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The villous cytotrophoblastic cells have the ability to fuse and differentiate, forming the syncytiotrophoblast (STB). The syncytialisation process is essential for placentation. Nevertheless, the mechanisms involved in cell fusion and differentiation are yet to be fully elucidated. It has been suggested that cell surface glucose-regulated protein 78 (GRP78) was involved in this process. In multiple cancer cells, cell membrane-located GRP78 has been reported to act as a receptor binding to the active form of α2-macroglobulin (α2M*), activating thus several cellular signalling pathways implicated in cell growth and survival. We hypothesised that GRP78 interaction with α2M* may also activate signalling pathways in trophoblastic cells, which, in turn, may promote cell fusion. Here, we observed that α2M mRNA is highly expressed in trophoblastic cells, whereas it is not expressed in the choriocarcinoma cell line BeWo. We thus took advantage of forskolin-induced syncytialisation of BeWo cells to study the effect of exogenous α2M* on syncytialisation. We first demonstrated that α2M* induced trophoblastic cell fusion. This effect is dependent on α2M*-GRP78 interaction, ERK1/2 and CREB phosphorylation, and unfolded protein response (UPR) activation. Overall, these data provide novel insights into the signalling molecules and mechanisms regulating trophoblastic cell fusion.

GRP78 is a classical endoplasmic reticulum (ER)-localized protein, acting as a chaperone and master regulator of the unfolding protein response in this location. Interestingly, under certain conditions, GRP78 is also located at the cell surface. More concretely, it was observed at the cell surface of several types of cancer cells, but also of trophoblastic cells and stressed cells in general. Cell surface GRP78 can bind to extracellular proteins and promote the activation of different signaling pathways. One of these proteins is prostate apoptosis response 4 (Par-4), a pro-apoptotic protein which is secreted by cancer cells. It was observed that the secretion of Par-4 was increased in parallel with GRP78 cell-surface localization, suggesting a relationship between these events. In this review, we discuss the role of Par-4 in GRP78 relocation at the cell surface.

The unfolded protein response (UPR) is recognized as a key mechanism to promote protein folding and processing in eukaryotes when endoplasmic reticulum stress (ERS) occurs. Some conditions such as hypoxia or glucose deprivation are factors that may elicit ERS response. Recent literature collectively proposes that ERS response is crucial for mammalian reproduction by allowing decidualization and placentation to occur. However, prolonged ERS and activation of UPR pathways can lead to apoptosis and autophagy, which in turn could pose adverse effects on pregnancy outcomes and placentation. ERS associated pregnancy pathologies include intrauterine growth restriction and early-onset preeclampsia. Given these findings, evidence suggests that overactivation of UPR may lead to harmful reproductive circumstances, whereas physiological regulation of ERS response is essential for mammalian reproduction and placental function. In this review, we discuss the dual role of UPR activation with respect to its contribution to placental development as well as pathologies caused by pathway overactivation. In addition, we suggest potential protein markers associated with the UPR, as circulating C-terminal GRP78 or anti-GRP78 autoantibodies which may prove to be of clinical interest.

Polyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors and have the ability to survive to antimitotic drugs. Their appearance can result from paclitaxel treatment or hypoxia, two conditions known to induce unfolded protein response (UPR) activation. PGCCs produced under hypoxia may be formed by cell fusion and can contribute by bursting and budding to the generation of cancer stem-like cells which have a more aggressive phenotype than the parental cells. Despite the fact that PGCCs may contribute to tumor maintenance and recurrence, they were poorly studied. Here, we confirmed that PGCCs could derive, at least in part, from cell fusion. We also observed that PGCCs nuclei were able to fuse. The resulting cells were able to proliferate by mitosis and were more invasive than the parental cancer cells. Using two different ovarian cancer cell lines (COV318 and SKOV3), we showed that UPR activation with chemical inducers increased cell fusion and PGCCs appearance. Down-regulation of the UPR-associated protein PERK expression partially reversed the UPR-induced PGCCs formation, suggesting that the PERK arm of the UPR is involved in ovarian PGCCs onset.

The syncytiotrophoblast (STB) is a multinuclear layer forming the outer surface of the fetal part of the placenta deriving from villous cytotrophoblastic cell (vCTB) fusion and differentiation. This syncytialization process is characterized by morphological and biochemical alterations of the trophoblast, which probably require removal of pre-existing structures and proteins to maintain cell homeostasis and survival. Interestingly, autophagy, which allows degradation and recycling of cellular components, was shown to be activated in syncytiotrophoblast. Here we examined the involvement of endoplasmic reticulum stress (ERS) response in autophagy activation during vCTB syncytialization. We first demonstrated the activation of ERS response and autophagy during the time course of trophoblastic cell fusion and differentiation. Alteration of autophagy activation in vCTB by chemical treatments or Beclin-1 expression modulation leads to a decrease in trophoblastic syncytialization. Furthermore, ERS response inhibition by chemical treatment or siRNA strategy leads to a default in syncytialization, associated with alteration of autophagy markers and cell survival. From these data, we suggest that ERS response, by fine regulation of autophagy activation, may serve as an adaptive mechanism to promote cell survival during trophoblastic syncytialization.

Cell fusion is a physiological cellular process essential for fertilization, viral entry, muscle differentiation and placental development, among others. In this review, we will highlight the different cancer cell-cell fusions and the advantages obtained by these fusions. We will specially focus on the acquisition of metastatic features by cancer cells after fusion with bone marrow-derived cells. The mechanism by which cancer cells fuse with other cells has been poorly studied thus far, but the presence in several cancer cells of syncytin, a trophoblastic fusogen, leads us to a cancer cell fusion mechanism similar to the one used by the trophoblasts. The mechanism by which cancer cells perform the cell fusion could be an interesting target for cancer therapy.