Abstract
Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells.
Highlights
In contrast to most other cancers, testicular germ cell tumors (GCTs) have a very high cure rate of .90% even when the disease is widely metastatic at presentation
Current models of GCT differentiation suggest that embryonal carcinoma and seminoma are the undifferentiated types of tumors and that they share many features with normal embryonic stem cells including expression of pluripotency factors such as NANOG, POU5F1, and SOX-2 among others
The results of this study suggest that the linkage between differentiation and resistance to apoptosis found in nonmalignant embryonic stem (ES) and primordial germ cells is maintained when these cells become malignant
Summary
In contrast to most other cancers, testicular germ cell tumors (GCTs) have a very high cure rate of .90% even when the disease is widely metastatic at presentation. In some cases resistance evolves in the absence of any change in histology, but in others resistance is associated with the emergence of more differentiated teratomatous elements This latter observation suggests that initial sensitivity and acquired resistance are related to the state of differentiation. Prior studies have reported that GCTs previously treated with either cisplatin (cDDP) or carboplatin have mRNA expression profiles that are similar to the most differentiated types of GCTs suggesting that drug treatment may induce differentiation [9]. This concept is supported by the clinical observation that tumor masses that persist following Pt drug therapy usually have a differentiated teratomatous histology
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
