Differentiation of human embryonal carcinomas in vitro and in vivo reveals expression profiles relevant to normal development.
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 up-regulated 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.
Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital and University of Oslo, Norway.
Rolf I
RI
Skotheim
Guro E
GE
Lind
Outi
O
Monni
Jahn M
JM
Nesland
Vera M
VM
Abeler
Sophie D
SD
Fosså
Nur
N
Duale
Gunnar
G
Brunborg
Olli
O
Kallioniemi
Peter W
PW
Andrews
Ragnhild A
RA
Lothe
D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018236:Carcinoma, Embryonal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D019004:Galanin / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox / Q000235:genetics; D006801:Humans; D008297:Male; D050814:Octamer Transcription Factor-3; D020411:Oligonucleotide Array Sequence Analysis; D018239:Seminoma / Q000235:genetics / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D014157:Transcription Factors; D014212:Tretinoin; D019004:Galanin