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Thrombospondin‐2 plays a protective role in multistep carcinogenesis: a novel host anti‐tumor defense mechanism
Author(s) -
Hawighorst Thomas,
Velasco Paula,
Streit Michael,
Hong YoungKwon,
Kyriakides Themis R.,
Brown Lawrence F.,
Bornstein Paul,
Detmar Michael
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.11.2631
Subject(s) - angiogenesis , carcinogenesis , biology , thrombospondin 1 , cancer research , stromal cell , downregulation and upregulation , tumor progression , angiogenesis inhibitor , cancer , biochemistry , genetics , gene
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 signific antly 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.