevents efficient chemotherapeutic penetration. Cancer-associated fibroblasts (CAFs) in the tumor stroma release important angiogenic signals; however, the proteins secreted by these cells have generally been characterized at the genome level. Kugeratski et al. analyzed the proteome and secretome of CAFs and found that hypoxia altered the secretome of these cells. The authors identified a previously uncharacterized protein that they renamed HIAR. HIAR was increased in abundance in hypoxic CAFs, promoted the release of the pro-angiogenic factor VEGF from CAFs, and induced VEGF-dependent signaling in endothelial cells. These results provide an overview of the CAF secretome at the protein level and a new potential target for anti-angiogenic therapy.


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.

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