Regulation of human trophoblast migration and invasiveness

Abstract

The human placenta is an invasive structure in which highly proliferative, migratory, and invasive extravillous trophoblast (EVT) cells migrate and invade the uterus and its vasculature. Using in vitro propagated normal first-trimester EVT cells and immortalized EVT cells, which share all of the phenotypic and functional characteristics of the normal EVT cells, it has been shown that migration/invasion of human EVT cells is stringently regulated by many growth factors, their binding proteins, extracellular matrix (ECM) components, and some adhesion molecules in an autocrine/paracrine manner at the fetal-maternal interface in human pregnancy. Transforming growth factor beta (TGF-beta), decorin (a proteoglycan in the ECM), and melanoma cell adhesion molecule (Mel-CAM) inhibit, and insulin-like growth factor II (IGF-II), IGF-binding protein 1 (IGFBP-1), and endothelin 1 (ET-1) stimulate EVT cell migration/invasion. Inhibition of EVT cell migration by TGF-beta has been suggested to be due to upregulation of integrins, which make the cells more adhesive to the ECM. Its antiinvasive action is due to an upregulation of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) and plasminogen activator inhibitor (PAI-1) and a downregulation of urokinase-type plasminogen activator (uPA). Molecular mechanisms of inhibition of migration/invasion of EVT cells by decorin and Mel-CAM remain to be identified. IGF-II action has been shown to be mediated by IGF type I receptors (IGF-RII) independently of IGF type I receptors (IGF-RI) and IGFBPs. This action of IGF-II appears to involve inhibitory G proteins and phosphorylation of mitogen-activated protein kinase (MAPK) (extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and ERK-2)). IGFBP-1 stimulation of EVT cell migration appears to occur by binding its Arg-Gly-Asp (RGD) domain to alpha5beta1 integrin, leading to phosphorylation of focal adhesion kinase (FAK) and MAPK (ERK-1 and ERK-2). These studies may improve our understanding of diseases related to abnormal placentation, viz. hypoinvasiveness in preeclampsia and hyperinvasiveness in trophoblastic neoplasms.

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…For example, shallow invasion is a characteristic feature of pre-eclampsia and fetal growth restriction, while abnormal deep EVT invasion is associated with placenta accreta/increta/percreta 14 and uncontrolled invasion by EVT is associated with choriocarcinoma. 15 …”

CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties

“…FAK is involved in integrinmediated signal transduction pathways of the extracellular matrix and plays an important role in the regulation of cell proliferation, migration, and invasion. 53 It is known that the activation of Akt and ERK1/2 is related to cell migration and the activation of FAK [54][55][56][57] and that these kinases are involved in trophoblast migration and invasion (reviewed by Chakraborty et al 8 ). In SGHPL-5 cells, phosphorylation and thereby activation of FAK occurs only after treatment with glycosylated CCN3.…”

“…In humans, these two processes are tightly controlled by a plethora of multiple and complex signaling factors, such as growth factors, hormones, and chemokines. [8][9][10][11] Preeclampsia, a complication in pregnancy, is known to coincide with an insufficient invasion of trophoblast cells into the decidua and the maternal spiral arteries. Such placentas lack sufficient maternal vascular remodeling, and this characteristic, combined with a restricted supply of oxygen and nutrition for the embryo, may result in intrauterine growth restriction.…”

Inhibition of Cytotrophoblastic (JEG-3) Cell Invasion by Interleukin 12 Involves an Interferon γ-mediated Pathway

“…Although invasion normally results from the combined action of all these proteases, MMPs seem to contribute substantially during trophoblast invasion, digesting the chemically complex extracellular matrix collagens (42). Regulation of MMPs and uPA, thus, appear to form the crucial step in moderating invasion, which also involves the participation of metalloprotease inhibitors like tissue inhibitors of metalloproteases, TIMPs (4,41,43,44), and plasminogen activator inhibitors, PAIs (45,46). These inhibitors, thus, counteract the action of the respective proteases.…”

“…Trophoblast cells are instrumental during implantation and placentation both in terms of molecular recognition and cross-talk at the feto-maternal interface as well as a repository of variety of cytokines and growth factors that influence both the conceptus and the maternal physiology in an autocrine, paracrine, or juxtacrine manner (1,2). This represents a highly complex but coordinated process involving the participation of different trophoblast cell populations with specific functions (3,4). The interaction begins as the blastocyst enters the uterine lumen and becomes apposed to the uterine epithelium with its trophoblast cells penetrating deeper into the endometrium.…”