The role of metastasis-associated proteins in trophoblast motility and invasion

Abstract

During placental development, the pathways that regulate the invasion of trophoblasts into the decidua will lead to remodelling the uterine vasculature and will eventually give rise to placenta formation. The same pathways get reactivated during cancer development and can lead to tumour cell invasion and the metastatic process. As a consequence, there are striking similarities between the behaviour of tumour cells and the trophoblasts, due to their similar gene expression pattern and protein profile and we set about to determine whether factors which have been shown to play important roles in cancer biology are also expressed and regulate trophoblast function. In this study we have focused on three different metastasis-associated proteins with well-defined roles in cancer progression, which have been closely linked with poor prognosis for cancer patients but have not been greatly studied in the context of placental development. The proteins are a small calcium-binding protein S100P, the ERM protein ezrin and the cytoskeletonmembrane linking protein, IQGAP1. After showing their expression and localisation pattern in human placental villi, we showed that these proteins are highly expressed during the earlier stages of the gestation, suggesting a potential role in early placenta development and implantation. We then studied their expression and localisation in trophoblast cell lines and primary trophoblasts. Using the trophoblast cell lines, through loss-of-function, and where relevant, gain of function studies, we showed that these three metastasis-associated proteins promote trophoblast motility and invasion. We also investigated some of the possible mechanisms that might have been involved in the mentioned pathways including changes in focal adhesions, protein localisation and phosphorylation. We have yet to investigate the underlying mechanisms that link these three proteins to trophoblast motility and invasion, and whether all or two of them work together to make these processes possible.