Expression of the metastasis suppressor KAI1 in decidual cells at the human maternal-fetal interface: Regulation and functional implications.

At the human maternal-fetal interface, the decidua forms a dense matrix that is believed to limit trophoblast invasion. We investigated whether the metastasis suppressor KAI1 (CD82) is expressed at the maternal-fetal interface. Immunohistochemistry showed strong expression of KAI1 in decidual cells, whereas trophoblast cells were negative for KAI1. In luteal phase endometrium, KAI1 was present in decidualizing endometrial stromal cells. We investigated whether KAI1 expression in endometrial stromal cells is regulated by the decidualizing stimuli cAMP and progesterone or by the cytokine interleukin (IL)-1beta. Western blot analysis revealed induction of KAI1 protein by cAMP analog, but not by progesterone, in a delayed fashion. In contrast, IL-1beta rapidly stimulated KAI1 expression at the transcript level and at the protein level. Cultured decidual cells from term placenta expressed a basal level of KAI1 protein that was elevated on cAMP stimulation. Silencing of KAI1 by RNA interference attenuated expression of decorin, a decidual product implicated in limiting trophoblast invasion. This study shows for the first time the expression of KAI1 in decidual cells at the human maternal-fetal interface, where the metastasis suppressor might participate in intercellular communication with trophoblast cells and the control of trophoblast invasion.

Osteopontin expression in gestational trophoblastic diseases: correlation with expression of the adhesion molecule, CEACAM1.

The human placenta is a complex tissue with multiple endocrine and nutritional functions and a unique capacity for rapid proliferation but tightly controlled invasion, differentiating it from malignant tumors. Osteopontin (OPN) is a glycoprotein of the extracellular matrix, which has been shown to mediate cellular migration and invasion and to contribute to tumorigenesis in several types of cancers. OPN also could be implicated in regulating implantation and placentation by promoting cellular migration and invasion in a placenta-specific fashion. We could demonstrate the expression pattern of OPN in the normal human placenta in which it is localized in the extravillous (intermediate) trophoblast and the villous cytotrophoblast. CEACAM1 is an adhesion molecule, which we have recently found to be expressed at the maternal-fetal interface of the normal placenta with a localization to the extravillous (invasive) trophoblast and in gestational trophoblastic disease (GTD) and also to be potentially implicated in trophoblast invasion and tumorigenesis. Both OPN and CEACAM1 have been shown to interact with integrin beta3. The purpose of this study was to investigate the expression pattern of OPN in GTD and to correlate it with the expression of CEACAM1. To analyze the expression of OPN, we performed immunohistochemistry on a total of 27 cases of GTD, including 21 hydatidiform moles and 6 choriocarcinomas, which had previously been characterized with respect to their CEACAM1 expression. Hydatidiform moles showed a positivity for OPN in villous cytotrophoblast and in the trophoblast proliferations on the villous surface. The strongest OPN expression could be observed in the choriocarcinomas with a heterogenous OPN expression pattern. CEACAM1 had shown similar results and was found to be expressed in choriocarcinoma. The expression pattern of osteopontin in gestational trophoblastic diseases indicates that it might play a role in the pathogenesis of GTD (possibly as a functional complex with CEACAM1 and integrin beta3) and might be useful as an additional diagnostic marker for such lesions.

Osteopontin is colocalized with the adhesion molecule CEACAM1 in the extravillous trophoblast of the human placenta and enhances invasion of CEACAM1-expressing placental cells.

CONTEXT: The human placenta is a complex tissue and possesses, through its capacity to proliferate and to invade maternal tissue, qualities that are usually found in malignant tumors. Osteopontin (OPN) and CEACAM1 may regulate these processes. OBJECTIVE: The present study was designed to investigate the expression pattern of OPN in the human placental components and to correlate it with CEACAM1 expression and function in placental cell invasiveness. DESIGN: Immunohistochemistry with an OPN-specific antibody and immunofluorescence were performed on normal placental samples to investigate the expression pattern of OPN and CEACAM1 in the human placenta. Extravillous trophoblast (EVT) hybridoma cells transfected with CEACAM1 and stimulated with OPN were studied using the Matrigel invasion assay. RESULTS: All placentae presented very strong expression of OPN in the EVT at the invasion front, where it colocalized with CEACAM1. In addition, OPN was also present in the villous trophoblast, with strongest expression in the cytotrophoblast of the first trimester. Transfection with CEACAM1 followed by stimulation with OPN resulted in increased invasiveness of EVT hybridoma cells. CONCLUSION: The present study shows the first systematic analysis of OPN expression pattern in the human placenta showing strong expression in the EVT at the invasion front. Colocalization of OPN with CEACAM1 in the EVT indicates that they might act together to regulate invasiveness at the maternal-fetal interface. Using an in vitro model, we also demonstrated increased cellular invasiveness after OPN treatment. We speculate that OPN and CEACAM1 may act as a functional complex involved in the regulation of placental invasiveness.