Rainer Kunstfeld1, Thomas Hawighorst2, Michael Streit3, Young-Kwon Hong4, Lynh Nguyen3, Lawrence F Brown5, Michael Detmar6. 1. Department of Dermatology, Division of General Dermatology, Medical University Vienna, Vienna, Austria; Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. 2. Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA; Department of Gynecology and Obstetrics, Georg-August University Goettingen, Goettingen, Germany. 3. Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. 4. Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA; Department of Surgery, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 5. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. 6. Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland. Electronic address: michael.detmar@pharma.ethz.ch.
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.
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-2transgenic mice and their wild-type littermates to a chemical skin carcinogenesis regimen. RESULTS:TSP-2transgenic 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 transgenicTSP-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.
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