Curing metastatic cancer: lessons from testicular germ-cell tumours

Abstract

Most metastatic cancers are fatal. More than 80% of patients with metastatic testicular germ-cell tumours (TGCTs), however, can be cured using cisplatin-based combination chemotherapy. Why are TGCTs more sensitive to chemotherapeutics than most other tumour types? Answers to this question could lead to new treatments for metastatic cancers.

A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embyronal carcinoma

“…It is tempting to speculate that the pluripotent character of TGCTs provides greater genome-wide accessibility to transcriptional regulation in response to p53 compared with other solid tumors, and that this may be related to the sensitivity of TGCT to cisplatin and other DNA-damaging agents (Andrews, 1998;Chaganti and Houldsworth, 2000). Although p53 siRNA conferred modest (B3-fold) decreased sensitivity to cisplatin, this corresponds with several previous studies showing that TGCT lines have a 2-4-fold greater cisplatin sensitivity compared to various other cancer types, which has been suggested to account for the difference between cure and failure in the clinical setting of large tumor burden (reviewed in Masters and Koberle, 2003). It is important to note that the genes uncovered here may be generally involved in the hypersensitivity of TGCTs in response to DNA damage.…”

“…Various attempts have been made to understand the unique sensitivity of these tumors to therapy as well as the reasons for resistance; however to date, no explanation has been generally accepted. Suggested mechanisms that may play a role in cisplatin sensitivity of TGCTs include diminished drug exporters and detoxifiers, low levels of DNA repair proteins, and a high Bax/Bcl-2 ratio (reviewed in Masters and Koberle, 2003;Spierings et al, 2003a).…”

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

“…treatment of other solid cancers. It is widely accepted that there are many factors contributing to the unique chemosensitivity of TGCTs, including an inability to detoxify cisplatin and to repair DNA damage, and an intact apoptotic cascade not disrupted by anti-apoptotic stimuli [18].…”

“…Among them, an attractive hypothesis is that TGCTs are so readily curable because of a low threshold for induction of apoptosis. However, studies published so far on this topic have yielded contradictory results [18] and encourage further research in this direction. For example, the expression of the anti-apoptotic protein seladin-1 (selective Alzheimer's disease indicator-1) in the different histological types of TGCT is unknown so far, but might be of interest.…”

“…The molecular basis for the exquisite sensitivity of TGCTs to cisplatin is not yet known and a number of hypotheses have been suggested [18]. Among them, an attractive hypothesis is that TGCTs are so readily curable because of a low threshold for induction of apoptosis.…”