Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling
Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling
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DOI：
10.1093/jnci/94.11.819
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发表时间：
2002-06-05
期刊：
影响因子：
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通讯作者：
Alitalo, K
中科院分区：
文献类型：
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作者：
He, YL;Kozaki, KI;Alitalo, K
背景：血管内皮生长因子C（VEGF-C）刺激肿瘤淋巴管生成（即，淋巴管的形成）和通过与VEGF受体3（VEGFR-3）相互作用转移到区域淋巴结。我们试图确定抑制VEGFR-3信号传导，从而抑制肿瘤淋巴管生成，是否会抑制肿瘤转移。研究方法：我们使用高转移性人肺癌细胞系NCI-H460-LNM 35（LNM 35）及其具有低转移能力的亲本系NCI-H460-N15（N15）。我们通过转染插入基因，建立了分泌VEGF-C的稳定N15细胞系和分泌可溶性融合蛋白VEGF受体3-免疫球蛋白（VEGFR-3-IG，结合VEGF-C并抑制VEGFR-3信号传导）的LNM 35细胞系。对照系用模拟载体转染。将肿瘤细胞皮下植入严重联合免疫缺陷小鼠（每组n = 6），6周后检查肿瘤和转移。在另一种方法中，将表达VEGFR-3-IG（AdR 3-IG）或β-半乳糖苷酶（AdLacZ）的重组腺病毒静脉内注射到携带LNM 35肿瘤的小鼠中（分别为n = 14和7）。结果：LNM 35细胞VEGF-C RNA和蛋白表达水平高于N15细胞。与VEGFR-3-Ig转染的LNM 35肿瘤（4.1个血管/网格; 95%CI = 3.4 - 4.7; P < 0.05）相比，异种移植模拟载体转染的LNM 35肿瘤显示更多的瘤内淋巴管（15.3个血管/网格; 95%CI = 13.3 - 17.4）和更多的引流淋巴结转移（12/12）。
Background: Vascular endothelial growth factor C (VEGF-C) stimulates tumor lymphangiogenesis (i.e., formation of lymphatic vessels) and metastasis to regional lymph nodes by interacting with VEGF receptor 3 (VEGFR-3). We sought to determine whether inhibiting VEGFR-3 signaling, and thus tumor lymphangiogenesis, would inhibit tumor metastasis. Methods: We used the highly metastatic human lung cancer cell line NCI-H460-LNM35 (LNM35) and its parental line NCI-H460-N15 (N15) with low metastatic capacity. We inserted genes by transfection and established a stable N15 cell line secreting VEGF-C and a LNM35 cell line secreting the soluble fusion protein VEGF receptor 3-immunoglobulin (VEGFR-3-Ig, which binds VEGF-C and inhibits VEGFR-3 signaling). Control lines were transfected with mock vectors. Tumor cells were implanted subcutaneously into severe combined immunodeficient mice (n = 6 in each group), and tumors and metastases were examined 6 weeks later. In another approach, recombinant adenoviruses expressing VEGFR-3-Ig (AdR3-Ig) or P-galactosidase (AdLacZ) were injected intravenously into LNM35 tumor-bearing mice (n = 14 and 7, respectively). Results: LNM35 cells expressed higher levels of VEGF-C RNA and protein than did N15 cells. Xenograft mock vector-transfected LNM35 tumors showed more intratumoral lymphatic vessels (15.3 vessels per grid; 95% confidence interval [CI] = 13.3 to 17.4) and more metastases in draining lymph nodes (12 of 12) than VEGFR-3-Ig-transfected LNM35 tumors (4.1 vessels per grid; 95% CI = 3.4 to 4.7; P