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(American Journal of Pathology. 2005;167:1389-1403.)
© 2005 American Society for Investigative Pathology

Rapid Vessel Regression, Protease Inhibition, and Stromal Normalization upon Short-Term Vascular Endothelial Growth Factor Receptor 2 Inhibition in Skin Carcinoma Heterotransplants

Daniel W. Miller^*, Silvia Vosseler^*, Nicolae Mirancea^*, Daniel J. Hicklin, Peter Bohlen, Hans E. Völcker, Frank G. Holz and Norbert E. Fusenig^*

From the Division of Differentiation and Carcinogenesis,^* German Cancer Research Center, Heidelberg, Germany; the Department of Ophthalmology, University of Heidelberg Hospitals and Clinics, Heidelberg, Germany; the Department of Ophthalmology, University of Bonn, Bonn, Germany; and ImClone Systems Incorporated, New York, New York

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis, and blockade of VEGF receptor 2 (VEGFR-2), with the monoclonal antibody DC101, inhibits angiogenesis and tumor growth. To examine the short-term effects of DC101, we surface transplanted the squamous cell carcinoma cell line A5-RT3 onto nude mice. After short-term treatment with DC101, we observed rapid reduction in vascularization and reversion of the tumor phenotype. Beginning 24 hours after treatment, VEGFR-2 inhibition resulted in decreased vessel density within the tenascin-c-staining tumor-associated stroma and reduced endothelial cell proliferation. Stromal expression of matrix metalloproteinase-9 and -13 was drastically reduced 96 hours after VEGFR-2 inhibition as detected by in situ hybridization and in situ zymography. Moreover, the morphology of the tumor-stroma border changed from a highly invasive carcinoma to a well-demarcated, premalignant phenotype. The latter was characterized by the appearance of a regular basement membrane in immunostaining and ultrastructural analyses. These findings suggest that VEGFR-2 inhibition by DC101 evokes very rapid reduction of preformed vessels and decreases both stromal protease expression and gelatinolytic activity, resulting in the modulation of the tumor-stroma border zone and reversion of the tumor phenotype. Thus, short-term inhibition of VEGF signaling results in complex stromal alterations with crucial consequences for the tumor phenotype.

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