Cell-cell and cell-matrix interactions involved in cancer invasion
Author
Bair, Elisabeth LaurineIssue Date
2004Advisor
Bowden, G. Timothy
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The University of Arizona.Rights
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.Abstract
In order for a cancer to metastasize, it must first invade through the basement membrane that surrounds it, invade blood vessels and travel through the bloodstream to a new location where it extravasates the vessel and begins growing at the new site. The mechanisms by which a cancer becomes able to invade and metastasize are currently under intense study. Interactions of the cell with its environment via cell-cell contacts, extracellular matrix (ECM) interactions, and circulating proteins are thought to play a major role in signaling for these invasive processes to occur. Upregulation of proteolytic enzymes, such as the matrix metalloproteases, is suspected of being involved in the metastatic process. Cell-cell and cell-matrix contacts via integrins and cadherins are necessary for upregulation of the matrix metalloprotease matrilysin in oral squamous cell carcinoma. In an effort to identify the factors involved in upregulation of matrilysin expression detected in a co-culture of oral squamous cell carcinoma (SCC) cells and fibroblast cells, a coculture model designed to represent the actual tumor environment, we show that inhibition of beta1 integrin, E-cadherin, and N-cadherin with blocking antibodies thoroughly decreases the induction of matrilysin in the co-culture model. This demonstrates that interactions between cancer cells and normal cells surrounding them may allow for invasion and metastasis. The protein 90K may also play a role in the invasive process of prostate cancer. It functions as an immune modulator upregulating cytokines that induce MMPs and we show that it can induce matrilysin expression in prostate cancer cells. It also functions in cell aggregation, which can help cells survive during metastasis. For this reason, expression of 90K in prostate cancer, which we examined, may be indicative of aggressive disease, making 90K a potentially useful tumor marker. Cell-matrix contacts are also important for the transmembrane matrix metalloprotease MT1-MMP cleavage of laminin-10. We demonstrate that recombinant MT1-MMP is able to cleave human laminin-10 into four distinct products. This allows for prostate cancer cell migration on laminin-10 coated substrates, which can be inhibited with the addition of MT1-MMP antisense oligonucleotides. Ln-10 cleavage also occurs in vivo in human prostate tissue, indicating that this cell-matrix interaction has in vivo relevance in human prostate cancer.Type
textDissertation-Reproduction (electronic)
Degree Name
Ph.D.Degree Level
doctoralDegree Program
Graduate CollegeCancer Biology