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Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice

Oncogene volume 21, pages 7945–7956 (2002)Cite this article

Abstract

The roles played by the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) in the early stages of multi-step carcinogenesis and in the control of hematogenous versus lymphatic metastasis are unknown. To investigate these issues we compared tumor development in normal mice and in transgenic mice with targeted overexpression of TSP-1 in the epidermis following a standard two-step chemical skin carcinogenesis regimen. Overexpression of TSP-1 resulted in delayed and reduced development of premalignant epithelial hyperplasias, but did not inhibit the malignant conversion to squamous cell carcinomas. TSP-1 overexpression also suppressed tumor angiogenesis and distant organ metastasis, but failed to inhibit tumor-associated lymphangiogenesis or lymphatic tumor spread to regional lymph nodes. Concomitant with these results, we found that the endothelial TSP-1 receptor CD36 was mostly absent from cutaneous lymphatic vessels. Our findings indicate the potential use of TSP-1 for the prevention of premalignant stages of tumorigenesis and are likely to have implications for the further development of anti-angiogenic cancer therapies.

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Acknowledgements

The authors thank R Silverstein, P Thorpe, R Brekken and R Swerlick for the generous gift of antibodies, M Mihm and S Dadras for advice on mouse skin pathology, J Nagy for statistical advice and M Constant for technical assistance. This work was supported by NIH/NCI grants CA69184, CA86410 and CA91861 (M Detmar), by NIH grants GM58462 and EY12162 (G Oliver), by American Cancer Society Program Project Grant 99-23901 (M Detmar), by the Deutsche Forschungsgemeinschaft (T Hawighorst), by Deutscher Akademischer Austauschdienst (M Streit), by the Dermatology Foundation (M Streit), by the American Lebanese Syrian Associated Charities (G Oliver) and by the Cutaneous Biology Research Center through the Massachusetts General Hospital/Shiseido Co. Ltd., Agreement (M Detmar).

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Authors and Affiliations

  1. Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, Massachusetts, MA, USA

    Thomas Hawighorst, Hajimu Oura, Michael Streit, Lauren Janes, Lynh Nguyen & Michael Detmar

  2. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts, MA, USA

    Lawrence F Brown

  3. Department of Genetics, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, TN, USA

    Guillermo Oliver

  4. IMCR Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, OX3 9DS, Oxford, UK

    David G Jackson

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  1. Thomas Hawighorst
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Correspondence to Michael Detmar.

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Hawighorst, T., Oura, H., Streit, M. et al. Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene 21, 7945–7956 (2002). https://doi.org/10.1038/sj.onc.1205956

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