在一些惡性腫瘤類(lèi)型中，缺氧和轉(zhuǎn)化生長(zhǎng)因子-β1（轉(zhuǎn)化生長(zhǎng)因子-β1）能增加血管內(nèi)皮生長(zhǎng)因子（VEGFA）的表達(dá)。這種低氧和TGF-β1可能對(duì)晚期前列腺癌患者腫瘤的進(jìn)展和轉(zhuǎn)移具有關(guān)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(dǎo)正常細(xì)胞株（HPV7和RWPE1）和前列腺癌的細(xì)胞株（DU145和PC3）分泌VEGFA（165）,。相反，缺氧刺激VEGFA（165）的分泌效應(yīng)只有在前列腺癌細(xì)胞株中被觀察到,。
缺氧誘導(dǎo)PC-3前列腺癌細(xì)胞TGF-β1的表達(dá),，TGF-β型受體（ALK5）激酶抑制劑能部分阻斷缺氧介導(dǎo)的VEGFA（165）分泌,。缺氧增加前列腺癌細(xì)胞VEGFA的表達(dá)有一種新的機(jī)制。
雖然VEGFA分泌已經(jīng)被證實(shí)與前列腺癌的進(jìn)展和轉(zhuǎn)移有關(guān)聯(lián),，但早期研究結(jié)果并不能有效闡述其中相關(guān)機(jī)制,。VEGFA活性有血管內(nèi)皮生長(zhǎng)因子受體（VEGFR）1（FLT-1）和2（Flk-1/KDR）介導(dǎo)。在正常前列腺上皮細(xì)胞中有VEGFR-1 mRNA的表達(dá),，而VEGFR-2 mRNA和血管內(nèi)皮生長(zhǎng)因子受體蛋白表達(dá)僅存在于PC-3細(xì)胞中,。
VEGFA（165）處理PC-3細(xì)胞后能誘導(dǎo)細(xì)胞外信號(hào)調(diào)節(jié)激酶1/2（ERK1/2）的磷酸化，但HPV7細(xì)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(guān),。VEGFA（165）激活VEGFR-2后，PC-3細(xì)胞的遷移能力增強(qiáng),。用TGF-β1和低氧誘導(dǎo)內(nèi)源性VEGFA表達(dá)后,，也觀察到PC-3細(xì)胞的遷移能力增強(qiáng)。這些結(jié)果表明VEGFA通過(guò)VEGFR-2自分泌對(duì)TGF-β1的致瘤性以及缺氧對(duì)轉(zhuǎn)移性前列腺的效果都至關(guān)重要,。（生物谷：Bioon.com）
doi:10.1038/aja.2011.197
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PMID:
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
