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(American Journal of Pathology. 2002;160:1381-1392.)
© 2002 American Society for Investigative Pathology

Regular Articles

Activation of the Tie2 Receptor by Angiopoietin-1 Enhances Tumor Vessel Maturation and Impairs Squamous Cell Carcinoma Growth

Thomas Hawighorst^*, Mihaela Skobe^*, Michael Streit^*, Young-Kwon Hong^*, Paula Velasco^*, Lawrence F. Brown, Lucia Riccardi^*, Bernhard Lange-Asschenfeldt^* and Michael Detmar^*

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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