在一些惡性腫瘤類型中,，缺氧和轉化生長因子-β1（轉化生長因子-β1）能增加血管內(nèi)皮生長因子（VEGFA）的表達,。這種低氧和TGF-β1可能對晚期前列腺癌患者腫瘤的進展和轉移具有關鍵影響。
近日,，刊登在Asian Journal of Andrology雜志上的一則研究中，研究人員發(fā)現(xiàn)TGF-β1能誘導正常細胞株（HPV7和RWPE1）和前列腺癌的細胞株（DU145和PC3）分泌VEGFA（165）。相反,，缺氧刺激VEGFA（165）的分泌效應只有在前列腺癌細胞株中被觀察到。
缺氧誘導PC-3前列腺癌細胞TGF-β1的表達,，TGF-β型受體（ALK5）激酶抑制劑能部分阻斷缺氧介導的VEGFA（165）分泌,。缺氧增加前列腺癌細胞VEGFA的表達有一種新的機制,。
雖然VEGFA分泌已經(jīng)被證實與前列腺癌的進展和轉移有關聯(lián)，但早期研究結果并不能有效闡述其中相關機制,。VEGFA活性有血管內(nèi)皮生長因子受體（VEGFR）1（FLT-1）和2（Flk-1/KDR）介導,。在正常前列腺上皮細胞中有VEGFR-1 mRNA的表達，而VEGFR-2 mRNA和血管內(nèi)皮生長因子受體蛋白表達僅存在于PC-3細胞中,。
VEGFA（165）處理PC-3細胞后能誘導細胞外信號調(diào)節(jié)激酶1/2（ERK1/2）的磷酸化,，但HPV7細胞不存在上述現(xiàn)象，這表明VEGFA分泌功能可能只與前列腺癌有關,。VEGFA（165）激活VEGFR-2后,，PC-3細胞的遷移能力增強。用TGF-β1和低氧誘導內(nèi)源性VEGFA表達后,，也觀察到PC-3細胞的遷移能力增強,。這些結果表明VEGFA通過VEGFR-2自分泌對TGF-β1的致瘤性以及缺氧對轉移性前列腺的效果都至關重要。（生物谷：Bioon.com）
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
