- Angiogenesis is a stepwise process involving vascular hyperpermeability, degradation of extracellular matrix, endothelial cell migration and proliferation, and formation and maturation of new capillary tubes. Whereas primary angiogenesis is a prominent feature of mammalian embryonic development, normal adult skin exhibits little or no vascular proliferation. However, skin retains the capacity to initiate a brisk neovascular response in many disorders including tissue repair, inflammation, and neoplasia. The normal quiescence of adult cutaneous vasculature suggests that vascular homeostasis in the skin is maintained by a balance between secreted factors that enhance or inhibit endothelial cell growth. While several epidermis-derived angiogenic factors have been identified, little is known about inhibitors of skin angiogenesis. Thromposbondin-1 (TSP-1) is a member of a small group of recently identified endogenous inhibitors of angiogenesis. TSP-1 expression is downregulated in squamous cell carcinomas of the skin, lesions that are characterized by richly angiogenic stroma as compared to non-neoplastic epidermis. TSP-1 inhibited several biological effects induced by the potent skin angiogenesis factor, vascular endothelial growth factor (VEGF), including dermal microvascular endothelial cell proliferation, spreading, and matrix metalloproteinase expression in vitro and sprouting of blood microvessels in vivo. Overexpression of TSP-1 inhibited tumor growth and angiogenesis of human squamous cell carcinoma xenotransplants in vivo. In addition, preliminary studies by the principal investigator recently established transgenic mouse models for skin skin-specific TSP-1 overexpression and deficiency; and in contrast to his prior studies of skin-specific VEGF transgenic mice, these new studies suggest that TSP-1 is an important regulator of skin angiogenesis.
Three aims are proposed: 1) Determine the importance of TSP-1 in normal skin vascularization and in experimental skin inflammation, making use of skin specific TSP-1 and TSP-1 null mice and of crosses with VEGF transgenic mice; 2) determine the role of TSP-1 in the multistep process of skin carcinogenesis, and 3) determine the function of transfected wild type and distinct mutated TSP-1 gene constructs in modulating angiogenesis and malignant growth of human squamous cell carcinoma xenotransplants.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086410-05
Application #
6692657
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Macleod, Carol L
Project Start
2000-02-18
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2005-12-31
Support Year
5
Fiscal Year
2004
Total Cost
$319,912
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Liersch, Ruediger; Shin, Jay W; Bayer, Michael et al. (2012) Analysis of a novel highly metastatic melanoma cell line identifies osteopontin as a new lymphangiogenic factor. Int J Oncol 41:1455-63
Liersch, Ruediger; Hirakawa, Satoshi; Berdel, Wolfgang E et al. (2012) Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator. Int J Oncol 41:2073-8
Marino, Daniela; Dabouras, Vasilios; Brändli, André W et al. (2011) A role for all-trans-retinoic acid in the early steps of lymphatic vasculature development. J Vasc Res 48:236-51
Velasco, Paula; Huegel, Rainer; Brasch, Jochen et al. (2009) The angiogenesis inhibitor thrombospondin-1 inhibits acute cutaneous hypersensitivity reactions. J Invest Dermatol 129:2022-30
Shin, Jay W; Huggenberger, Reto; Detmar, Michael (2008) Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis. Blood 112:2318-26
Dadras, Soheil S; Skrzypek, Adrienne; Nguyen, Lynh et al. (2008) Prox-1 promotes invasion of kaposiform hemangioendotheliomas. J Invest Dermatol 128:2798-806
Shin, Jay W; Jurisic, Giorgia; Detmar, Michael (2008) Lymphatic-specific expression of dipeptidyl peptidase IV and its dual role in lymphatic endothelial function. Exp Cell Res 314:3048-56
Hirakawa, Satoshi; Brown, Lawrence F; Kodama, Shohta et al. (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109:1010-7
Kajiya, Kentaro; Hirakawa, Satoshi; Detmar, Michael (2006) Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 169:1496-503
Shin, Jay W; Min, Michael; Larrieu-Lahargue, Frederic et al. (2006) Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 17:576-84

Showing the most recent 10 out of 48 publications