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Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon could represent a central element in the understanding of the onset of testicular morphogenetic disorders. RSpondin-1 (RSPO1) has been clearly established as a candidate for ovary determination both in mice and humans. On the contrary, very few data are available on the expression and role of RSPO1 during testicular development. Tis study aims to clarify the distribution pattern of RSPO1 as well as of other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this complex system in testicular development. To this end we frst studied the distribution pattern of RSPO1, its antagonist Dickkopf-1 (DKK1), and the signaling efector β-catenin during testis development, from 11.5 to 18.5 dies post coitum (dpc). Our results clearly demonstrate that RSPO1 and DKK1 distribution pattern partially overlaps but, intriguingly, RSPO1 is always detectable in the testicular coelomic portion, the region that organizes testicular vasculature, whilst DKK1 is never detectable in this area. Moreover, performing organ culture experiments of embryonic testes, we demonstrated that DKK1 acted as an inhibitor of testis recruitment of endothelial mesonephric cells. Interestingly, this inhibition was rescued by the co-administration of RSPO1. In addition, RSPO1 alone has been able to enhance, in culture, testicular vasculogenesis. Tese results let us to conclude that RSPO1 machinery is involved in the control of the correct testicular vascular compartment organization.

Type II testicular germ cell tumors (TGCTs) represent the most frequent malignancy in Caucasian males (20-40 years). Even if diagnosed with disseminated disease, > 80% of patients are cured; however, a small percentage of cases progress and result in death. It is commonly accepted that these cancers arise from a disturbed testicular embryonic niche that leads to the block of gonocyte differentiation. The subsequent development of the invasive seminomas and nonseminomas is due to a combination of genetic, epigenetic and microenvironmentbased alterations (genvironment). Hepatocyte growth factor (HGF) is present in the testicular microenvironment, together with its receptor c-MET, from early embryonic development to an adult stage. In addition, c-MET is a well-known proto-oncogene involved in the onset and progression of various human cancers. Herein, we have investigated the expression and availability of HGF and c-MET in TCam-2, NCCIT and NT2D1 cells, which are type II (T)GCT representative cell lines, and the effect of c-MET activation/repression on the regulation of cancerous biological processes. We found that NT2D1 cells increase their proliferation, polarized migration, and invasion in response to HGF administration. NCCIT cells respond to HGF stimulation only partially, whereas TCam-2 cells do not respond to HGF, at least according to the investigated parameters. Interestingly, the immunohistochemical study of c-MET distribution in TGCTs confirm its presence in both seminoma and non-seminoma lesions with different patterns. Notably, we found the highest c-MET immunoreactivity in the epithelial elements of the various components of TGCTs: teratoma, yolk sac tumor and choriocarcinoma. Type II testicular germ cell tumors (TGCTs) represent the most frequent malignancy in Caucasian males (20-40 years). Even if diagnosed with disseminated disease, > 80% of patients are cured; however, a small percentage of cases progress and result in death. It is commonly accepted that these cancers arise from a disturbed testicular embryonic niche that leads to the block of gonocyte differentiation. The subsequent development of the invasive seminomas and nonseminomas is due to a combination of genetic, epigenetic and microenvironmentbased alterations (genvironment). Hepatocyte growth factor (HGF) is present in the testicular microenvironment, together with its receptor c-MET, from early embryonic development to an adult stage. In addition, c-MET is a well-known proto-oncogene involved in the onset and progression of various human cancers. Herein, we have investigated the expression and availability of HGF and c-MET in TCam-2, NCCIT and NT2D1 cells, which are type II (T)GCT representative cell lines, and the effect of c-MET activation/repression on the regulation of cancerous biological processes. We found that NT2D1 cells increase their proliferation, polarized migration, and invasion in response to HGF administration. NCCIT cells respond to HGF stimulation only partially, whereas TCam-2 cells do not respond to HGF, at least according to the investigated parameters. Interestingly, the immunohistochemical study of c-MET distribution in TGCTs confirm its presence in both seminoma and non-seminoma lesions with different patterns. Notably, we found the highest c-MET immunoreactivity in the epithelial elements of the various components of TGCTs: teratoma, yolk sac tumor and choriocarcinoma.