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Hypoxic cancer–associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling
Science Signaling ( IF 6.7 ) Pub Date : 2019-02-05 , DOI: 10.1126/scisignal.aan8247
Fernanda G Kugeratski 1 , Samuel J Atkinson 1 , Lisa J Neilson 1 , Sergio Lilla 1 , John R P Knight 1 , Jens Serneels 2 , Amelie Juin 1 , Shehab Ismail 1, 3 , David M Bryant 1, 3 , Elke K Markert 3 , Laura M Machesky 1, 3 , Massimiliano Mazzone 2, 4 , Owen J Sansom 1, 3 , Sara Zanivan 1, 3
Affiliation  

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.



中文翻译:


缺氧的癌症相关成纤维细胞增加 NCBP2-AS2/HIAR,通过增强 VEGF 信号传导促进内皮出芽



肿瘤内缺氧会导致功能失调的血管形成,从而导致肿瘤转移并降低治疗效果。血管嵌入肿瘤基质中,其中癌症相关成纤维细胞(CAF)构成了重要的细胞成分。我们发现缺氧的人乳腺 CAF 在体外 CAF 与内皮细胞共培养物中促进血管生成。基于质谱的 CAF 分泌蛋白组蛋白质组分析揭示,缺氧 CAF 通过改变各种促血管生成因子和抗血管生成因子的分泌而导致血管异常。缺氧诱导了 CAF 蛋白质组的显着重塑,包括以前与此过程无关的蛋白质。其中,我们将其重命名为 HIAR(缺氧诱导血管生成调节因子)的未表征蛋白 NCBP2-AS2 是缺氧 CAF 中丰度增加最多的蛋白。 HIAR的沉默通过减少促血管生成因子VEGFA的分泌而消除了缺氧CAF的促血管生成和促迁移功能,从而减少了内皮细胞中的VEGF/VEGFR下游信号传导。我们的研究已经确定了血管生成的调节因子,并提供了乳腺 CAF 中缺氧诱导的分子改变的图谱。

更新日期:2019-02-06
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