Rapid vessel regression, protease inhibition, and stromal normalization upon short-term vascular endothelial growth factor receptor 2 inhibition in skin carcinoma heterotransplants.
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.
Miller
Daniel W
DW
Division of Differentiation and Carcinogenesis (A080), German Cancer Research Center, and the Department of Ophthalmology, University of Heidelberg Hospitals and Clinics, Germany.
Vosseler
Silvia
S
Mirancea
Nicolae
N
Hicklin
Daniel J
DJ
Bohlen
Peter
P
Völcker
Hans E
HE
Holz
Frank G
FG
Fusenig
Norbert E
NE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001485:Basement Membrane / Q000648:ultrastructure; D001808:Blood Vessels / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017364:Collagenases / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000473:pathology; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D051381:Rats; D012878:Skin Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology
D000911:Antibodies, Monoclonal; D040301:Vascular Endothelial Growth Factor Receptor-2; D017364:Collagenases; D018093:Gelatinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D020780:Matrix Metalloproteinase 9