Embryonic Stem Cell-Like Features of Testicular Carcinoma in Situ Revealed by Genome-Wide Gene Expression Profiling

Abstract

Carcinoma in situ (CIS) is the common precursor of histologically heterogeneous testicular germ cell tumors (TGCTs), which in recent decades have markedly increased and now are the most common malignancy of young men. Using genome-wide gene expression profiling, we identified >200 genes highly expressed in testicular CIS, including many never reported in testicular neoplasms. Expression was further verified by semiquantitative reverse transcription-PCR and in situ hybridization. Among the highest expressed genes were NANOG and POU5F1, and reverse transcription-PCR revealed possible changes in their stoichiometry on progression into embryonic carcinoma. We compared the CIS expression profile with patterns reported in embryonic stem cells (ESCs), which revealed a substantial overlap that may be as high as 50%. We also demonstrated an over-representation of expressed genes in regions of 17q and 12, reported as unstable in cultured ESCs. The close similarity between CIS and ESCs explains the pluripotency of CIS. Moreover, the findings are consistent with an early prenatal origin of TGCTs and thus suggest that etiologic factors operating in utero are of primary importance for the incidence trends of TGCTs. Finally, some of the highly expressed genes identified in this study are promising candidates for new diagnostic markers for CIS and/or TGCTs.

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

“…Ectopic expression of Nanog leads to dedifferentiation and blocks further developmental processes (Taranger et al, 2005). Malignant transformation of teratocarcinomas and germline tumors are caused by ectopic expression of Nanog (Almstrup et al, 2004;Hoei-Hansen et al, 2005;Skotheim et al, 2005). Overexpression of the full-length retrogene Nanog P8 has been identified in a large variety of different solid tumors or cancer cell lines .…”

Origin of pluripotent germ cell tumours: The role of microenvironment during embryonic development

“…These markers are now commonly used in the clinical setting to help identify CIS in surgical biopsies. More recently, the expression profiles of CIS cells studied by microarrays (Almstrup et al, 2004;Skotheim et al, 2005) provided a series of candidate marker genes, such as TFAP2C (AP2γ) (Hoei-Hansen et al, 2004), which has shown promising results as a possible marker of CIS cells in semen samples (Hoei-Hansen et al, 2007).…”

“…Stem cells have been isolated from adult mouse testes that exhibit properties similar to ES cells (Guan et al, 2006;Seandel et al, 2007), and these studies showed that a subset of spermatogonial stem cells in mouse testes retain the embryonic phenotype of PG cells and gonocytes. In humans a different scenario is seen, where NANOG and OCT3/4 (together with KIT and AP2γ) are expressed in PG cells and gonocytes, but are downregulated during the second half of pregnancy and until 2-4½ months of post-natal age (Jorgensen et al, 1995;Rajpert-De Meyts et al, 2004;Hoei-Hansen et al, 2004;Honecker et al, 2004;HoeiHansen et al, 2005). During this early infantile period, a transient increase in the production of testicular hormones occurs, known as the 'mini-puberty ' (Forest et al, 1973), which coincides with Page 6 of 22 A c c e p t e d M a n u s c r i p t 6 the final stage of differentiation of gonocytes into infantile spermatogonia (Hadziselimovic et al, 1986).…”

Cancer stem cells as targets for cancer therapy: selected cancers as examples

“…Of these, tumors of types a, c, and d are composed of differentiated tissues, whereas type b GCTs demonstrate pluripotent potential. A close resemblance between testicular GCTs and embryonic stem (ES) cells has been shown [4]. Specific expression of Oct 3/4 has been related to the pluripotent capacity of testicular GCTs, suggesting their origin from transformed pluripotent progenitor cells, such as PGCs [100].…”

“…Despite differential histology, seminomas and IGCNU share a high overlap of gene expression with ES cells [4,20,21]. Pluripotency genes such as Oct 3/4 and Nanog are highly expressed in IGCNU, seminomas, and embryonal carcinomas, but not in other histological types of TGCTs.…”