Molecular mechanisms of tumor invasion in three-dimensional collagen matrices

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Cancer remains a significant cause of morbidity and mortality worldwide, and invasion and metastasis substantially contribute to poor prognosis and survival outcomes. Current therapeutics lack specificity and do not target these malignant properties of tumor cells due mainly to our incomplete understanding of the molecular mechanisms governing these biological processes. Thus, it is imperative to develop experimental models and investigate the molecular mechanisms of tumor invasion. The experiments in this dissertation were designed to identify (in developed novel in vitro systems) the molecular requirements for tumor invasion. The data herein suggests that tumor cells invade collagen matrices in response to lysophosphatidic acid in a membrane-type matrix metalloproteinase 1 (MT1-MMP)-dependent manner. Furthermore, invading cells use MT1-MMP to create single cell invasion tunnels (SCITs). SCITs are physical entities that are products of proteolysis. SCITs serve as a two-dimensional substrate that cells then migrate upon. Additionally, cells utilize differential molecular mechanisms when they create SCITs versus migrating through them. By defining differential signaling requirements during different stages of tumor invasion, this work may yield potentially specific molecular therapeutic targets for cancer treatment.