Decreased multistep carcinogenesis in transgenic mice overexpressing the endogenous angiogenesis inhibitor thrombospsondin-2

Introduction: Chemically-induced skin carcinogenesis is a well established cancer model in mice that allows a detailed evaluation of distinct stages of carcinogenesis, and that has also provided a more in-depth understanding of human epithelial cancer development. We have recently reported stromal upregulation of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistage skin carcinogenesis, and we found accelerated and enhanced tumor development and angiogenesis in TSP-2 deficient mice. Aim: To investigate whether enhanced levels of TSP-2 might protect from cancer development. Methods: We generated transgenic FVB mice overexpressing TSP-2 under the control of the keratin K14 promoter. TSP-2 transgenic mice and wild-type littermates were subjected to a standard two-step skin carcinogenesis regimen. For initiation, mice were treated once with 50µg DMBA, applied to the dorsal skin, followed by 20 weekly topical applications of 5µg of the tumor promoter PMA. Results: TSP-2 transgenic mice showed a delayed onset of tumor formation with an average latency period of 18 weeks, as compared to 14 weeks in wild-type mice. At 18 weeks after initiation of PMA promotion, the percentage of tumor-bearing mice was 100% in wild-type, as compared to 52% in TSP-2 transgenic mice. Moreover, the number of benign papillomas and malignant SCCs was significantly reduced in TSP-2 transgenic mice when compared to wild-type littermates. However, the ratio of malignant conversion papillomas to SCC was comparable in both genotypes. Quantitative analysis of tumor-associated blood vessels revealed that both vessel density and vessel size were decreased in TSP-2 transgenic mice. Conclusion: These results demonstrate that enhanced levels of TSP-2 result in reduced susceptibility to chemically-induced skin carcinogenesis, and they identify TSP-2 as a potential new target for the prevention of cancer development and progression.

Eingereicht von: PD Dr. Thomas Hawighorst

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