Testicular dysgenesis syndrome and the origin of carcinoma in situ testis

Abstract

Recent increases in male reproductive disorders have been linked to exposure to environmental factors leading to the testicular dysgenesis syndrome (TDS). Testicular cancer is the most severe condition in TDS and studies have shown a clear correlation between risk of testicular cancer and other components of TDS and that the geographical location of the mother during pregnancy can be a risk factor. This suggests that the dysgenesis has its origin in utero and that TDS is initiated by environmental factors, including possibly hormone-disrupting compounds that act on the mother and the developing foetus, but the genetic background may also play a role. The morphological similarity of carcinoma in situ (CIS) cells (the precursor of the majority of invasive testicular cancers) with primordial germ cells and gonocytes, and overlap in expression of protein markers suggests an origin of CIS from primordial germ cells or gonocytes. CIS cells and germ cell-derived cancers of the human type have so far not been described in any animal model of TDS, which could be caused by species differences in the development of the male gonad. Regardless of this, it is plausible that the dysgenesis, and hence the development of CIS cells, is a result of disturbed signalling between nurse cells and germ cells that allow embryonic germ cells to survive in the pre-pubertal and adult testis. The post-pubertal proliferation of CIS cells combined with aberrant signalling then leads to an accumulation of genetic changes in the CIS cells, which eventually results in the development of invasive testicular cancer in the adult.

Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK)-dependent Signaling

“…Testicular dysgenesis can be caused by impaired germ cell differentiation, hormone insufficiency, and dysfunction of Leydig and/or Sertoli cells (which both provide paracrine support) (23). The present study revealed marked differences in the structure and morphology of testes between Ppard ϩ/ϩ and Ppard Ϫ/Ϫ mice and elucidated a cooperative role of PPARD in Sertoli cells/germ cell interactions, thus demonstrating for the first time that PPARD Normal spermatid head shape is required for male fertility as demonstrated by previous studies (24 -28).…”

An oncofetal and developmental perspective on testicular germ cell cancer

“…These SNPs should therefore not be interpreted as independent risk signals. (B) Global and schematic representation of the integrated role of genetic and environmental risk factors in the pathogenesis of TGCC inspired by the TDS model proposed by Sonne and colleagues [183].…”

The role of apparent diffusion coefficient values in detecting testicular intraepithelial neoplasia: Preliminary results

“…TIN is found in testicular tissue adjacent to TGCNs in about 90% of cases, and it is observed in all clinical groups known to be at high risk for testicular cancer, including contralateral testis of patients with TGCN, cryptorchidism, infertility and ambiguous genitalia. If TIN is left untreated, there is a 50% probability of progressing to frank TGCN within 5 years and a 70% probability of developing malignancy within 7 years [3][4][5]7,8].…”

“…Testicular germ cell neoplasms (TGCNs) constitute 90-95% of testicular tumors [1]. Testicular intraepithelial neoplasia (TIN) or intratubular germ cell neoplasia of unclassified type (ITGCNU) is considered the precursor of most TGCNs [2][3][4][5][6][7]. TIN is found in testicular tissue adjacent to TGCNs in about 90% of cases, and it is observed in all clinical groups known to be at high risk for testicular cancer, including contralateral testis of patients with TGCN, cryptorchidism, infertility and ambiguous genitalia.…”