Testicular germ cell tumours: the paradigm of chemo-sensitive solid tumours.
Testicular germ cell tumours (TGCTs) are the most frequent solid malignant tumour in men 20-40 years of age and the most frequent cause of death from solid tumours in this age group. Up to 50% of the patients suffer from metastatic disease at diagnosis. The majority of metastatic testicular cancer patients, in contrast to most other metastatic solid tumours, can be cured with highly effective cisplatin-based chemotherapy. From a genetic point of view, almost all TGCTs in contrast to solid tumours are characterised by the presence of wild type p53. High p53 expression levels are associated with elevated Mdm2 levels and a loss of p21(Waf1/Cip1) expression suggesting a changed functionality of p53. Expression levels of other proteins involved in the regulation of cell cycle progression indicate a deregulated G1-S phase checkpoint in TGCTs. After cisplatin-induced DNA damage, the increasing levels of p53 lead to the trans-activation of a number of genes but not of p21(Waf1/Cip1), preferentially directing TGCT cells into apoptosis or programmed cell death, both via the mitochondrial and the death receptor apoptosis pathways. The sensitivity of TGCTs to chemotherapeutic drugs may lay in the susceptibility of germ cells to apoptosis. Taken together, this provides TGCT as a tumour type model to investigate and understand the molecular determinants of chemotherapy sensitivity of solid tumours. This review aims to summarise the current knowledge on the biological basis of cisplatin-induced apoptosis and response to chemotherapy in TGCTs.
di Pietro
Alessandra
A
Department of Medical Oncology, Internal Medicine, University of Groningen and University Medical Center Groningen, 9713 GZ Hanzeplein 1, Groningen, The Netherlands.
Vries
Elisabeth G E de
EG
Gietema
Jourik A
JA
Spierings
Diana C J
DC
de Jong
Steven
S
D000328:Adult; D000818:Animals; D017209:Apoptosis; D002278:Carcinoma in Situ / Q000503:physiopathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000502:physiology; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor / Q000502:physiology; D018237:Germinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013737:Testis / Q000166:cytology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002945:Cisplatin