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The ADAMs family of proteins are unique in that they possess both A Disintegrin and Metalloprotease domain so potentially have multiple functions in cell adhesion via their integrin‐binding domain and extracellular matrix degradation/cell invasion/protease and/or growth factor activation via their metalloprotease domain. The ‘knock‐out’ of ADAM‐10 expression in the mouse is phenotypically lethal. This is due to the absolute requirement for ADAM‐10 during early embryo development.
ADAM‐10 has many crucial functions at this time including the activation of several growth factors and the regulation of the cell adhesion molecules, cadherins. Recent studies strongly implicate the down‐regulation of E‐cadherin as a rate‐limiting step in the Epithelial to Mesenchymal Transition (EMT). The EMT occurs during early embryo development in the development of the germ layers and is also implicated as a precursor to the ability of cancer cells to metastasise from a primary tumour to a secondary or metastatic site. Increased cancer cell migration and invasion capabilities are also precursors to metastasis.
Previous studies in our laboratory have examined the temporal and spatial expression profiles of ADAM‐10 in a model of normal trophoblast cell migration and invasion occurring during embryo implantation into the uterus and also malignant trophoblast cell invasion using human choriocarcinoma cells (a germ cell tumour).
Using mouse embryos and corresponding uterus (model of normal and regulated cell invasion), RT‐PCR and Western hybridisation studies demonstrated ADAM‐10 expression in fertilised eggs, 2‐cell embryos, morulae, blastocysts and day 7.5, 8.5 and 9.5 implanting embryos. Spatial expression of ADAM‐10 was also determined by in situ hybridisation on day 7.5 and 9.5 in utero sections and shown to be localised to the most invasive cells of the embryo, the cytotrophoblast cells with no measurable expression detected in the embryo proper, ectoplacental cone (EPC) or the maternal uterus.
The more sensitive technique of in situ RT‐PCR hybridisation did identify ADAM‐10 expression in the embryo proper, EPC and the maternal uterus but at a much lower level. Using our model of malignant trophoblast invasion, we demonstrated expression of ADAM‐10 at both the RNA and protein level in three different human choriocarcinoma cell lines.
The objective of this Honours project will be to determine the functional significance of ADAM‐10 expression by malignant trophoblast cells (choriocarcinoma cells) and to investigate the role of ADAM‐10 in stimulating the EMT, cell migration and cell invasion that precedes cancer metastasis (spread to secondary sites).