Testicular Germ Cell Tumors: A Paradigm for the Successful Treatment of Solid Tumor Stem Cells.

Treatment of testicular germ cell tumors (TGCTs) has been a success primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. Despite the promise of cure for the majority of TGCT patients, the effectiveness of therapy for some patients is limited by toxicity and the problem of resistance. There is compelling rationale to further understand the biology of TGCTs in order to better treat other solid tumors and to address the shortcomings of present TGCT therapies. TGCTs contain undifferentiated pluripotent stem cells, known as embryonal carcinoma, that share many properties with human embryonic stem cells. The importance of cancer stem cells in the initiation, progression and treatment of solid tumors is beginning to emerge. We discuss TGCTs in the context of solid tumor curability and targeted cancer stem cell therapy.

Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity.

Testicular germ cell tumors (TGCTs) are the most common carcinomas of young men aged 15-35. The molecular events involved in TGCT genesis are poorly understood. TGCTs have near universal amplification of the short arm of chromosome 12, however positional cloning efforts have not identified causative genes on 12p involved in formation or progression of TGCTs. Human embryonal carcinoma (EC) are the stem cells of TGCTs and are pluripotent. EC cells terminally differentiate toward a neuronal lineage with all-trans retinoic acid (RA) treatment resulting in a concomitant G1 cell cycle arrest and loss of tumorigenicity. Our efforts to define the molecular mechanisms of RA-mediated tumor cell differentiation at a critical "commitment to differentiate" window has identified a cassette of genes on 12p that are repressed with RA precisely as EC cells lose tumorigenic potential. These are Nanog, CD9, EDR1 (PHC1), SCNN1A, GDF3, Glut3 and Stella. The master pluripotency regulator Oct4 is located on chromosome 6 and is also repressed by RA. Notably, knockdown of Oct4 with siRNA results in repression of basal Nanog, EDR1, GDF3 and Stella gene expression. Nanog has recently been identified to play a role in maintenance of the pluripotency of mouse embryonic stem cells and CD9, EDR1, GDF3, and Stella have each been implicated as stem cell markers. Since RA suppresses the tumorigenicity of EC cells, these genes may have a critical role in the etiology of TGCTs, suggesting a link between enforced pluripotency and transformation.