Abstract
The angiogenic switch during tumorigenesis is thought to be induced by a change in the balance of pro- angiogenic and anti-angiogenic factors. To elucidate the biological role of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistep carcinogenesis, we subjected TSP-2-deficient and wild-type mice to a chemical skin carcinogenesis regimen. Surprisingly, TSP-2 expression was strongly upregulated in the mesenchymal stroma of wild-type mice throughout the consecutive stages of tumorigenesis whereas the angiogenesis factor, vascular endothelial growth factor, was induced predominantly in tumor cells. TSP-2 deficiency dramatically enhanced susceptibility to skin carcinogenesis and resulted in accelerated and increased tumor formation. The angiogenic switch occurred in early stages of pre-malignant tumor formation, and tumor angiogenesis was significantly enhanced in TSP-2-deficient mice. While TSP-2 deficiency did not affect tumor differentiation or proliferation, tumor cell apoptosis was significantly reduced. These results reveal upregulation of an endogenous angiogenesis inhibitor during multi step tumorigenesis and identify enhanced stromal TSP-2 expression as a novel host anti-tumor defense mechanism.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
9,10-Dimethyl-1,2-benzanthracene
-
Animals
-
Apoptosis
-
Cell Adhesion Molecules / physiology
-
Cell Division
-
Disease Susceptibility
-
Endothelial Growth Factors / genetics
-
Female
-
Gene Expression Regulation, Neoplastic
-
Lymphokines / genetics
-
Mice
-
Mice, Inbred Strains
-
Mice, Knockout
-
Neovascularization, Pathologic / genetics
-
Neovascularization, Pathologic / physiopathology
-
Oligodeoxyribonucleotides, Antisense / pharmacology
-
Papilloma / chemically induced
-
Papilloma / genetics
-
Papilloma / pathology
-
Papilloma / prevention & control*
-
Precancerous Conditions / chemically induced
-
Precancerous Conditions / genetics
-
Precancerous Conditions / pathology
-
Skin / drug effects
-
Skin / pathology
-
Skin Neoplasms / chemically induced
-
Skin Neoplasms / genetics
-
Skin Neoplasms / pathology
-
Skin Neoplasms / prevention & control*
-
Thrombospondins / deficiency
-
Thrombospondins / genetics
-
Thrombospondins / physiology*
-
Time Factors
-
Transcription, Genetic
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
Substances
-
Cell Adhesion Molecules
-
Endothelial Growth Factors
-
Lymphokines
-
Oligodeoxyribonucleotides, Antisense
-
Thrombospondins
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
-
thrombospondin 2
-
9,10-Dimethyl-1,2-benzanthracene