Matrix degrading proteases and collagen-derived angiogenesis inhibitors in the regulation of carcinoma cell growth
1University of Oulu, Faculty of Medicine, Institute of Dentistry, Department of Oral and Maxillofacial Surgery
|Online Access:||PDF Full Text (PDF, 1.8 MB)|
|Persistent link:|| http://urn.fi/urn:isbn:9514276612
|Publish Date:|| 2005-04-05
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 1 of the Institute of Dentistry, on April 15th, 2005, at 12 noon
Professor Jorma Keski-Oja
Professor Marikki Laiho
Cancer progression is a complex multi-step process. Two critical steps in tumor growth and invasion are the proteolytic processing of the extracellular matrix environment and the angiogenic switch enabling blood supply into the tumor.
Matrix metalloproteases (MMPs) are a group of proteolytic enzymes involved in physiological and pathological extracellular matrix processing. Trypsinogen, a serine protease, is one of the first proteolytic enzymes characterized. The amount of one of its isoforms, tumor associated trypsinogen-2 (TAT-2) correlates with the malignant phenotype of several forms of cancers. Both of these protease groups are critically dependent on their activation from latent proforms to fully active enzymes. We found that the overproduction of TAT-2 in malignant oral squamous cell carcinoma cell line was associated with elevated proMMP-9 (but not proMMP-2) activation, as well as enhanced cancer cell intravasation in an in vivo model. This indicates that TAT-2 and MMP-9 activation play a role in the invasive growth of oral carcinomas.
Proteases are involved in angiogenesis, the formation of new blood vessels, in several ways. One mechanism is the release of cryptic anti-angiogenic molecules from larger extracellular matrix components. Endostatin is one such cryptic endogenous inhibitor of angiogenesis. Certain MMPs were able to cleave endostatin from its parent molecule, collagen XVIII. The endostatin fragments generated by MMP-3, -7, -9, -13 and -20 inhibited angiogenesis in a similar fashion as the native endostatin. The regulation between MMPs and endostatin was shown to be reciprocal, as endostatin was able to block the activation and activities of MMP-2, -9 and -13. The inhibition of these tumor-associated MMPs explains at least in part the anti-tumor activity of endostatin. Endostatin not only affects endothelial cell growth as is usually thought, but it also inhibits the migration of oral carcinoma cells. In addition, cell density and proper concentration were proven to be critical for the activity of endostatin. Arresten is another endogenous inhibitor of angiogenesis and tumor growth derived from type IV collagen. We confirmed that arresten binds to integrin α1β1 on endothelial cell surface. We found that this binding is functionally significant for the anti-angiogenic properties of arresten, as tumors planted to integrin α1 knockout mice or endothelial cells derived from those mice did not respond to arresten treatment.
Acta Universitatis Ouluensis. D, Medica
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