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.

Keywords: Leydig cells; Sertoli cells; germ cell neoplasia in situ (GCNIS); primordial germ cell (PGC); testicular dysgenesis syndrome (TDS); testicular germ cell tumors (TGCTs).

Figure 1

The scheme illustrates the genvironmental risk model showing different etiological factors influencing the development of TGCTs. Suspected risk factors and not associated factors are also listed. Modified from Elzinga-Tinke et al. (7).

Figure 2

The scheme represents marker expression from early embryogenesis to puberty during the normal (gray bar) and impaired (red bar) testicular development leading to GCNIS. Germ cells (in different stages of maturation), and GCNIS cells are represented as black or red circles, respectively. Sertoli cells are represented as open white boxes. Modified from Elzinga-Tinke et al. (7).