Blocking Vascular Hyperpermeability, the Initiation Step of Tumor Angiogenesis Inhibits Mammary Tumor.

摘要

Mammary tumors growth, like most of the other solid tumors, beyond minimal size requires the generation of new blood vessels and other stromal elements. It is generally agreed that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is thought to he largely responsible for the hyperpermeability of tumor blood vessels. Information accumulating from different laboratories including ours have indicated that tumor angiogenesis and stroma formation develop sequentially as increased microvascular permeability triggered by VPF/VEGF secreted mainly by the tumor. This seems to be the key initiation step of angiogenesis. We, therefore, postulate that by blocking the vascular permeability, the growth of solid tumors as well as its metastasis can be prevented. Utilizing Cre/lox system, we have planned to generate mutant forms of VPF/VEGF in breast cancer cell lines (particularly MDA-MB435 cell line) which express either the potent vascular permeabilizing activity of native VPF/VEGF but is unable to stimulate endothelial cell division or lack of vascular permeabilizing activity but contains EC-mitogenic activity. Initial experiments are in progress by making those VEGF mutants into adneovirus vector and test whether the in vitro results can be reproducible in animal system. Meanwhile, in another project, we have defined the central role of p53 on regulation of VEGF in breast cancer.