[Inhibitation of tumor angiogenesis, growth and metastasis by blocking VEGF paracrine pathway].
Solid tumors require an adequate vascular supply to grow beyond a certain dimension. It is known that formation of new blood vessels in tumor is mediated by unbalanced expression of angiogenic factors and their inhibitors. Among the former, the vascular endothelial growth factor (VEGF) has been assumed prime candidacy as a major positive physiological effector. To investigate the role of VEGF in angiogenesis associated with development of breast cancer, a sense VEGF and an anti-sense VEGF expression plasmids were constructed, and then were introduced into a human breast carcinoma cell line, MCF-7, expressing middle level of endogenous VEGF. Anti-sense VEGF(121) transfected MCF-7 cells that expressed reduced constitutive levels of VEGF and showed the same growing potential as untransfected MCF-7 cells in vitro, but it showed longer latency, smaller tumor, slower growth and prolonged survival time compared to parental or sense VEGF(165) transfected MCF-7 cells in vivo. Moreover, the tumors derived from anti-sense VEGF(121) transfected MCF-7 cells characterized by minimal vascularization and extensive necrosis. Finally, mice with primary subcutaneous tumors treated with intratumoral administration of anti-sense VEGF, or the plasmid expressing extracellular domain of the Flk-1 VEGF receptor (sFlk-1) followed by electroporation, showed significant tumor suppression. These results suggest that VEGF plays a major angiogenic role in breast cancer and a strategy, which blocks the VEGF paracrine pathway, may provide a means to control tumor growth topically without the risk of systemic antiangiogenesis.
Wang
Feng
F
Central Experimental Laboratory, The First People's Hospital of Shanghai, Shanghai 200080 China. huangq@online.sh.cn
Tian
Yu-Hua
YH
Li
Li
L
Chen
Xia-Fang
XF
Hu
Hong-Hui
HH
Li
Chuan-Yuan
CY
Huang
Qian
Q
D016475:3T3 Cells; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D016373:DNA, Antisense / Q000008:administration & dosage / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D016373:DNA, Antisense; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors