Angiogenic switch as a molecular target of malignant tumors.

Abstract:

:In vivo progression to malignancy is characterized by the switch to an angiogenic phenotype. The angiogenic switch is a critical control point for tumor expansion. The ability of a tumor to become neovascularized permits rapid expansion of tumor growth and increases the likelihood of metastases. The genetic alterations that accompany the switch to the angiogenic phenotype are unknown. Discoveries of such genes lead to comprehension of molecular mechanisms of the tumor progression, as well as development of novel therapeutic tools. We have isolated a novel "angiogenic switch molecule," angiopoietin-2, upregulated specifically in hypervascular hepatocellular carcinoma (HCC). Angiopoietin family proteins have been originally identified as ligands of the vascular endothelial receptor of tyrosine kinase Tie2. Ectopic expression of angiopoietin-2 promotes the rapid development of human HCCs and produces hemorrhage within tumors in nude mice. These results suggest a role for angiopoietin-2 in the neovascularization of HCC. In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Angiopoietin protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells. Tumorigenicity with angiogenesis was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for angiopoietin/Tie2 signaling in the induction of HCC neovascularization and disease progression. More important, inhibition of the angiopoietin/Tie2 signal transduction cascade is a promising approach for HCC treatment.

journal_name

J Gastroenterol

authors

Tanaka S,Sugimachi K,Yamashita Y,Shirabe K,Shimada M,Wands JR,Sugimachi K

subject

Has Abstract

pub_date

2003-03-01 00:00:00

pages

93-7

eissn

0944-1174

issn

1435-5922

journal_volume

38 Suppl 15

pub_type

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