Pluripotent Very Small Embryonic-Like Stem Cells in Adult Testes - An Alternate Premise to Explain Testicular Germ Cell Tumors

Developmental exposure to endocrine disruptors has resulted in the increased incidence of infertility and testicular germ cell tumors (T2GCT) in young men residing in developed countries. Unlike T1GCT (infants and young children) and T3GCT (aged men), T2GCT arise from CIS/GCNIS that develops from pre-CIS. Pre-CIS represents undifferentiated, growth-arrested gonocytes that persist in fetal testes due to endocrine disruption. However, whether pre-CIS truly exist, do CIS develop into T2GCT, why no CIS in T1GCT/T3GCT, why germ cell tumors (GCT) also occur along midline at extra-gonadal sites, why T1GCT show partial erasure and T2GCT show complete erasure of genomic imprints are open questions that are awaiting answers. We propose that rather than pre-CIS, pluripotent, very small embryonic-like stem cells (VSELs) get affected by exposure to endocrine disruption. Since VSELs are developmentally equivalent to primordial germ cells (PGCs), T2GCT cells show complete erasure of genomic imprints and CIS represents growth-arrested clonally expanding stem/progenitor cells. PGCs/VSELs migrate along the midline to various organs and this explains why GCT occur along the midline, T1GCT show partial erasure of imprints as they develop from migrating PGCs. T3GCT possibly reflects effects of aging due to compromised differentiation and expansion of pre-meiotic spermatocytes. Absent spermatogenesis in pre-pubertal and aged testes explains absence of CIS in T1GCT and T3GCT. Endocrine disruptors possibly alter epigenetic state of VSELs and thus rather than maintaining normal tissue homeostasis, VSELs undergo increased proliferation and compromised differentiation resulting in reduced sperm count, infertility and TGCT. This newly emerging understanding offers alternate premise to explain TGCT and warrants further exploration.