Control mechanisms in human trophoblast proliferation and invasiveness: Their derangement during trophoblastic tumor progression: A review

Abstract

Summary Extravillous trophoblast (EVT) cells of the human placenta proliferate, migrate and invade the decidua and its vasculature. By utilizing in vitro propagated normal first trimester human EVT cells in functional assays, we have shown that proliferative, migratory and invasive functions of these cells are stringently regulated in situ by numerous growth factors, their binding proteins and proteoglycans and extracellular matrix (ECM) components. Growth factors in the EGF family (EGF, TGFβ and amphiregulin), CSF-1, VEGF and PIGF all stimulate EVT cell proliferation without affecting migratory or invasive abilities, whereas IGF-II and its binding protein IGFBP-1 stimulate EVT cell migration and invasiveness without affecting proliferation. Finally, TGFβ a major decidual cell product, inhibits proliferation, migration and invasiveness of normal EVT cells, whereas choriocarcinoma cells defy the TGFβ mediated control. We have produced “premalignant” derivatives of normal EVT cells by SV40 Tag transfection, some of which are immortal (as opposed to normal EVT cells which senesce at 5–15 passages), hyperproliferative, hyperinvasive, resistant to antiproliferative and antiinvasive action of TGFβ and deficient in gap junctional intercellular communication, but are yet incapable of anchorage independent growth or tumorigenicity in nude mice. Transition of the normal EVT cell to the premalignant stage is associated with multiple genetic changes, e.g., a downregulation of connexins, TIMP-1, TIMP-2 and PAI-I, which partially account for the phenotypic changes. We have recently intruduced activated H-ras oncogene into a premalignant EVT cell line to induce malignant/metastatic phenotype. Normal, premalignant and malignant EVT cell lines derived from a single placenta provide us with an exquisite in vitro model for studies of stage-specific genetic changes responsible for trophoblastic tumor progression.