VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors
VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors
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DOI：
10.1002/ijc.10283
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发表时间：
2002-04-20
影响因子：
6.4
通讯作者：
Härkönen, PL
中科院分区：
文献类型：
--
作者：
Mattila, MMT;Ruohola, JK;Härkönen, PL
癌细胞通过淋巴系统扩散到区域淋巴结是乳腺癌扩散的第一步。在包括乳腺癌和前列腺癌在内的几种人类癌症中，血管内皮生长因子C（VEGF-C）的表达与淋巴结转移有关。我们的研究是为了评估VEGF-C对侵袭性差的雌激素依赖性人MCF-7乳腺癌细胞转移的影响。用VEGF-C转染的MCF-7乳腺癌细胞（MCF-7-VEGF-C）在皮下植入雌激素颗粒的裸鼠的乳房脂肪垫中作为肿瘤生长。用抗淋巴管透明质酸受体-I（LYVE-I）、VEGF受体-3（VEGFR-3）、PECAM-I、泛细胞角蛋白和雌激素依赖性pS2蛋白的抗体，用免疫组织化学方法研究肿瘤淋巴管生成和淋巴结转移。转染的MCF-7细胞中VEGF-C的过表达刺激异种移植小鼠体内肿瘤生长，而不影响雌激素反应性。在携带由MCF-7-VEGF-C细胞形成的原位肿瘤的小鼠中，75%（8只小鼠中的6只，实验I）和62%（8只小鼠中的5只，实验II）的所得肿瘤转移至区域淋巴结，而在携带对照载体转染的MCF-7细胞（MCF-7-Mock）的肿瘤的小鼠中未观察到转移。在MCF-7-VEGF-C细胞来源的肿瘤中，瘤内和瘤周淋巴管密度增加，但在MCF-7-Mock细胞来源的肿瘤中不增加。总之，我们的研究结果表明，VEGF-C过表达刺激肿瘤淋巴管生成，并诱导正常转移性差的雌激素依赖性MCF-7肿瘤扩散到局部淋巴结。这些数据表明，VEGF-C在乳腺癌的淋巴结转移中具有重要作用，即使在其依赖于乳腺癌的早期阶段。(C)2002 Wiley-Liss，Inc.
The spread of cancer cells to regional lymph nodes through the lymphatic system is the first step in the dissemination of breast cancer. In several human cancers including those of the breast and prostate, the expression of vascular endothelial growth factor C (VEGF-C) is associated with lymph node metastasis. Our study was undertaken to evaluate the effect of VEGF-C on metastasis of poorly invasive, estrogen dependent human MCF-7 breast cancer cells. MCF-7 breast cancer cells transfected with VEGF-C (MCF-7-VEGF-C) were grown as tumors in the mammary fat pads of nude mice implanted with subcutaneous estrogen pellets. Tumor lymphangiogenesis and lymph node metastasis were studied immunohistochemically using antibodies against lymphatic vessel hyaluronan receptor -I (LYVE-I), VEGF receptor-3 (VEGFR-3), PECAM-I, pan-cytokeratin and estrogen dependent pS2 protein. Overexpression of VEGF-C in transfected MCF-7 cells stimulated in vivo tumor growth in xenotransplanted mice without affecting estrogen responsiveness. The resulting tumors metastasized to the regional lymph nodes in 75% (in 6 mice out of 8, Experiment I) and in 62% (in 5 mice out of 8, Experiment II) of mice bearing orthotopic tumors formed by MCF-7-VEGF-C cells whereas no metastases were observed in mice bearing tumors of control vector-transfected MCF-7 cells (MCF-7-Mock). The density of intratumoral and peritumoral lymphatic vessels was increased in tumors derived from MCF-7-VEGF-C cells but not MCF-7-Mock cells. Taken together, our results show that VEGF-C overexpression stimulates tumor lymphangiogenesis and induces normally poorly metastatic estrogen-dependent MCF-7 tumors to disseminate to local lymph nodes. These data suggest that VEGF-C has an important role in lymph node metastasis of breast cancer even at its hormone-dependent early stage. (C) 2002 Wiley-Liss, Inc.