关键词: 血管内皮生长因子；转移；血管内皮生长因子受体；肺肿瘤；动物模型

Abstract:

Objective  To investigate the mechanism by which vascular endothelial growth factor (VEGF) promotes lung metastasis. Methods  VEGF levels of nine human lung carcinoma cell lines were examined with ELISA and the proliferation was tested by MTT. Two cell lines with distinctive VEGF expression and similar proliferation were subcutaneously injected to the back of SCID mice or intravenously injected by the tail vein to build the metastasis model. The volume of tumors on back of mice were measured every 3 days till sacrificed. Pulmonary metastasis and vascular density were verified by HE staining and CD31 immunofluorescence. Neutralizing antibodies specific for mouse VEGFR1 (MF1) and VEGFR2 (DC101) were administrated to verify which receptor was involved in VEGF induced  pulmonary metastases. Results  ELISA showed that VEGF levels of nine human lung carcinoma cell lines were in a range of 13.39-182.7ng/mL. A549 cell with high VEGF expression (182.7ng/mL) and SPCA1 with low VEGF expression (13.39ng/mL) were chosen to build mouse model. The proliferation of A549 and SPCA1 had no significant difference. A549 cell formed much larger tumor on the back of SCID mice than SPCA1. Angiogenesis in A549 formed tumor was significantly increased than SPCA1 formed tumor (P<0.01). In lung metastasis model, number of metastatic lesions in lung tissues found in A549 mice was 2.3 folds compared with SPCA1. After treatment with anti-mouse VEGFR1 monoclonal antibody, the total number of metastatic tumors induced by A549 decreased from 54 to 13, while anti-VEGFR2 treatment had no significant difference in metastasis numbers(P>0.05). Conclusion  VEGF secreted by lung cancer cells could promote tumor growth and tumor angiogenesis. VEGF promotes pulmonary metastasis by VEGFR1 pathways. The blockage of VEGFR1 induced metastasis may provide a novel approach for prevention and treatment of tumor metastasis.

Key words: Vascular endothelial growth factor; Metastasis; Vascular endothelial growth factor receptor; Lung carcinoma; Animal model