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The Matrix Metalloproteinase-1/protease activated receptor-1 signaling axis in melanoma progression.

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Call No.	QP609.C64 B63 2009
Author	Blackburn, Jessica Susanne.
Title	The Matrix Metalloproteinase-1/protease activated receptor-1 signaling axis in melanoma progression.
Date	2009
Abstract	The inappropriate expression of Matrix Metalloproteinases (MMPs) contributes to the pathology of many cancers. Among these, melanoma is a particularly insidious disease in that it is almost completely resistant to every known the therapy, and the average survival of patients with dissemination is only 8 months. There is therefore interest in identifying the molecular mechanisms governing melanoma invasion and metastasis. Of the MMPs, the interstitial collagenase MMP-1 is expressed specifically by invasive and metastatic melanomas; however, the role of MMP-1 in melanoma progression is unknown. Work in this thesis begins to define the role of MMP-1 in melanoma invasion and metastasis. Knock-down of MMP-1 expression in a human melanoma cell line, using RNAi, was found to prevent melanoma metastases from the skin to the lung in a xenograft model. This effect was partly linked to the collagenolytic activity of MMP-1, which was found to be necessary for melanoma cell invasion. MMP-1 was also found to be directly pro-angiogenic, promoting vessel formation in vivo via activation of Protease Activated Receptor-1 (PAR-1), expressed by endothelial cells. Importantly, MMP-1 and thrombin were found to differentially cleave and activate PAR-1, inducing the expression of different pro-angiogenic genes in endothelial cells. In vitro and in vivo , the effects of MMP-1 and thrombin were additive, inducing more angiogenesis melanoma metastasis. MMP-1 also activated PAR-1 expressed by melanoma cells, in an autocrine manner, to induce pro-invasive gene expression. Additionally, MMP-1 expression in a non-invasive and non-metastatic human melanoma cell line induced a pro-invasive and metastatic phenotype. Together, data presented in this thesis suggest that MMP-1 is an important mediator of melanoma invasion and metastasis, and may represent a therapeutic target in controlling this disease.
Description	xv, 201 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Brinckerhoff, Constance E., Turk, Mary Jo, Lowrey, Christopher, Madri, Joseph
Subject	Collagenases -- Pathophysiology. Metalloproteinases -- Pathophysiology. Melanoma -- Molecular aspects. Matrix Metalloproteinase 1.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.304

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	The Matrix Metalloproteinase-1/Protease Activated Receptor-1 signaling axis in melanoma progression A Thesis Submitted to the Faculty In partial fulfillment of the requirements for Doctor of Philosophy in Biochemistry by Jessica Susanne Blackburn DARTMOUTH COLLEGE Hanover, NH May, 2009 Examining Committee: Mary Jo Turk, Ph.D. (chair) Christopher Lowrey, M.D. Joseph Madri, M.D., Ph.D. Brian W. Pogue, Ph.D. Dean of Graduate Studies Constance Brinckerhoff, Ph.D.

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