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From the Cutaneous Biology Research Center, Department ofDermatology,* Massachusetts General Hospital and HarvardMedical School, Charlestown; and the Department ofPathology, Beth Israel Deaconess MedicalCenter and Harvard Medical School, Boston, Massachusetts
The distinct roles of angiopoietin (Ang)-1 and Ang2,
counteracting ligands for the endothelium-specific Tie2
receptor, in tumor development and progression have remained
poorly understood. We investigated the expression of Ang1 and Ang2
during multistep mouse skin carcinogenesis and in human squamous cell
carcinoma (SCC) xenografts. Expression of Ang2, but not of
Ang1, was up-regulated in angiogenic tumor vessels already in
early stages of skin carcinogenesis and was also strongly increased in
SCCs. Stable overexpression of Ang1 in human A431 SCCs resulted in a
more than 70% inhibition of tumor growth, associated with
enhanced Tie2 phosphorylation levels, as compared with low
levels in control transfected tumors. No major changes in the vascular
density, vascular endothelial growth factor mRNA and protein
expression, and vascular endothelial growth factor receptor-2
phosphorylation levels were observed in Ang1-expressing tumors.
However, the fraction of tumor blood vessels with coverage by
-smooth muscle actin-positive periendothelial cells was
significantly increased, indicative of an increased vascular
maturation status. These findings identify an inhibitory role of
Ang1/Tie2 receptor-mediated vessel maturation in SCC growth and suggest
that up-regulation of its antagonist, Ang2, during
early-stage epithelial tumorigenesis contributes to the angiogenic
switch by counteracting specific vessel-stabilizing effects of
Ang1.
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