Corticotropin-Releasing Hormone Modulates Human Trophoblast Invasion through Carcinoembryonic Antigen-Related Cell Adhesion Molecule-1 Regulation

Abstract

Abnormalities in the process of trophoblast invasion may result in abnormal placentation. Both the embryonic trophoblast and maternal decidua produce corticotropin-releasing hormone (CRH), which promotes implantation. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is expressed in extravillous trophoblasts (EVTs) of normal human placenta, may also function in trophoblast/endometrial interactions. We investigated whether locally produced CRH plays a role in trophoblast invasion, primarily by regulating CEACAM1 expression. We examined cultures of freshly isolated human EVTs, which express CEACAM1, and an EVTbased hybridoma cell line, which is devoid of endogenous CEACAM1. CRH inhibited EVT invasion in Matrigel invasion assays, and this effect was blocked by the CRH receptor type 1 (CRHR1)-specific antagonist antalarmin. Additionally, CRH decreased CEACAM1 expression in EVTs in a dose-dependent manner. After transfection of the hybridoma cell line with a CEACAM1 expression vector, the invasiveness of these cells was strongly enhanced. This effect was inhibited by addition of blocking monoclonal antibody against CEACAM1. Furthermore, blocking of endogenous CEACAM1 in EVTs inhibited the invasive potential of these cells. Taken together these findings suggest that CRH inhibits trophoblast invasion by decreasing the expression of CEACAM1 through CRHR1, an effect that might be involved in the pathophysiology of clinical conditions, such as preeclampsia and placenta accreta. The complex developmental process of implantation involves a series of steps leading to an effective cross-talk between invasive trophoblast cells and the maternal endometrium. This dynamic process requires a precisely coordinated development of a hormonally primed adhesive endometrium and a blastocyst competent to implant. The trophoblast undergoes a number of distinct interactions with the underlying endometrial surface initiated by apposition, which involves close proximity between trophoblast and endometrial epithelium, followed by attachment, and concluded by invasion of trophoblast into the decidualized stroma.1 However, the molecular interactions at the embryo-maternal interface during the time of adhesion and subsequent invasion are not fully understood.The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced in several organs of the female reproductive system, including the endometrial glands, decidualized stroma, and trophoblast. [2][3][4][5][6] In addition, the gene encoding the CRH receptor type 1Supported by the Alexander Onassis Foundation (grant to A.M. and S.N.K.) and the Deutsche Krebshilfe (grant 10-2063 to A.M.B. and J.B.).

CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases

“…However, instead of promoting growth, we show that CEACAM1 functions to retard several parameters of neoplastic growth and to enhance cell-matrix adhesion. This finding is consistent with the expression of CEACAM1 in extravillous intermediate trophoblast where it has been functionally implicated in mediating trophoblast/endometrial interactions during trophoblastic invasion of the endometrium (Bamberger et al, 2000(Bamberger et al, , 2006, and with its correlation with invasion in cutaneous malignant melanoma (Thies et al, 2002;Ebrahimnejad et al, 2004). These findings can be reconciled by a model in which upregulation of CEACAM1 during cell transformation may reflect a mechanism serving to impede further growth at the expense of promoting metastatic behavior.…”

Expression of the Metastasis Suppressor KAI1 in Decidual Cells at the Human Maternal-Fetal Interface

“…Corticotropin-releasing hormone, produced both by the trophoblast and the maternal decidua, has been shown to down-regulate expression of the carcinoembryonic antigen-related cell adhesion molecule 1, a cell surface molecule implicated in the invasive potential of EVTs. 41,42 In this study, we investigated for the first time the expression pattern of the metastasis suppressor KAI1 in the utero-placental unit. As shown by immunohistochemistry, strong expression of KAI1 was observed at the maternal-fetal interface, where KAI1 was expressed by the decidual cells and localized to the plasma membrane.…”

Expansion of decidual CD45RO+ T cells with high expression of CEACAM1 in the early stage of pregnancy

“…These data further implied that the soluble immune mediators resulting from the direct interaction between trophoblast cells and monocytes may contribute to the increase in the expression of CEACAM1 on the surface of CD4 + CD45RO + T cells, but not on that of CD8 + CD45RO + T cells, in first trimester human decidua. CEACAM1 has been detected on the surface of extravillous trophoblast cells, and is hypothesized to promote the invasion of these cells (33)(34)(35). In addition, numerous studies have demonstrated that CEACAM1 inhibits the cytokine production, proliferation and cytotoxic activity of activated T cells, by homophilic and heterophilic interactions (26)(27)(28)(29).…”