Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer.
Testicular cancer is the most frequent solid malignant tumour type in men 20-40 years of age. At the time of diagnosis up to 50% of the patients suffer from metastatic disease. In contrast to most other metastatic solid tumours, the majority of metastatic testicular cancer patients can be cured with highly effective cisplatin-based chemotherapy. This review aims to summarise the current knowledge on response to chemotherapy and the biological basis of cisplatin-induced apoptosis in testicular cancer. The frequent presence of wild-type TP53 and the low levels of p53 in complex with the p53 negative feed-back regulator MDM2 contribute to cisplatin sensitivity. Moreover, the high levels of the pluripotency regulator Oct4 and as a consequence of Oct4 expression high levels of miR-17/106b seed family and pro-apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1) appear to be causative for the exquisite sensitivity to cisplatin-based therapy of testicular cancer. However, resistance of testicular cancer to cisplatin-based therapy does occur and can be mediated through aberrant levels of the above mentioned key players. Drugs targeting these key players showed, at least pre-clinically, a sensitising effect to cisplatin treatment. Further clinical development of such treatment strategies will lead to new treatment options for platinum-resistant testicular cancers.
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.
R
R
Koster
M A T M
MA
van Vugt
H
H
Timmer-Bosscha
J A
JA
Gietema
S
S
de Jong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D002945:Cisplatin