## 4 Discussion  
The effects of microgravity on cell cytoskeletal and junctional features of mammalian cells in vitro has been extensively investigated [27 27 27 2], even if studies on germ cells are still limited [20 ]. TCam-2 seminoma cells represent a good model to study mitotically active male germ cells, since this transformed cell line partially maintains the germ cell features [27 ]. We previously demonstrated that simulated microgravity exposure transiently modulated TCam-2 cell microtubule organization, activated autophagy [27 ], altered mitochondria morphology, and promoted ROS production [20 ]. Herein, extending our previous studies, we found, in the same cell line, that simulated microgravity upregulates cadherin expression and stimulates its distribution at the membrane level. In line with these results, ultrastructural organized adhesive junctional contacts have been observed together with a jagged interconnected cell-to-cell interface. It is worth mentioning that, even though TCam-2 seminoma cells grow in the culture as an epithelial-like sheet, these cells are not able to form ultra-structurally defined adherent junctions when cultured in basal conditions [27 ]. Notably, this cellular behavior is common in epithelial transformed cells. It is well known that during tumor progression, the loss of cadherins at cell-to-cell junctional contacts, in transformed cells of epithelial origin, drives the worsening of the cellular malignancy, promoting cell instability and metastasis [27 28 ]. Intercellular contacts mediated by cadherins, are essential even for normal germ cell migration, during embryogenesis, as well as for their maturation. These molecules are in fact finely modulated during germ cell differentiation, being barely detectable in immature cells and finely regulated during spermatogenetic processes. Primordial germ cells (PGC), which are the immature fetal form of male germ cells, express E-cadherin even if at a low level, but seminomas, that represent their malignant counterpart, lose the expression of E-cadherin at cell-to-cell contacts. Moreover, it is worth highlighting that the co-expression of cadherins and beta-catenin correlates with a male germ cell differentiated phenotype [27 ]. In a previous paper, we obtained the E-cadherin/beta-catenin upregulation in TCam-2 seminoma cells using an egg white complex [27 ], concluding that \"embryonal cues\" are probably used by TCam-2 cells to reprogram their proper differentiation attitude despite their malignant transformation. In this paper, we reported a similar cadherin/catenin upregulation and distribution as a consequence of the exposure to simulated microgravity, indicating how the modulation of not only chemical but also physical microenvironmental cues can modify a cell adhesive, and possibly cell differentiating attitude. It is worth highlighting that many papers reported a negative effect of microgravity on the cadherin expression level and its depletion at the membrane level, in some cellular models such as in MCF-7 cells and human keratinocytes [27 28 ]. However, recent papers reported an increase of E-cadherin in microgravity exposed fibroblasts, and a pro-angiogenic activity (which means mesenchyme-epithelial transition) of microgravity exposure on human adipose-derived stem cells [27 28 ]. In light of these published results, we can hypothesize that the effect of real or simulated microgravity exposure on cell adhesion is not univocal, but it depends on the cell differentiation state. This means that the decrease of gravitational force seems to have opposite effects on cells that have epithelial features with respect to those that have connective features or that are derived from mesenchymal progenitors. In this scenario, it is important to be reminded that, even if TCam-2 seminoma cells are of an epithelial origin, they have lost partially their differentiated state, presenting an impaired cell-to-cell adhesion capability.