Differential Effects of VEGFR-1 and VEGFR-2 Inhibition on Tumor Metastases Based on Host Organ Environment
Differential Effects of VEGFR-1 and VEGFR-2 Inhibition on Tumor Metastases Based on Host Organ Environment
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DOI：
10.1158/0008-5472.can-10-1138
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Yoon, Sam S.
中科院分区：
文献类型：
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作者：
Lee, Yoon-Jin;Karl, Daniel L.;Yoon, Sam S.
肿瘤主要由宿主器官微血管内皮细胞(EC)诱导新生血管生长，肺和肝脏的微血管构筑明显不同。血管内皮生长因子或血管内皮生长因子-A促进肿瘤血管生成主要是通过血管内皮生长因子受体-2(VEGFR-2)介导的。在本研究中，VEGFR-2抗体(DC101)对Renca肾癌细胞肺转移的抑制作用为26%，而VEGFR-1抗体(MF-1)则无此作用。然而，VEGFR-2中和对Renca肝转移无影响，而VEGFR-1中和可使Renca肝转移减少31%。对于CT26结肠癌肝转移瘤，需要同时抑制VEGFR-1和VEGFR-2以诱导生长延迟。VEGFR-1或VEGFR-2抑制不是通过阻止微转移的建立，而是通过分别阻止55%和43%的微转移的血管形成和生长来减少肿瘤负担。VEGF诱导肺内皮细胞VEGFR-2磷酸化，肝内皮细胞VEGFR-1磷酸化。VEGFR-2抑制肺EC和VEGFR-1抑制肝EC更能抑制EC的增殖、迁移和毛细血管的形成。总而言之，我们的结果表明，肝转移瘤比肺转移瘤更依赖于VEGFR-1来介导血管生成，这是由于VEGFRs在肝脏EC和肺EC上的活性不同。因此，抑制特定的血管内皮生长因子受体的治疗应该考虑转移性疾病的靶点。癌症资源；70(21)；8357-67。(C)2010年AACR。
Tumors induce new blood vessel growth primarily from host organ microvascular endothelial cells (EC), and microvasculature differs significantly between the lung and liver. Vascular endothelial growth factor (VEGF or VEGF-A) promotion of tumor angiogenesis is thought to be mediated primarily by VEGF receptor-2 (VEGFR-2). In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung metastases by 26%, whereas VEGFR-1 antibody (MF-1) had no effect. However, VEGFR-2 neutralization had no effect on RenCa liver metastases, whereas VEGFR-1 neutralization decreased RenCa liver metastases by 31%. For CT26 colon carcinoma liver metastases, inhibition of both VEGFR-1 and VEGFR-2 was required to induce growth delay. VEGFR-1 or VEGFR-2 inhibition decreased tumor burden not by preventing the establishment of micrometastases but rather by preventing vascularization and growth of micrometastases by 55% and 43%, respectively. VEGF induced greater phosphorylation of VEGFR-2 in lung ECs and of VEGFR-1 in liver ECs. EC proliferation, migration, and capillary tube formation in vitro were suppressed more by VEGFR-2 inhibition for lung EC and more by VEGFR-1 inhibition for liver EC. Collectively, our results indicate that liver metastases are more reliant on VEGFR-1 than lung metastases to mediate angiogenesis due to differential activity of VEGFRs on liver EC versus lung EC. Thus, therapies inhibiting specific VEGFRs should consider the targeted sites of metastatic disease. Cancer Res; 70(21); 8357-67. (C) 2010 AACR.