title: Thrombospondin-2 overexpression in the skin of transgenic mice reduces the susceptibility to chemically induced multistep skin carcinogenesis.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Rainer
authors: R
authors: Kunstfeld
authors: 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.
authors: Thomas
authors: T
authors: Hawighorst
authors: Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors: Michael
authors: M
authors: Streit
authors: 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.
authors: Young-Kwon
authors: YK
authors: Hong
authors: Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors: Lynh
authors: L
authors: Nguyen
authors: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors: Lawrence F
authors: LF
authors: Brown
authors: 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.
authors: Michael
authors: M
authors: Detmar
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099262:Thrombospondin 2
chemical_list: D015415:Biomarkers; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D000099262:Thrombospondin 2; C467480:vascular endothelial growth factor A, mouse
keywords: Angiogenesis; Carcinogenesis; Skin cancer; Thrombospondin