Asian J Androl：VEGFA的非促血管生成作用

在一些恶性肿瘤类型中，缺氧和转化生长因子-β1（转化生长因子-β1）能增加血管内皮生长因子（VEGFA）的表达。这种低氧和TGF-β1可能对晚期前列腺癌患者肿瘤的进展和转移具有关键影响。

近日，刊登在Asian Journal of Andrology杂志上的一则研究中，研究人员发现TGF-β1能诱导正常细胞株（HPV7和RWPE1）和前列腺癌的细胞株（DU145和PC3）分泌VEGFA（165）。相反，缺氧刺激VEGFA（165）的分泌效应只有在前列腺癌细胞株中被观察到。

缺氧诱导PC-3前列腺癌细胞TGF-β1的表达，TGF-β型受体（ALK5）激酶抑制剂能部分阻断缺氧介导的VEGFA（165）分泌。缺氧增加前列腺癌细胞VEGFA的表达有一种新的机制。

虽然VEGFA分泌已经被证实与前列腺癌的进展和转移有关联，但早期研究结果并不能有效阐述其中相关机制。VEGFA活性有血管内皮生长因子受体（VEGFR）1（FLT-1）和2（Flk-1/KDR）介导。在正常前列腺上皮细胞中有VEGFR-1 mRNA的表达，而VEGFR-2 mRNA和血管内皮生长因子受体蛋白表达仅存在于PC-3细胞中。

VEGFA（165）处理PC-3细胞后能诱导细胞外信号调节激酶1/2（ERK1/2）的磷酸化，但HPV7细胞不存在上述现象，这表明VEGFA分泌功能可能只与前列腺癌有关。VEGFA（165）激活VEGFR-2后，PC-3细胞的迁移能力增强。用TGF-β1和低氧诱导内源性VEGFA表达后，也观察到PC-3细胞的迁移能力增强。这些结果表明VEGFA通过VEGFR-2自分泌对TGF-β1的致瘤性以及缺氧对转移性前列腺的效果都至关重要。

doi:10.1038/aja.2011.197
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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.

Darrington E, Zhong M, Vo BH, Khan SA.

Hypoxia and transforming growth factor-β1 (TGF-β1) increase vascular endothelial growth factor A (VEGFA) expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 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-β1 expression in PC3 prostate cancer cells, and the TGF-β 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-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.