Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype

Abstract

Cytotrophoblasts of the anchoring villi convert during human placentation from a transporting epithelium to an invasive, extravillous phenotype that expresses a distinct repertoire of adhesion molecules. Developing extravillous trophoblasts accumulate heparin-binding EGF-like growth factor (HB-EGF), a multifunctional cytokine, which binds HER1 and HER4 of the human EGF receptor (HER/ErbB) family. HB-EGF is downregulated in placentae of women with preeclampsia, a disorder associated with deficient trophoblast invasion, raising important questions about its physiological impact on cytotrophoblasts. Addition of HB-EGF during explant culture of first-trimester chorionic villi enhanced extravillous trophoblast differentiation and invasive activity. Using a first-trimester human cytotrophoblast line, the potential for autocrine and paracrine regulation of the developing trophoblast was established based on the expression of all four HER isoforms, as well as HB-EGF and related growth factors. HB-EGF did not alter proliferation, but initiated extravillous differentiation, with decreased alpha6 integrin expression, increased alpha1, and elevated cell migration. Function-blocking antibodies against EGF family members reduced basal cell motility and antibody inhibition of either HER1 or HER4 ligation prevented HB-EGF-induced integrin switching. We conclude that HER-mediated autocrine and paracrine signaling by HB-EGF or other EGF family members induces cytotrophoblast differentiation to an invasive phenotype.

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

“…(54) In addition, HB-EGF is downregulated in the placenta of women with pre-eclampsia, a disorder associated with deficient trophoblast invasion, and the addition of HB-EGF to explant cultures of first-trimester chorionic villi enhances extravillous trophoblast differentiation and invasive activity. (55,56) Thus, sHB-EGF plays key roles in various physiological processes, including cell motility, cell migration and invasion.…”

Prophylactic Low Molecular Weight Heparin Improving Perinatal Outcome in Non-thrombophilic Placental-Mediated Complications

“…LMWH promotes the differentiation and invasion of the trophoblast in vivo [17,18], prevents monocyte adhesion to activated endothelium [19], and inhibits tumor necrosis factor-a-induced leukocyte rolling [20]. These drugs decrease vascular resistance in vitro [21] and in vivo [15][16][17][18][19][20][21][22].…”

The physiologic and therapeutic role of Heparin in implantation and placentation

“…For example, during extravillous differentiation in vivo, integrin expression is altered from predominantly α6β4 in the villous trophoblast to α1β1 in cytotrophoblasts migrating throughout the decidual stroma 17 or engaging in endovascular invasion 18 . Leach et al 34 demonstrated the role of HB-EGF in regulating the conversion of human cytotophoblasts into invasive phenotype and the motility of these cells. This study demonstrated the ability of HB-EGF to induce 'integrin switching' through intracellular signaling induced by ligation of HER tyrosine kinases, alters integrin gene expression to stimulate cytotrophoblast invasion at a molecular level.…”