Vascular endothelial growth factor A, secreted in response to transforming growth factor-β1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells

被引：35

作者：

Darrington, Eric ^{[1
]}

Zhong, Miao ^{[1
]}

Vo, Bao-Han ^{[1
]}

Khan, Shafiq A. ^{[1
]}

机构：

[1] Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA

来源：

ASIAN JOURNAL OF ANDROLOGY | 2012年 / 14卷 / 05期

关键词：

cell migration; hypoxia; prostate cancer; transforming growth factor-beta 1 (TGF-beta 1); vascular endothelial growth factor A (VEGFA); TUMOR-CELLS; TYROSINE KINASE; GENE-EXPRESSION; TGF-BETA; MESSENGER-RNA; SOLID TUMORS; FACTOR-C; RECEPTOR; VEGF; ANGIOGENESIS;

D O I：

10.1038/aja.2011.197

中图分类号：

R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

100221 [泌尿外科学];

摘要：

Hypoxia and transforming growth factor-beta 1 (TGF-beta 1) increase vascular endothelial growth factor A (VEGFA) expression in a number of malignancies. This effect of hypoxia and TGF-beta 1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-beta 1 was shown to induce VEGFA(165) secretion from both normal cell lines (HPV7 and RWPE1) and prostate cancer cell lines (DU145 and PC3). Conversely, hypoxia-stimulated VEGFA(165) secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-beta 1 expression in PC3 prostate cancer cells, and the TGF-beta type I receptor (ALK5) kinase inhibitor partially blocked hypoxia-mediated VEGFA(165) secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor (VEGFR) 1 (Flt-1) and 2 (Flk-1/KDR). Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA(165) treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA(165) was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-beta 1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-beta 1 and hypoxia on metastatic prostate cancers. Asian Journal of Andrology (2012) 14, 745-751; doi:10.1038/aja.2011.197; published online 18 June 2012

引用

页码：745 / 751

页数：7

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