1. Thrombospondin-2 overexpression in the skin of transgenic mice reduces the susceptibility to chemically induced multistep skin carcinogenesis.
- Author
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Kunstfeld R, Hawighorst T, Streit M, Hong YK, Nguyen L, Brown LF, and Detmar M
- Subjects
- Animals, Apoptosis, Biomarkers metabolism, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Differentiation, Epidermis metabolism, Epidermis pathology, Female, Genotype, Mice, Mice, Transgenic, Neovascularization, Pathologic, Skin Neoplasms metabolism, Skin Neoplasms pathology, Thrombospondins genetics, Vascular Endothelial Growth Factor A metabolism, Carcinogenesis, Carcinoma, Squamous Cell etiology, Skin Neoplasms etiology, Thrombospondins metabolism
- Abstract
Background: We have previously reported stromal upregulation of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistep carcinogenesis, and we found accelerated and enhanced skin angiogenesis and carcinogenesis in TSP-2 deficient mice., Goals: To investigate whether enhanced levels of TSP-2 might protect from skin cancer development., Methods: We established transgenic mice with targeted overexpression of TSP-2 in the skin and subjected hemizygous TSP-2 transgenic mice and their wild-type littermates to a chemical skin carcinogenesis regimen., Results: TSP-2 transgenic mice showed a significantly delayed onset of tumor formation compared to wild-type mice, whereas the ratio of malignant conversion to squamous cell carcinomas was comparable in both genotypes. Computer-assisted morphometric analysis of blood vessels revealed pronounced tumor angiogenesis already in the early stages of carcinogenesis in wild type mice. TSP-2 overexpression significantly reduced tumor blood vessel density in transgenic mice but had no overt effect on LYVE-1 positive lymphatic vessels. The percentage of desmin surrounded, mature tumor-associated blood vessels and the degree of epithelial differentiation remained unaffected. The antiangiogenic effect of transgenic TSP-2 was accompanied by a significantly increased number of apoptotic tumor cells in transgenic mice., Conclusion: Our results demonstrate that enhanced levels of TSP-2 in the skin result in reduced susceptibility to chemically-induced skin carcinogenesis and identify TSP-2 as a new target for the prevention of skin cancer., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
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