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Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer

Published online by Cambridge University Press:  30 September 2013

R. Koster ,
M.A.T.M. van Vugt ,
H. Timmer-Bosscha ,
J.A. Gietema  and
S. de Jong
R. Koster
Affiliation:
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
M.A.T.M. van Vugt
Affiliation:
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands
H. Timmer-Bosscha
Affiliation:
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands
J.A. Gietema
Affiliation:
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands
S. de Jong*
Affiliation:
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands
*
*Corresponding author: S. de Jong, PhD, Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: [email protected]
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Abstract

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.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 15 , 2013 , e12
Copyright
Copyright © Cambridge University Press 2013 

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References

1Einhorn, L.H. (2002) Curing metastatic testicular cancer. Proceedings of the National Academy of Sciences of the United States of America 99, 4592-4595Google Scholar
2Masters, J.R. and Koberle, B. (2003) Curing metastatic cancer: lessons from testicular germ-cell tumours. Nature Reviews Cancer 3, 517-525CrossRefGoogle ScholarPubMed
3Oosterhuis, J.W. and Looijenga, L.H. (2005) Testicular germ-cell tumours in a broader perspective. Nature Reviews Cancer 5, 210-222Google Scholar
4Kondagunta, G.V. et al. (2004) Relapse-free and overall survival in patients with pathologic stage. II. Nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. Journal of Clinical Oncology 22, 464-467Google Scholar
5Einhorn, L.H. (2007) Role of the urologist in metastatic testicular cancer. Journal of Clinical Oncology 25, 1024-1025Google Scholar
6Horwich, A., Shipley, J. and Huddart, R. (2006) Testicular germ-cell cancer. Lancet 367, 754-765Google Scholar
7Print, C.G. and Loveland, K.L. (2000) Germ cell suicide: new insights into apoptosis during spermatogenesis. BioEssays 22, 423-4303.0.CO;2-0>CrossRefGoogle ScholarPubMed
8Janus, F. et al. (1999) The dual role model for p53 in maintaining genomic integrity. Cellular and Molecular Life Sciences 55, 12-27Google Scholar
9Vousden, K.H. and Lu, X. (2002) Live or let die: the cell's response to p53. Nature Reviews Cancer 2, 594-604Google Scholar
10Lowe, S.W. et al. (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957-967CrossRefGoogle ScholarPubMed
11Levine, A.J. (1997) p53, the cellular gatekeeper for growth and division. Cell 88, 323-331CrossRefGoogle ScholarPubMed
12Cheng, M. et al. (1999) The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO Journal 18, 1571-1583CrossRefGoogle ScholarPubMed
13Wahl, G.M. and Carr, A.M. (2001) The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biology 3, E277-E286Google Scholar
14Johnstone, R.W., Ruefli, A.A. and Lowe, S.W. (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153-164Google Scholar
15Heidenreich, A. et al. (1998) Immunohistochemical and mutational analysis of the p53 tumour suppressor gene and the bcl-2 oncogene in primary testicular germ cell tumours. APMIS 106, 90-99; discussion 99–100Google Scholar
16Spierings, D.C. et al. (2004) Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis. Oncogene 23, 4862-4872Google Scholar
17Houldsworth, J. et al. (2006) Biology and genetics of adult male germ cell tumors. Journal of Clinical Oncology 24, 5512-5518Google Scholar
18Greenblatt, M.S. et al. (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research 54, 4855-4878Google ScholarPubMed
19Olivier, M. et al. (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Human Mutation 19, 607-614Google Scholar
20Hamroun, D. et al. (2006) The UMD TP53 database and website: update and revisions. Human Mutation 27, 14-20Google Scholar
21Petitjean, A. et al. (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Human Mutation 28, 622-629Google Scholar
22Lutzker, S.G. and Levine, A.J. (1996) A functionally inactive p53 protein in teratocarcinoma cells is activated by either DNA damage or cellular differentiation. Nature Medicine 2, 804-810Google Scholar
23Lutzker, S.G., Mathew, R. and Taller, D.R. (2001) A p53 dose-response relationship for sensitivity to DNA damage in isogenic teratocarcinoma cells. Oncogene 20, 2982-2986Google Scholar
24Datta, M.W. et al. (2001) Transition from in situ to invasive testicular germ cell neoplasia is associated with the loss of p21 and gain of mdm-2 expression. Modern Pathology 14, 437-442Google Scholar
25Kersemaekers, A.M. et al. (2002) Role of P53 and MDM2 in treatment response of human germ cell tumors. Journal of Clinical Oncology 20, 1551-1561Google Scholar
26Houldsworth, J. et al. (1998) Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. Oncogene 16, 2345-2349Google Scholar
27Riou, G. et al. (1995) The p53 and mdm-2 genes in human testicular germ-cell tumors. Molecular Carcinogenesis 12, 124-131Google Scholar
28Hanahan, D. and Weinberg, R.A. (2000) The hallmarks of cancer. Cell 100, 57-70Google Scholar
29Bartkova, J. et al. (2003) Deregulation of the RB pathway in human testicular germ cell tumours. Journal of Pathology 200, 149-156CrossRefGoogle ScholarPubMed
30Bartkova, J. et al. (2003) Deregulation of the G1/S-phase control in human testicular germ cell tumours. APMIS 111, 252-265; discussion 265–266Google Scholar
31Bartkova, J. et al. (2000) Cell cycle regulators in testicular cancer: loss of p18INK4C marks progression from carcinoma in situ to invasive germ cell tumours. International Journal of Cancer 85, 370-375Google Scholar
32Strohmeyer, T. et al. (1991) Correlation between retinoblastoma gene expression and differentiation in human testicular tumors. Proceedings of the National Academy of Sciences of the United States of America 88, 6662-6666Google Scholar
33Guillou, L. et al. (1996) Germ cell tumors of the testis overexpress wild-type p53. American Journal of Pathology 149, 1221-1228Google Scholar
34Vaughn, D.J. et al. (2009) Treatment of growing teratoma syndrome. New England Journal of Medicine 360, 423-424Google Scholar
35Spierings, D.C., de Vries, E.G., Vellenga, E. and de Jong, S. (2003) The attractive Achilles heel of germ cell tumours: an inherent sensitivity to apoptosis-inducing stimuli. Journal of Pathology 200, 137-148Google Scholar
36di Pietro, A. et al. (2005) Testicular germ cell tumours: the paradigm of chemo-sensitive solid tumours. International Journal of Biochemistry and Cell Biology 37, 2437-2456Google Scholar
37Di Vizio, D. et al. (2005) Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene 24, 1882-1894Google Scholar
38Bagui, T.K. et al. (2003) p27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Molecular and Cellular Biology 23, 7285-7290Google Scholar
39Blagosklonny, M.V. (2002) Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle 1, 391-393Google Scholar
40Koster, R. et al. (2010) Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. Journal of Clinical Investigation 120, 3594-3605Google Scholar
41Josephson, R. et al. (2007) Qualification of embryonal carcinoma 2102Ep as a reference for human embryonic stem cell research. Stem Cells 25, 437-446Google Scholar
42Giuliano, C.J. et al. (2005) Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochimica et Biophysica Acta 1731, 48-56Google Scholar
43Marson, A. et al. (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521-533Google Scholar
44Foshay, K.M. and Gallicano, G.I. (2009) miR-17 family miRNAs are expressed during early mammalian development and regulate stem cell differentiation. Developmental Biology 326, 431-443Google Scholar
45Ivanovska, I. et al. (2008) MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Molecular Cell Biology 28, 2167-2174Google Scholar
46Petrocca, F. et al. (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13, 272-286Google Scholar
47Koster, R. and de Jong, S. (2010) Lessons learned from testicular cancer: identification of cytoplasmic p21 as an Achilles' heel of cisplatin resistance. Cell Cycle 9, 4776-4777Google Scholar
48Gibcus, J.H. et al. (2009) Hodgkin lymphoma cell lines are characterized by a specific miRNA expression profile. Neoplasia 11, 167-176Google Scholar
49Vousden, K.H. and Prives, C. (2009) Blinded by the light: the growing complexity of p53. Cell 137, 413-431Google Scholar
50Zhang, Y. and Xiong, Y. (2001) Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth and Differentiation 12, 175-186Google Scholar
51Koster, R. et al. (2011) Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death and Disease 2, e148CrossRefGoogle ScholarPubMed
52Stad, R. et al. (2001) Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Reports 2, 1029-1034Google Scholar
53Bothner, B. et al. (2001) Defining the molecular basis of Arf and Hdm2 interactions. Journal of Molecular Biology 314, 263-277Google Scholar
54Honda, R. and Yasuda, H. (1999) Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO Journal 18, 22-27Google Scholar
55Kamijo, T. et al. (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proceedings of the National Academy of Sciences of the United States of America 95, 8292-8297Google Scholar
56Lowe, S.W. and Sherr, C.J. (2003) Tumor suppression by Ink4a-Arf: progress and puzzles. Current Opinion in Genetics and Development 13, 77-83Google Scholar
57di Pietro, A. et al. (2012) Pro- and anti-apoptotic effects of p53 in cisplatin-treated human testicular cancer are cell context-dependent. Cell Cycle 11, 4552-4562Google Scholar
58Voorhoeve, P.M. et al. (2006) A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124, 1169-1181Google Scholar
59Bartkova, J. et al. (2007) DNA damage response in human testes and testicular germ cell tumours: biology and implications for therapy. International Journal of Andrology 30, 282-291; discussion 291Google Scholar
60Bartek, J., Lukas, J. and Bartkova, J. (2007) DNA damage response as an anti-cancer barrier: damage threshold and the concept of ‘conditional haploinsufficiency’. Cell Cycle 6, 2344-2347Google Scholar
61Kelland, L. (2007) The resurgence of platinum-based cancer chemotherapy. Nature Reviews Cancer 7, 573-584Google Scholar
62Siddik, Z.H. (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22, 7265-7279Google Scholar
63Rabik, C.A. and Dolan, M.E. (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treatment Reviews 33, 9-23Google Scholar
64Khanna, K.K. and Jackson, S.P. (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genetics 27, 247-254Google Scholar
65Espinosa, J.M. (2008) Mechanisms of regulatory diversity within the p53 transcriptional network. Oncogene 27, 4013-4023Google Scholar
66Murray-Zmijewski, F., Slee, E.A. and Lu, X. (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nature Reviews Molecular Cell Biology 9, 702-712CrossRefGoogle ScholarPubMed
67Giaccia, A.J. and Kastan, M.B. (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes and Development 12, 2973-2983Google Scholar
68Toledo, F. and Wahl, G.M. (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Reviews Cancer 6, 909-923Google Scholar
69Ashcroft, M., Kubbutat, M.H. and Vousden, K.H. (1999) Regulation of p53 function and stability by phosphorylation. Molecular Cell Biology 19, 1751-1758Google Scholar
70Meulmeester, E. et al. (2005) ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 4, 1166-1170Google Scholar
71Cheng, Q. et al. (2009) ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO Journal 28, 3857-3867Google Scholar
72Cheng, Q. and Chen, J. (2010) Mechanism of p53 stabilization by ATM after DNA damage. Cell Cycle 9, 472-478Google Scholar
73Vassilev, L.T. et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848Google Scholar
74Marine, J.C., Dyer, M.A. and Jochemsen, A.G. (2007) MDMX: from bench to bedside. Journal of Cell Science 120(Pt 3), 371-378Google Scholar
75Ogawara, Y. et al. (2002) Akt enhances Mdm2-mediated ubiquitination and degradation of p53. Journal of Biological Chemistry 277, 21843-21850Google Scholar
76Koberle, B. et al. (2010) Cisplatin resistance: preclinical findings and clinical implications. Biochimica et Biophysica Acta 1806, 172-182Google Scholar
77Gosland, M. et al. (1996) Insights into mechanisms of cisplatin resistance and potential for its clinical reversal. Pharmacotherapy 16(1 I), 16-39Google Scholar
78Masters, J.R.W. et al. (1996) Sensitivity of testis tumour cells to chemotherapeutic drugs: role of detoxifying pathways. European Journal of Cancer Part A 32, 1248-1253Google Scholar
79Wang, H. et al. (2004) ATR affecting cell radiosensitivity is dependent on homologous recombination repair but independent of nonhomologous end joining. Cancer Research 64, 7139-7143Google Scholar
80Rosell, R. et al. (2003) Nucleotide excision repair pathways involved in cisplatin resistance in non-small-cell lung cancer. Cancer Control 10, 297-305CrossRefGoogle ScholarPubMed
81Koberle, B. et al. (1999) Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Current Biology 9, 273-276Google Scholar
82Welsh, C. et al. (2004) Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. International Journal of Cancer 110, 352-361Google Scholar
83Honecker, F. et al. (2003) Xeroderma Pigmentosum Group A Protein and Chemotherapy Resistance in Human Germ Cell Tumors. Laboratory Investigation 83, 1489-1495Google Scholar
84Koberle, B. et al. (1996) DNA repair in cisplatin-sensitive and resistant human cell lines measured in specific genes by quantitative polymerase chain reaction. Biochemical Pharmacology 52, 1729-1734Google Scholar
85Koberle, B. et al. (1997) DNA repair capacity and cisplatin sensitivity of human testis tumour cells. International Journal of Cancer 70, 551-555Google Scholar
86Usanova, S. et al. (2010) Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Molecular Cancer 9, 248Google Scholar
87Cavallo, F. et al. (2012) Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to Cisplatin and poly (adp-ribose) polymerase inhibition. PLoS ONE 7, e51563Google Scholar
88Devouassoux-Shisheboran, M. et al. (2001) Expression of hMLH1 and hMSH2 and assessment of microsatellite instability in testicular and mediastinal germ cell tumours. Molecular Human Reproduction 7, 1099-1105Google Scholar
89Lothe, R.A. et al. (1995) Molecular genetic changes in human male germ cell tumors. Laboratory Investigation 73, 606-614Google Scholar
90Chresta, C.M., Masters, J.R.W. and Hickman, J.A. (1996) Hypersensitivity of human testicular tumors to etoposide-induced apoptosis is associated with functional p53 and a high Bax:Bcl-2 ratio. Cancer Research 56, 1834-1841Google Scholar
91Arriola, E.L. et al. (1999) Bcl-2 overexpression results in reciprocal downregulation of Bcl-X(L) and sensitizes human testicular germ cell tumours to chemotherapy-induced apoptosis. Oncogene 18, 1457-1464Google Scholar
92Timmer-Bosscha, H. et al. (1998) Differential effects of all-trans-retinoic acid, docosahexaenoic acid, and hexadecylphosphocholine on cisplatin-induced cytotoxicity and apoptosis in a cisplantin-sensitive and resistant human embryonal carcinoma cell line. Cancer Chemotherapy and Pharmacology 41, 469-476Google Scholar
93Friesen, C., Fulda, S. and Debatin, K.M. (1999) Cytotoxic drugs and the CD95 pathway. Leukemia 13, 1854-1858Google Scholar
94Petak, I. and Houghton, J.A. (2001) Shared pathways: death receptors and cytotoxic drugs in cancer therapy. Pathology and Oncology Research 7, 95-106Google Scholar
95Fulda, S. et al. (2000) Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells. Blood 95, 301-308Google Scholar
96Fulda, S. et al. (2001) Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 20, 1063-1075Google Scholar
97Spierings, D.C. et al. (2003) Loss of drug-induced activation of the CD95 apoptotic pathway in a cisplatin-resistant testicular germ cell tumor cell line. Cell Death and Differentiation 10, 808-822Google Scholar
98Gutekunst, M. et al. (2011) p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin. PLoS ONE 6, e19198Google Scholar
99Mueller, T. et al. (2003) Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer. Cancer Res 63, 513-521Google Scholar
100Scaffidi, C. et al. (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO Journal 17, 1675-1687Google Scholar
101Martinou, J.C. and Green, D.R. (2001) Breaking the mitochondrial barrier. Nature Reviews Molecular Cell Biology 2, 63-67Google Scholar
102Li, B. et al. (2010) p53 inactivation by MDM2 and MDMX negative feedback loops in testicular germ cell tumors. Cell Cycle 9, 1411-1420Google Scholar
103Kerley-Hamilton, J.S. et al. (2005) A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. Oncogene 24, 6090–100Google Scholar
104Mao, P. et al. (2011) Serine/threonine kinase 17A is a novel p53 target gene and modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells. Journal of Biological Chemistry 286, 19381-19391Google Scholar
105Asada, M. et al. (1999) Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO Journal 18, 1223-1234Google Scholar
106Schepers, H. et al. (2003) Constitutive cytoplasmic localization of p21(Waf1/Cip1) affects the apoptotic process in monocytic leukaemia. Leukemia 17, 2113-2121Google Scholar
107Zhan, J. et al. (2007) Negative regulation of ASK1 by p21Cip1 involves a small domain that includes Serine 98 that is phosphorylated by ASK1 in vivo. Molecular Cell Biology 27, 3530-3541Google Scholar
108Zhou, B.B. et al. (1998) Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells. Proceedings of the National Academy of Sciences of the United States of America 95, 6785-6790Google Scholar
109Choi, J.S. et al. (2007) Cyclin-dependent protein kinase 2 activity is required for mitochondrial translocation of Bax and disruption of mitochondrial transmembrane potential during etoposide-induced apoptosis. Apoptosis 12, 1229-1241Google Scholar
110Jin, Y.H. et al. (2003) Cdk2 activity is associated with depolarization of mitochondrial membrane potential during apoptosis. Biochemical and Biophysical Research Communications 305, 974-980Google Scholar
111Huang, H. et al. (2006) CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314, 294-297Google Scholar
112Grande, L. et al. (2012) Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin. Journal of Biological Chemistry 287, 26495-26505Google Scholar
113Gutekunst, M. et al. (2013) Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct4. Cancer Research 73, 1460-1469Google Scholar
114Wu, Y.C. et al. (2012) Chemotherapeutic sensitivity of testicular germ cell tumors under hypoxic conditions is negatively regulated by SENP1-controlled sumoylation of OCT4. Cancer Research 72, 4963-4973Google Scholar
115Zamble, D.B. et al. (2002) Testis-specific HMG-domain protein alters the responses of cells to cisplatin. Journal of Inorganic Biochemistry 91, 451-462Google Scholar
116Evans, A.R., Limp-Foster, M. and Kelley, M.R. (2000) Going APE over ref-1. Mutation Research – DNA Repair 461, 83-108Google Scholar
117Robertson, K.A. et al. (2001) Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Cancer Research 61, 2220-2225Google Scholar
118Honecker, F. et al. (2009) Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. Journal of Clinical Oncology 27, 2129-2136Google Scholar
119Mayer, F. et al. (2002) Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment. Cancer Research 62, 2758-2760Google Scholar
120Mayer, F. et al. (2011) Histopathological and molecular features of late relapses in non-seminomas. BJU International 107, 936-943Google Scholar
121Lane, D.P. (1994) p53 and human cancers. British Medical Bulletin 50, 582-599Google Scholar
122Burger, H. et al. (1999) Distinct p53-independent apoptotic cell death signalling pathways in testicular germ cell tumour cell lines. International Journal of Cancer 81, 620-628Google Scholar
123Abbas, T. and Dutta, A. (2009) p21 in cancer: intricate networks and multiple activities. Nature Reviews Cancer 9, 400-414Google Scholar
124Noel, E.E. et al. (2010) The association of CCND1 overexpression and cisplatin resistance in testicular germ cell tumors and other cancers. American Journal of Pathology 176, 2607-2615Google Scholar
125Ajiro, M. et al. (2009) Involvement of RQCD1 overexpression, a novel cancer-testis antigen, in the Akt pathway in breast cancer cells. International Journal of Oncology 35, 673-681Google Scholar
126Ajiro, M. et al. (2010) Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis. International Journal of Oncology 37, 1085-1093Google Scholar
127Philp, A.J. et al. (2001) The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Research 61, 7426-7429Google Scholar
128Goswami, A., Ranganathan, P. and Rangnekar, V.M. (2006) The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target. Cancer Research 66, 2889-2892Google Scholar
129Juric, D. et al. (2005) Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures. Proceedings of the National Academy of Sciences of the United States of America 102, 17763-17768Google Scholar
130Korkola, J.E. et al. (2006) Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Research 66, 820-827Google Scholar
131Korkola, J.E. et al. (2005) Gene expression-based classification of nonseminomatous male germ cell tumors. Oncogene 24, 5101-5107Google Scholar
132Korkola, J.E. et al. (2009) Identification and validation of a gene expression signature that predicts outcome in adult men with germ cell tumors. Journal of Clinical Oncology 27, 5240-5247Google Scholar
133Sperger, J.M. et al. (2003) Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proceedings of the National Academy of Sciences of the United States of America 100, 13350-13355Google Scholar
134Mueller, T. et al. (2006) Loss of Oct-3/4 expression in embryonal carcinoma cells is associated with induction of cisplatin resistance. Tumour Biology 27, 71-83Google Scholar
135Mueller, T. et al. (2010) Histological evidence for the existence of germ cell tumor cells showing embryonal carcinoma morphology but lacking OCT4 expression and cisplatin sensitivity. Histochemistry and Cell Biology 134, 197-204Google Scholar
136Matin, M.M. et al. (2004) Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cells. Stem Cells 22, 659-668Google Scholar
137Hohjoh, H. and Fukushima, T. (2007) Marked change in microRNA expression during neuronal differentiation of human teratocarcinoma NTera2D1 and mouse embryonal carcinoma P19 cells. Biochemical and Biophysical Research Communications 362, 360-367Google Scholar
138Hromas, R. et al. (1999) Genesis, a Winged Helix transcriptional repressor, has embryonic expression limited to the neural crest, and stimulates proliferation in vitro in a neural development model. Cell Tissue Research 297, 371-382Google Scholar
139Curtin, J.C. et al. (2001) Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function. Oncogene 20, 2559-2569Google Scholar
140Baldassarre, G. et al. (2000) Retinoic acid induces neuronal differentiation of embryonal carcinoma cells by reducing proteasome-dependent proteolysis of the cyclin-dependent inhibitor p27. Cell Growth and Differentiation 11, 517-526Google Scholar
141Oosterhuis, J.W., Suurmeyer, A.J.H. and Sleyfer, D.T. (1983) Effects of multiple-drug chemotherapy (cis-diammine-dichloroplatinum, bleomycin, and vinblastine) on the maturation of retroperitoneal lymph node metastases of nonseminomatous germ cell tumors of the testis. No evidence for de novo induction of differentiation. Cancer 51, 408-4163.0.CO;2-4>CrossRefGoogle Scholar
142Logothetis, C.J. et al. (1982) The growing teratoma syndrome. Cancer 50, 1629-1635Google Scholar
143Skakkebaek, N.E. et al. (1987) Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. International Journal of Andrology 10(1 SPEC.), 19-28Google Scholar
144Rajpert-de Meyts, E. and Hoei-Hansen, C.E. (2007) From gonocytes to testicular cancer: the role of impaired gonadal development. Annals of the New York Academy of Sciences 1120, 168-180Google Scholar
145Almstrup, K. et al. (2004) Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling. Cancer Research 64, 4736-4743Google Scholar
146Sonne, S.B. et al. (2009) Analysis of gene expression profiles of microdissected cell populations indicates that testicular carcinoma in situ is an arrested gonocyte. Cancer Research 69, 5241-5250Google Scholar
147Aponte, P.M. et al. (2005) Spermatogonial stem cells: characteristics and experimental possibilities. APMIS 113, 727-742Google Scholar
148Kunwar, P.aS., Siekhaus, D.E. and Lehmann, R. (2006) In vivo migration: a germ cell perspective. Annual Review of Cell and Developmental Biology 22, 237-265Google Scholar
