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Human placentation : the characterization of novel molecular mechanisms involved in trophoblast invasion Beristain, Alexander Guillermo


For normal human placental development to occur, cytotrophoblasts located within implanting chorionic villi, differentiate into extravillous cytotrophoblasts that invade into and remodel the maternal stroma and blood vasculature. Extravillous cytotrophoblast invasion is in part regulated by proteolytic and cell-extracellular matrix adhesion mechanisms that have also been shown to play key roles in regulating cancer cell invasion. Trophoblast invasion has therefore been likened to cancer cell invasion, however, unlike tumorigenesis, trophoblast invasion is highly regulated. ADAMTS, a novel gene family of metalloproteinases, have been shown to play important roles in regulating extracellular matrix remodeling events in both physiological and pathological processes. In addition to extracellular matrix remodeling, ADAMTS have the ability to regulate cell-extracellular matrix adhesion, highlighting the possibility that these proteins perform multifunctional roles. To determine whether members of the ADAMTS family play key roles in early placentation, I have characterized the expression of members of this gene family in first trimester placental chorionic villi and in subpopulations of trophoblastic cells. I determined that ADAMTS-12 is expressed in first trimester chorionic villous tissues, and furthermore is preferentially expressed in highly invasive extravillous cytotrophoblasts. Utilizing loss-of and gain-of function studies, I demonstrated that ADAMTS-12 plays a functional role in promoting an invasive phenotype in human trophoblastic cells through a mechanism independent of its proteolyic activity. As cell invasion is also regulated by changes in cell-cell adhesion, I examined the roles that the classical/type-I cadherins, E-cadherin and N-cadherin, play in controlling trophoblast invasion. I determined that E-cadherin and N-cadherin are differentially expressed between poorly-invasive and highly-invasive trophoblastic cells. Additionally, I demonstrated that E-cadherin inhibits trophoblast invasion in a cell adhesion dependent manner, whereas N-cadherin promoted an invasive phenotype through a mechanism dependent upon its extracellular domain. Collectively, these studies describe novel molecular mechanisms that regulate human trophoblast invasion in vitro. These studies are the first to describe a role for N - cadherin in promoting an invasive phenotype in trophoblastic cells, and are the first to describe a role for ADAMTS-12 in regulating cellular invasion. Additionally, these findings shed insight into the cellular mechanisms that regulate cytotrophoblast differentiation along the extravillous cytotrophoblast pathway.

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