Rapid vessel regression, protease inhibition, and stromal normalization upon short-term vascular endothelial growth factor receptor 2 inhibition in skin carcinoma heterotransplants

Am J Pathol. 2005 Nov;167(5):1389-403. doi: 10.1016/S0002-9440(10)61226-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Basement Membrane / ultrastructure
  • Blood Vessels / pathology*
  • Carcinoma, Squamous Cell / blood supply
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Collagenases / metabolism*
  • Endothelial Cells / cytology
  • Endothelium, Vascular / pathology
  • Gelatinases / metabolism*
  • Humans
  • In Situ Hybridization
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Neoplasm Transplantation
  • Rats
  • Skin Neoplasms / blood supply
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / pathology*
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / immunology

Substances

  • Antibodies, Monoclonal
  • Vascular Endothelial Growth Factor Receptor-2
  • Collagenases
  • Gelatinases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Mmp13 protein, rat
  • Matrix Metalloproteinase 9