Differentiation of Human Embryonal Carcinomas In vitro and In vivo Reveals Expression Profiles Relevant to Normal Development

Abstract

Embryonal carcinoma is a histologic subgroup of testicular germ cell tumors (TGCTs), and its cells may follow differentiation lineages in a manner similar to early embryogenesis. To acquire new knowledge about the transcriptional programs operating in this tumor development model, we used 22k oligo DNA microarrays to analyze normal and neoplastic tissue samples from human testis. Additionally, retinoic acid-induced in vitro differentiation was studied in relevant cell lines. We identified genes characterizing each of the known histologic subtypes, adding up to a total set of 687 differentially expressed genes. Among these, there was a significant overrepresentation of gene categories, such as genomic imprinting and gene transcripts associated to embryonic stem cells. Selection for genes highly expressed in the undifferentiated embryonal carcinomas resulted in the identification of 58 genes, including pluripotency markers, such as the homeobox genes NANOG and POU5F1 (OCT3/4), as well as GAL, DPPA4, and NALP7. Interestingly, abundant expression of several of the pluripotency genes was also detected in precursor lesions and seminomas. By use of tissue microarrays containing 510 clinical testicular samples, GAL and POU5F1 were upregulated in TGCT also at the protein level and hence validated as diagnostic markers for undifferentiated tumor cells. The present study shows the unique gene expression profiles of each histologic subtype of TGCT from which we have identified deregulated components in selected processes operating in normal development, such as WNT signaling and DNA methylation. (Cancer Res 2005; 65(13): 5588-98)

MMSET is overexpressed in cancers: Link with tumor aggressiveness

“…Overexpression of MMSET was found in glioblastoma compared to normal brain (P = 1.7E-14, P = .009, P = .002) [11; 12; 13]; in hepatocellular carcinoma compared to normal liver (P = 2.9E-7, 1.3E-6) [14; 15]; in head and neck cancer compared to the normal (P = .008, P = 2.7E-5) [16; 17]; in bladder carcinoma compared to normal bladder (P = 4.1E-11, P = 1.8E-7) [18; 19]; in primary colon cancer compared to normal adjacent mucosa (P = 9.5E-6) [20]; in esophagus adenocarcinoma compared to normal esophagus (P = .004) [21]; in breast carcinoma compared to normal breast (P = 3.8E-8) [22]; in T-cell acute lymphoblastic leukemia compared to normal bone marrow (P = 5.1E-7) [23]; in B-cell acute lymphoblastic leukaemia compared to normal bone marrow (P = .001) [23]; in lung adenocarcinoma compared to normal lung (P = .009, P = 8.4E-4, 1.7E-6) [24; 25; 26]; in lymphoma compared to normal B-cell (P = 3.5E-5, 7.3E-5) [27]; in cutaneous melanoma compared to normal melanocyte ( P = 6.46E-13, P = .01, P =.009) [28; 29; 30]; in smoldering multiple myeloma compared to normal bone marrow (P = 7.3E-4) [31]; in prostate cancer compared to normal prostate (P = 1.8E-6, P = .039, P = 5.1E-8, P = .002, P = .009, P = .006, P = .009) [32; 33; 34; 35; 36; 37; 38]; in yolk sac tumor compared to normal testis (P = .003) [39]; in ovarian carcinoma compared to normal ovary (P = .002, P = 1.1E-4) [40; 41] and in clear cell carcinoma compared to normal kidney tissue (P = .006) [42].…”

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).…”