Abstract
Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including hypospadias, undescended testes and type II testicular germ cell tumours (TGCTs). The increase in TGCTs cannot be accounted for by genetic changes in the population. Therefore exposure to environmental toxicants appears to be a major contributor to the aetiology of TGCTs and men with a genetic predisposition are particularly vulnerable. In particular, Type II TGCTs have been identified to arise from a precursor lesion Carcinoma in situ (CIS), identified as a dysfunctional gonocyte; however, the exact triggers for CIS development are currently unknown. Therefore the transition from gonocytes into spermatogonia is key to those studying TGCTs. Recently we have identified seven miRNA molecules (including members of the miR-290 family and miR-136, 463* and 743a) to be significantly changed over this transition period. These miRNA molecules are predicted to have targets within the CXCR4, PTEN, DHH, RAC and PDGF pathways, all of which have important roles in germ cell migration, proliferation and homing to the spermatogonial stem cell niche. Given the plethora of potential targets affected by each miRNA molecule, subtle changes in miRNA expression could have significant consequences e.g. tumourigenesis. The role of non-traditional oncogenes and tumour suppressors such as miRNA in TGCT is highlighted by the fact that the majority of these tumours express wild type p53, a pivotal tumour suppressor usually inactivated in cancer. While treatment of TGCTs is highly successful, the impact of these treatments on fertility means that identification of exact triggers, earlier diagnosis and alternate treatments are essential. This review examines the genetic factors and possible triggers of type II TGCT to highlight target areas for potential new treatments.
Highlights
Testicular cancers are generally grouped into three broad categories with type I testicular germ cell tumours (TGCTs) being observed primarily in neonatal boys and young children and consisting of benign teratomas and malignant yolk sac tumours[1]
We have independently looked at the expression of CXCL12 and CXCR4 in TGCTs (McIver SC, Loveland KL, Roman SD, Nixon B, Kitazawa R, McLaughlin EA, unpublished observations) and confirmed that CXCR4 mRNA was overexpressed in seminomas
Concluding remarks Research into both the genetic and environmental factors that predispose an individual to type II TGCTs has been hampered by the lack of a suitable animal model for the study this tumour type
Summary
Testicular cancers are generally grouped into three broad categories with type I testicular germ cell tumours (TGCTs) being observed primarily in neonatal boys and young children and consisting of benign teratomas and malignant yolk sac tumours[1]. Possible mechanisms of germ cell cancer specification Several risk factors have been identified in a mouse model of teratoma formation (strain 129/Ter)[70] These include the continued expression of pluripotency markers and proliferation as well as premature differentiation, e.g. precocious entry into meiosis. Pluripotency factors such as NANOG, SOX2, and OCT 3/4, are down-regulated following cell cycle arrest at E13.5, but the germ cells of Ter mice continue to proliferate and express NANOG at E15.570 In this mouse model, PGCs appear to prematurely differentiate with the detection of cyclin D1 as early as E13.570, compared to its normal expression in spermatogonia at postnatal day 471. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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