The aim of this project is to investigate the role of serine, cysteine and metallo-proteases in the development and progression of mouse epithelial cancers and to test the effects of anti-protease therapy in inhibiting these processes. Transgenic models for the development and progression of mouse tumors will be used to characterize the nature of protease involvement in transformation of epithelial cells as well as primary tumor growth. Invasion and metastasis. By crossing these animals into mouse backgrounds that are null for specific proteases or protease inhibitors, or that overexpress specific protease inhibitors on constitutive or temporally regulated promoter/enhancers, it will be possible to determine when specific proteases or classes of proteases act, and which processes (growth, invasion, metastasis, genomic instability) are downstream from protease action. The relative contributions of proteases from epithelial and/or stromal sources will be evaluated by transplanting neoplastic tissue or cells from one type of protease background onto animals of a distinct background. Angiogenesis, stromal activation and tumor development will then be assessed. Taken together, these model systems will elucidate the role of proteases in the development of the preneoplastic lesions as well as in malignant conversion, and provide proof-of- concept for anti-protease therapy in different stages of the development and progression of epithelial cancers.
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| LeBeau, Aaron M; Duriseti, Sai; Murphy, Stephanie T et al. (2013) Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. Cancer Res 73:2070-81 |
| Darragh, Molly R; Schneider, Eric L; Lou, Jianlong et al. (2010) Tumor detection by imaging proteolytic activity. Cancer Res 70:1505-12 |
| Sounni, Nor E; Dehne, Kerstin; van Kempen, Leon et al. (2010) Stromal regulation of vessel stability by MMP14 and TGFbeta. Dis Model Mech 3:317-32 |
| Littlepage, Laurie E; Sternlicht, Mark D; Rougier, Nathalie et al. (2010) Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res 70:2224-34 |
| Kessenbrock, Kai; Plaks, Vicki; Werb, Zena (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52-67 |
| Lederle, Wiltrud; Hartenstein, Bettina; Meides, Alice et al. (2010) MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma. Carcinogenesis 31:1175-84 |
| Barkan, David T; Hostetter, Daniel R; Mahrus, Sami et al. (2010) Prediction of protease substrates using sequence and structure features. Bioinformatics 26:1714-22 |
| Sun, Cheng; Su, Kai-Hung; Valentine, Jason et al. (2010) Time-resolved single-step protease activity quantification using nanoplasmonic resonator sensors. ACS Nano 4:978-84 |
| Andreu, Pauline; Johansson, Magnus; Affara, Nesrine I et al. (2010) FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17:121-34 |
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