Paracrine and autocrine regulators of trophoblast invasion--a review

Cytotrophoblastic cells (CTBs) from first trimester placenta follow one of two existing differentiation pathways: villous CTBs (vCTBs) form a monolayer of polarized epithelial stem cells which proliferate and eventually differentiate by fusion to form a syncytiotrophoblast (STB) covering the entire surface of the villus, or they can break through the STB at selected sites (in anchoring villi) to form multilayered columns of non-polarized but invasive CTBs. In vitro, CTBs invade a reconstituted basement membrane, they thus behave like metastatic cells. This invasive behaviour is due to the ability of CTBs to secrete matrix metalloproteinases (MMPs) since tissue inhibitor of MMP (TIMP) inhibits their invasiveness. MMPs are a family of at least 17 human zinc-dependent endopeptidases collectively capable of degrading essentially all components of the extracellular matrix (ECM). Although CTBs behave like metastatic cells, in vivo they are only transiently invasive (first trimester) and their invasion is normally limited only to the endometrium and to the proximal third of the myometrium. This temporal and spatial regulation of trophoblast invasion is believed to be mediated in an autocrine way by trophoblastic factors and in a paracrine way by uterine factors. Several types of regulators have been investigated: hormones, cytokines, growth factors and ECM glycoproteins. This review is not intended to be an exhaustive catalogue of all the potential regulators but is aimed at emphasizing those factors relevant in trophoblast-endometrial interactions.