Genetics and biology of adult human male germ cell tumors.
Adult human male germ cell tumors (GCTs) provide a unique opportunity to study the generation of a transformed pluripotential cell from a totipotential GC in lineage differentiation and on the path to gametogenesis. The pluripotentiality of the tumor cells manifests as histological differentiation into GC-like undifferentiated (SE), primitive zygotic (EC), embryonal-like somatically differentiated (TE), and extra-embryonally differentiated (CC, YST) phenotypes. The tumors and cell lines derived from them comprise exceptional model systems for the molecular analysis of human embryonal cell fate and lineage differentiation. The majority of GCTs show exquisite sensitivity to cisplatin-based treatment and have served as models for the development of chemotherapy for solid tumors. Until recently, the molecular mechanisms of GC transformation, GCT differentiation, or GCT chemotherapy sensitivity and resistance were understood poorly. Very recent studies of GCTs have suggested that: (a) overexpression of cyclin D2 is a very early, possibly the oncogenic, event in GC tumorigenesis; (b) differentiation in GCTs may be governed by several possibly interacting pathways, such as loss of regulators of GC totipotentiality and of embryonic development, and genomic imprinting; and (c) chemotherapy sensitivity and resistance may be rooted in part in a p53-dependent apoptotic pathway. In this review, these new data are discussed in the context of GC and GCT biology, and several novel testable genetic models are proposed.
Chaganti
R S
RS
Department of Human Genetics and the Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. chagantr@mskcc.org
Houldsworth
J
J
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental; D018237:Germinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013737:Testis / Q000196:embryology / Q000254:growth & development / Q000473:pathology
D000970:Antineoplastic Agents; D002945:Cisplatin