期刊
JOURNAL OF DERMATOLOGICAL SCIENCE
卷 74, 期 2, 页码 106-115出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.jdermsci.2014.01.002
关键词
Angiogenesis; Skin cancer; Thrombospondin; Carcinogenesis
类别
资金
- National Institutes of Health [CA69184]
- Swiss National Foundation [3100A0-108207, 31003A-130627]
- Advanced European Research Council Grant LYVICAM
- Jubilaeumsfonds of the Austrian Federal Reserve Bank [12747]
- Deutsche Forschungsgemeinschaft [HA 2898 4-1, HA 2898 4-2]
- Krebsliga Schweiz and Krebsliga Zurich
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. (C) 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
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