Genetic control of susceptibility to spontaneous testicular germ cell tumors in mice

Abstract

Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men. TGCT is a polygenic trait and genes that control susceptibility for TGCT development have not yet been identified. The 129/Sv inbred strain of mice is an important experimental model to study the genetics and development of TGCTs. We review several novel approaches that were developed to study the susceptibility of TGCTs in the 129/Sv mouse model and its application in humans. These approaches showed that several spontaneous and engineered mutations interact with 129/Sv-derived susceptibility genes to enhance or suppress susceptibility; two of these mutations (Ter and Trp53) revealed novel linkages for susceptibility genes in sensitized polygenic trait analysis. Linkage analysis with a chromosome substitution strains suggests that as many as 100 genes control susceptibility. Bilateral TGCTs result from the coincidental occurrence of unilateral tumors. These results highlight the important contributions that this mouse model can make to studies of TGCT susceptibility in humans.

Genetic and epigenetic properties of mouse male germline stem cells during long-term culture

“…The origin of these mGS cells in neonatal testis cell culture is currently unknown (Kanatsu-Shinohara et al, 2004b); it is possible that they arise from a population of distinct undifferentiated pluripotent cells that persist in the testis from fetal stage. However, we previously demonstrated the direct conversion of GS cells into mGS cells in experiments using GS cells derived from p53 mutant mice that have a high frequency of teratoma (Lam and Nadeau, 2003;Kanatsu-Shinohara et al, 2004b). Based on this observation, we speculated that spermatogonial stem cells retain the ability to become multipotent cells during the early passages in vitro, an ability that may be lost during long-term cell culture (Kanatsu-Shinohara et al, 2004b).…”

Neoplastic and Nonneoplastic Lesions in Aging Mice of Unique and Common Inbred Strains Contribution to Modeling of Human Neoplastic Diseases

“…33 More than 15 genes, including Ter (having the strongest effect), Kitl(Sl), Ay, and Trp53, are involved in susceptibility to testicular teratomas. 34,39 The data obtained from this study provide an overview of the types and variety of lesions observed in aging mice of multiple strains. As expected, the examined strains differ in susceptibility to neoplasia as well as prevalence and severity of nonneoplastic lesions.…”

Epigenetic reprogramming and induced pluripotency

“…Moreover, Wnt pathway activation has beneficial effects not only on the growth of ES cells (Sato et al, 2004), but also for the reprogramming of somatic cells into pluripotent cells by transcription factors (Marson et al, 2008) and for cell fusion between somatic cells and ES cells (Lluis et al, 2008). Likewise, loss of the tumor suppressor protein p53, which normally inhibits the immortal growth of primary fibroblasts, enhances the transformation of PGCs into embryonal carcinomas (Lam and Nadeau, 2003) and increases the number of mGS cells derived from GS cells (Kanatsu-Shinohara et al, 2004), as well as the number of iPS colonies derived from fibroblasts (Zhao et al, 2008), possibly by conferring immortality and/or by de-repressing Nanog (Lin et al, 2005).…”