149Skotheim, R.I. et al. (2005) Differentiation of human embryonal carcinomas in vitro and in vivo reveals expression profiles relevant to normal development. Cancer Research 65, 5588-5598Google Scholar
150Papiani, G. and Einhorn, L.H. (2007) Salvage chemotherapy with high-dose carboplatin plus etoposide and autologous peripheral blood stem cell transplant in male pure choriocarcinoma: a retrospective analysis of 13 cases. Bone Marrow Transplantation 40, 235-237Google Scholar
151Lee, S.C. et al. (2009) Mixed testicular germ cell tumor presenting as metastatic pure choriocarcinoma involving multiple lung metastases that was effectively treated with high-dose chemotherapy. Cancer Research Treatment 41, 229-232Google Scholar
152IGCCCG (1997) International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. Journal of Clinical Oncology 15, 594-603Google Scholar
153Fulop, V., Mok, S.C., Genest, D.R., Gati, I., Doszpod, J. and Berkowitz, R.S. (1998) p53, p21, Rb and mdm2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma. Journal of Reproductive Medicine 43, 119-127Google Scholar
154Nishikawa, R. and Matsutani, M. (1998) Immunohistochemical analysis of p53 and p21(WAF1/Cip1) expression in primary intracranial germ cell tumors. Neurosurgical Focus 5, e2Google Scholar
155Sato, T. et al. (1995) FAP-1: a protein tyrosine phosphatase that associates with Fas. Science 268, 411-415Google Scholar
156Li, Y. et al. (2000) Negative regulation of Fas-mediated apoptosis by FAP-1 in human cancer cells. International Journal of Cancer 87, 473-479Google Scholar
157Pesce, M. and Scholer, H.R. (2001) Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19, 271-278Google Scholar
158Zhang, H.J. et al. (2008) Oct4 is epigenetically regulated by methylation in normal placenta and gestational trophoblastic disease. Placenta 29, 549-554Google Scholar
159Almstrup, K. et al. (2010) Carcinoma in situ testis displays permissive chromatin modifications similar to immature foetal germ cells. British Journal of Cancer 103, 1269-1276Google Scholar
160Netto, G.J. et al. (2008) Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors. Modern Pathology 21, 1337-1344Google Scholar
161Smiraglia, D.J. et al. (2002) Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors. Oncogene 21, 3909-3916Google Scholar
162Wermann, H. et al. (2010) Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. Journal of Pathology 221, 433-442Google Scholar
163Koul, S. et al. (2002) Characteristic promoter hypermethylation signatures in male germ cell tumors. Mol Cancer 1, 8Google Scholar
164Portela, A. and Esteller, M. (2010) Epigenetic modifications and human disease. Nature Biotechnology 28, 1057-1068Google Scholar
165Biermann, K. et al. (2007) Genome-wide expression profiling reveals new insights into pathogenesis and progression of testicular germ cell tumors. Cancer Genomics Proteomics 4, 359-367Google Scholar
166Nettersheim, D. et al. (2011) NANOG promoter methylation and expression correlation during normal and malignant human germ cell development. Epigenetics 6, 114-122Google Scholar
167Koul, S. et al. (2004) Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. Molecular Cancer 3, 16Google Scholar
168Biswal, B.K. et al. (2012) Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS ONE 7, e53003Google Scholar
169Beyrouthy, M.J. et al. (2009) High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors. Cancer Research 69, 9360-9366Google Scholar
170Fizazi, K. et al. (2013) A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: results of GETUG 13. Journal of Clinical Oncology (suppl; abstr LBA4500)Google Scholar
171Bauer, S. et al. (2010) Therapeutic potential of Mdm2 inhibition in malignant germ cell tumours. European Urology 57, 679-687Google Scholar
172Gomes, N.P. and Espinosa, J.M. (2010) Differential regulation of p53 target genes: it's (core promoter) elementary. Genes and Development 24, 111-114Google Scholar
173Morachis, J.M., Murawsky, C.M. and Emerson, B.M. (2010) Regulation of the p53 transcriptional response by structurally diverse core promoters. Genes and Development 24, 135-147Google Scholar
