Inhibitation
of Tumor Angiogenesis, Growth and
Metastasis by Blocking VEGF Paracrine Pathway
WANG Feng, TIAN Yu-Hua, LI
Ling, CHEN Xia-Fang, HU Hong-Hui, LI Chuan-Yuan1, HUANG Qian*
( Central Experimental Laboratory,
The First People’s Hospital of Shanghai, Shanghai 200080, China; 1Department of Radiation
Oncology, Duke University Medical
Center, Durham, NC 27710, USA )
Abstract 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 theirinhibitors. 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 VEGF121 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 VEGF165 transfected MCF-7 cells in vivo.
Moreover, the tumors derived from anti-sense VEGF121
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.
Key words tumor; angiogenesis; vascular endothelial
growth factor (VEGF); anti-sense; gene therapy
*Corresponding author: Tel,
86-21-63240090-4601; Fax, 86-21-65872314; e-mail, [email protected]