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【Cancer research】血管内皮生长因子降低他莫西酚
Zhican Qu1,2, Sabrina Van Ginkel1, Anshu M. Roy1, Louise Westbrook1, Mubina Nasrin2, Yulia Maxuitenko1, Andra R. Frost2, Delicia Carey2, Wenquan Wang2, Rongbao Li1, William E. Grizzle2, Jaideep V. Thottassery1,2 and Francis G. Kern1,2
Key Words: VEGF • breast cancer • tamoxifen resistance • metastatic colonization • desmoplasia
Clinical studies have shown that decreased tamoxifen effectiveness correlates with elevated levels of vascular endothelial growth factor (VEGF)-A165 in biopsy samples of breast cancers. To investigate the mechanisms underlying tamoxifen resistance and metastasis, we engineered the estrogen receptor (ER)–positive MCF-7 human breast cancer cell line to express VEGF to clinically relevant levels in a doxycycline-regulated manner. Induction of VEGF expression in orthotopically implanted xenografts that were initially tamoxifen responsive and noninvasive resulted in tamoxifen-resistant tumor growth and metastasis to the lungs. Lung metastases were also observed in a VEGF-dependent manner following tail vein injection of tumor cells. At both primary and metastatic sites, VEGF-overexpressing tumors exhibited extensive fibroblastic stromal content, a clinical feature called desmoplasia. VEGF-induced metastatic colonies were surrounded by densely packed stromal cells before detectable angiogenesis, suggesting that VEGF is involved in the initiation of desmoplasia. Because expression of VEGF receptors R1 and R2 was undetectable in these tumor cells, the observed VEGF effects on reduction of tamoxifen efficacy and metastatic colonization are most likely mediated by paracrine signaling that enhances tumor/stromal cell interactions and increases the level of desmoplasia. This study reveals new roles for VEGF in breast cancer progression and suggests that combination of antiestrogens and VEGF inhibitors may prolong tamoxifen sensitivity and prevent metastasis in patients with ER-positive tumors. [Cancer Res 2008;68(15):6232–40] 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。 Vascular Endothelial Growth Factor Reduces Tamoxifen Efficacy and Promotes Metastatic Colonization and Desmoplasia in Breast Tumors
血管内皮生长因子降低他莫西酚的疗效并促进乳腺癌转移性病灶的形成和结缔组织生成
Zhican Qu1,2, Sabrina Van Ginkel1, Anshu M. Roy1, Louise Westbrook1, Mubina Nasrin2, Yulia Maxuitenko1, Andra R. Frost2, Delicia Carey2, Wenquan Wang2, Rongbao Li1, William E. Grizzle2, Jaideep V. Thottassery1,2 and Francis G. Kern1,2
Key Words: VEGF • breast cancer • tamoxifen resistance • metastatic colonization • desmoplasia
关键词：血管内皮生长因子，乳腺癌，他莫昔芬，转移性病灶，结缔组织
Clinical studies have shown that decreased tamoxifen effectiveness correlates with elevated levels of vascular endothelial growth factor (VEGF)-A165 in biopsy samples of breast cancers.
临床研究已经证实乳腺癌活组织样本中血管内皮生长因子升高与他莫昔芬的疗效降低有关。
To investigate the mechanisms underlying tamoxifen resistance and metastasis, we engineered the estrogen receptor (ER)–positive MCF-7 human breast cancer cell line to express VEGF to clinically relevant levels in a doxycycline-regulated manner.
为了调查他莫昔芬耐药与肿瘤转移的潜在机制，我们通过多西环素调节的方式在雌激素受体阳性的MCF-7人乳腺癌细胞株上表达血管内皮生长因子。
Induction of VEGF expression in orthotopically implanted xenografts that were initially tamoxifen responsive and noninvasive resulted in tamoxifen-resistant tumor growth and metastasis to the lungs.
在肿瘤细胞引物中表达的血管内皮生长因子与他莫昔芬反应并使其无法起作用导致他莫昔芬抵抗后的肿瘤生长及肺转移。
Lung metastases were also observed in a VEGF-dependent manner following tail vein injection of tumor cells. At both primary and metastatic sites, VEGF-overexpressing tumors exhibited extensive fibroblastic stromal content, a clinical feature called desmoplasia.
肺部转移灶中也能通过末梢血管注射肿瘤细胞观察到血管内皮生长因子依赖性行为。原发部位和转移部位都能看到血管内皮生长因子过度表达的肿瘤病灶中存在广泛的间质纤维化，这种临床特征叫结缔组织增生。
VEGF-induced metastatic colonies were surrounded by densely packed stromal cells before detectable angiogenesis, suggesting that VEGF is involved in the initiation of desmoplasia.
在血管形成之前，引入血管内皮生长因子表达的转移灶被高密度的间质细胞包裹，表明血管内皮生长因子参与结缔组织增生的过程。
Because expression of VEGF receptors R1 and R2 was undetectable in these tumor cells, the observed VEGF effects on reduction of tamoxifen efficacy and metastatic colonization are most likely mediated by paracrine signaling that enhances tumor/stromal cell interactions and increases the level of desmoplasia.
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作者:admin@医学,生命科学 2011-06-15 17:14
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