Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo.
Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo.
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DOI：
10.4161/cc.8.14.9101
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Cance WG
中科院分区：
文献类型：
--
作者：
Kurenova EV;Hunt DL;He D;Fu AD;Massoll NA;Golubovskaya VM;Garces CA;Cance WG
血管内皮生长因子受体-3是一种酪氨酸激酶受体，在某些人类肿瘤中过度表达，但其在肿瘤发生中的作用尚未完全阐明。我们检测了VEGFR-3在正常、非肿瘤性和早期恶性乳腺组织中的表达，并表明乳腺癌中VEGFR-3的上调先于肿瘤细胞的侵袭，这表明VEGFR-3可能起生存信号的作用。我们基于两种方法表征了人乳腺癌细胞中VEGFR-3过表达的生物学效应：通过在MCF-7乳腺癌细胞中过表达VEGFR-3获得功能，以及通过在MCF-7-VEGFR-3和BT474细胞中RNAi介导的VEGFR-3沉默丧失功能。当MCF 7-VEGFR-3细胞与亲本MCF 7细胞相比时，VEGFR-3过表达使细胞增殖增加40%，并且当BT474细胞中内源性VEGFR-3下调时，增殖减少超过40%。VEGFR-3过表达促进了运动性和侵袭性的三倍增加，并且运动性和侵袭性都被VEGFR-3的下调抑制。此外，VEGFR-3过表达促进了星形孢菌素处理诱导的应激条件下的细胞存活，并导致锚定非依赖性生长。VEGFR-3过表达显著增加了肿瘤依赖性和非依赖性异种移植模型中的肿瘤形成。在雌激素刺激下，MCF 7-VEGFR-3异种移植物比对照异种移植物大十倍。最后，两种异种移植模型细胞系中VEGFR-3表达的下调导致肿瘤生长的显著减少。我们首次证明，VEGFR-3过表达促进乳腺癌细胞增殖，运动，生存，锚定非依赖性生长和肿瘤发生在配体表达的情况下。
Vascular endothelial growth factor receptor-3 is a receptor tyrosine kinase that is overexpressed in some human carcinomas, but its role in tumorigenesis has not been fully elucidated. We examined VEGFR-3 expression in normal, nonneoplastic and early stage malignant breast tissues and have shown that VEGFR-3 upregulation in breast cancer preceded tumor cell invasion, suggesting that VEGFR-3 may function as a survival signal. We characterized the biological effects of VEGFR-3 over-expression in human breast cancer cells based on two approaches: gain of function by overexpressing VEGFR-3 in MCF-7 breast cancer cells and loss of function by RNAi-mediated silencing of VEGFR-3 in MCF-7-VEGFR-3 and BT474 cells. VEGFR-3 overexpression increased cellular proliferation by 40% when MCF7-VEGFR-3 cells were compared to parental MCF7 cells, and proliferation was reduced by more than 40% when endogenous VEGFR-3 was downregulated in BT474 cells. VEGFR-3 overexpression promoted a three-fold increase in motility and invasion and both motility and invasion were inhibited by downregulation of VEGFR-3. Furthermore, VEGFR-3 overexpression promoted cellular survival under stress conditions induced by staurosporine treatment and led to anchorage-independent growth. VEGFR-3 overexpression dramatically increased tumor formation in both hormone-dependent and independent xenograft models. With estrogen stimulation, MCF7-VEGFR-3 xenografts were ten times larger than control xenografts. Finally, downregulation of VEGFR-3 expression in both xenograft model cell lines led to a significant reduction of tumor growth. For the first time, we have demonstrated that VEGFR-3 overexpression promotes breast cancer cell proliferation, motility, survival, anchorage-independent growth and tumorogenicity in the absence of ligand expression.
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