Journal of Pathology J Pathol 2003; 200: 137–148. Published online 18 March 2003 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/path.1373 Review Article The attractive Achilles heel of germ cell tumours: an inherent sensitivity to apoptosis-inducing stimuli Diana CJ Spierings, Elisabeth GE de Vries,* Edo Vellenga and Steven de Jong Departments of Medical Oncology and Haematology, University of Groningen, The Netherlands *Correspondence to: Elisabeth GE de Vries, MD, PhD, Department of Medical Oncology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: e.g.e.de.vries@int.azg.nl Received: 20 August 2002 Revised: 22 November 2002 Accepted: 30 January 2003 Abstract Testicular germ cell tumours (TGCTs) are extremely sensitive to cisplatin-containing chemotherapy. The rapid time course of apoptosis induction after exposure to cisplatin suggests that TGCT cells are primed to undergo programmed cell death as an inherent property of the cell of origin. In fact, apoptosis induction of germ cells in the testis is an important physiological mechanism to control the quality and quantity of the gametes produced. Although p53 protein is highly expressed in the majority of TGCTs, almost no p53 mutations have been detected. Interestingly, p53 overexpression is associated with loss of p21 and gain of mdm2 expression, which might indicate a partial loss in functionality of the p53 regulatory pathway in TGCTs. Besides p21, TGCTs often show low expression of other proteins involved in the regulation of cell cycle progression, such as the retinoblastoma protein and members of the INK4 family. It can be postulated that the deregulated G 1 –S phase checkpoint results in premature entry into the S phase upon DNA damage. In addition to Bcl-2 family members that are involved in the regulation of germ cell apoptosis in the normal testis via the mitochondrial death pathway, the Fas death pathway is also known to regulate apoptosis of germ cells in the testis. Since chemotherapy has been shown to activate the Fas death pathway and TGCTs co-express both Fas and its ligand FasL, TGCT cells might undergo apoptosis upon cisplatin treatment via autocrine or paracrine activation of the Fas system by FasL. The hypothesis suggested here is that the lack of cell cycle arrest following a cisplatin-containing treatment, together with the activation of the Fas death pathway and the mitochondrial death pathway, explains the rapid and efficient apoptosis of TGCT cells. Defining the mechanisms involved in the cisplatin sensitivity of TGCTs will provide tools to increase cisplatin sensitivity in other human tumours with acquired or intrinsic resistance. Copyright  2003 John Wiley & Sons, Ltd. Keywords: germ cells; testicular germ cell tumour; apoptosis; p53; Fas; p21 Introduction Testicular germ cell tumours (TGCTs) can be divided into seminomas and non-seminomas [1]. They rep- resent one of the few solid tumour types that, when metastasized, are curable by cisplatin-containing chemotherapy, with an overall cure rate of more than 80% [2]. Moreover, several studies have shown that carboplatin monotherapy as an adjuvant therapy to surgical resection appears to be equivalent to the tradi- tional radiotherapeutic treatment of stage I seminomas [3,4]. Most cell lines derived from human TGCTs also consistently display an unusually high sensitivity to chemotherapeutic agents, with cisplatin as key drug [5,6]. Analysis of potentially relevant parameters in cisplatin sensitivity, including cellular detoxification mechanisms (eg the glutathione and the metalloth- ionein systems), platinum accumulation, DNA plati- nation and repair, p53 status, and expression of Bcl-2 family proteins, has not been able, so far, to elucidate the identity of this inherent sensitivity of testicular tumours [7–12]. The rapid time course of apoptosis induction after exposure to chemotherapeutic drugs suggests that TGCT cells may already be primed to undergo programmed cell death. Sensitivity to apop- totic stimuli may well be an inherent property of the cell of origin. This is supported by the observation that treatment with cytotoxic chemotherapy and radio- therapy can be associated with significant testicular germ cell damage and impairment of fertility [13,14]. In addition, during normal spermatogenesis, sponta- neous apoptosis occurs in the testis as an important physiological mechanism to adjust germ cell numbers to that of the supporting Sertoli cells and to ensure quality control of the gametes produced [15–18]. Besides the involvement of Bcl-2 family members, the Fas–FasL system between Sertoli cells and germ cells has been proposed as another important cellular mech- anism underlying germ cell apoptosis. In the present review, we discuss the involvement of p53 in the drug sensitivity of TGCT cells, focusing on p53-activated mechanisms such as cell cycle arrest (p21 waf1/Cip1 ) or apoptosis (Bcl-2 family members and the Fas death system). Copyright  2003 John Wiley & Sons, Ltd.