On the Origin of Testicular Germ Cell Tumors: From Gonocytes to Testicular Cancer

Abstract

Human primordial germ cells (PGCs) have been described in the yolk sac wall around the beginning of the third week. From week 4 to 5, they migrate under control of SCF/c-KIT signaling pathway to the genital ridge, where they become gonocytes. PGCs and gonocytes express classic pluripotency markers, such as KIT, NANOG, and OCT3/4 that, during spermatogonia differentiation, are gradually suppressed, and substituted by the expression of some germ cell specific genes, such as VASA, SOX17, and TSPY. These genes, during normal development of germ cells, are tightly regulated by epigenetic modification, in terms of microRNA expression and DNA methylation. In adolescents and young adults, testicular germ cell tumors (TGCT) have a common precursor, the germ cell neoplasia in situ (GCNIS); the hypothesis of their origin from PGCs or gonocytes, whose maturation is altered, is widely accepted. The origin of TGCT, probably starting at early stages of embryogenesis, seems to be a part of the Testicular Dysgenesis Syndrome (TDS) where some early PGC/gonocytes, for still unclear reasons, are blocked in their differentiation, retaining their early marker profile. In this paper, current knowledge on the combination of epidemiological and genomic factors, involved in the development of testicular germ cell tumors, is reviewed.

In Search of TGCT Biomarkers: A Comprehensive In Silico and Histopathological Analysis

“…So far, early clinical GCNIS diagnostics are done only in situ by classical histology and immunohistochemistry on testicular biopsies in patients with a risk for TGCT development (testis atrophy, infertility, cryptorchidism, or suspicious ultrasound), and no protein marker is specific enough for the detection of GCNIS cells by noninvasive methods such as immunocytochemistry in body fluids [ 9 , 48 ]. Our results show for the first time a significant increase in two additional markers in GCNIS, i.e., RASSF1A and PRSS21 (testisin) protein expression, in comparison to both healthy seminiferous tubules and TGCT as a group; however, they have not made the 70% diagnostic positivity cut-off for the inclusion in the diagnostic panel.…”

“…PGCs are pluripotent cells that rise from the epiblast during embryonic development. As a consequence of genetic and (micro) environmental events, this cell population may be blocked or arrested in differentiation and transformed into GCNIS [ 9 ].…”

“…Until this overrun, molecular analysis on tumor tissue/biopsies without HE and IHC could result in an aggressive TGCT component going undetected. One also has to keep in mind the presence of GCNIS in the samples with their distinct molecular profiles [ 9 ].…”

“…They are crucial for stem cell specification, maintenance of the somatic stem cell population, gastrulation, and embryo development [ 30 ]. After birth, their expression decreases and finally disappears [ 9 ]. C-KIT is a transmembrane receptor that is important for the regulation of cell proliferation, survival, and migration.…”

Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis

“…TGCTs are classified into two sub-categories, based on their histological characteristics, seminoma and non-seminoma (embryonal carcinoma, teratoma, choriocarcinoma and yolk sac tumors), both aroused from a non-invasive form of disease named germ cell neoplasia in situ (CIS) [109]. TGCTs mainly occur in young men (18-35 years old) and their incidence shows geographical and ethnic differences [110]. TGCTs, particularly seminomas, display a good sensitivity to cisplatin-based chemotherapy and radiation; unfortunately, the non-seminoma histotype is more aggressive and has a poor prognosis, since it is less sensitive to chemotherapy and radiotherapy [111,112].…”