174Shikama, N. et al. (1999) A novel cofactor for p300 that regulates the p53 response. Molecular Cell 4, 365-376Google Scholar
175Samuels-Lev, Y. et al. (2001) ASPP proteins specifically stimulate the apoptotic function of p53. Molecular Cell 8, 781-794CrossRefGoogle ScholarPubMed
176Enge, M. et al. (2009) MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53. Cancer Cell 15, 171-183Google Scholar
177Brummelkamp, T.R. et al. (2006) An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nature Chemical Biology 2, 202-206Google Scholar
178Bernal, F. et al. (2010) A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18, 411-422Google Scholar
179Joseph, T.L., Lane, D. and Verma, C.S. (2010) Stapled peptides in the p53 pathway: computer simulations reveal novel interactions of the staples with the target protein. Cell Cycle 9, 4560-4568Google Scholar
180Gembarska, A. et al. (2012) MDM4 is a key therapeutic target in cutaneous melanoma. Nature Medicine 18, doi:10.1038/nm2863Google Scholar
181Mir, R. et al. (2013) Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells. International Journal of Cancer 132, 1525-1536Google Scholar
182Etter, A.L. et al. (2007) The combination of chemotherapy and intraperitoneal MegaFas Ligand improves treatment of ovarian carcinoma. Gynecologic Oncology 107, 14-21Google Scholar
183Altena, R. et al. (2009) Cardiovascular toxicity caused by cancer treatment: strategies for early detection. Lancet Oncology 10, 391-399Google Scholar
184de Haas, E.C. et al. (2010) The metabolic syndrome in cancer survivors. Lancet Oncology 11, 193-203Google Scholar
185Zhou, B.P. et al. (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature Cell Biology 3, 245-252Google Scholar
186Xia, W. et al. (2004) Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clinical Cancer Research 10, 3815-3824Google Scholar
187Lin, P.Y. et al. (2007) Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance. Molecular Cancer 6, 16Google Scholar
188Menendez, J.A., Mehmi, I. and Lupu, R. (2005) Heregulin-triggered Her-2/neu signaling enhances nuclear accumulation of p21WAF1/CIP1 and protects breast cancer cells from cisplatin-induced genotoxic damage. International Journal of Oncology 26, 649-659Google Scholar
189Perez-Tenorio, G. et al. (2006) Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer. International Journal of Oncology 28, 1031-1042Google Scholar
190Xia, X. et al. (2011) Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer. BMC Cancer 11, 399Google Scholar
191Jin, H.O. et al. (2012) Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition. Cell Death and Disease 3, e319Google Scholar
192Ihle, N.T. and Powis, G. (2010) The biological effects of isoform-specific PI3-kinase inhibition. Current Opinion on Drug Discovery and Development 13, 41-49Google Scholar
193Palumbo, C. et al. (2002) Expression of the PDGF alpha-receptor 1.5 kb transcript, OCT-4, and c-KIT in human normal and malignant tissues. Implications for the early diagnosis of testicular germ cell tumours and for our understanding of regulatory mechanisms. Journal of Pathology 196, 467-477Google Scholar
194Rapley, E.A. et al. (2004) Somatic mutations of KIT in familial testicular germ cell tumours. British Journal of Cancer 90, 2397-2401Google Scholar
195McIntyre, A. et al. (2005) Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors. Neoplasia 7, 1047-1052Google Scholar
196Goddard, N.C. et al. (2007) KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature. International Journal of Andrology 30, 337-348; discussion 349Google Scholar
197Rapley, E.A. et al. (2009) A genome-wide association study of testicular germ cell tumor. Nature Genetics 41, 807-810Google Scholar
198Kanetsky, P.A. et al. (2009) Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nature Genetics 41, 811-815Google Scholar
199Gilbert, D., Rapley, E. and Shipley, J. (2011) Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nature Reviews Cancer 11, 278-288Google Scholar
200McIntyre, A. et al. (2005) Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Research 65, 8085-8089Google Scholar
201Viglietto, G. et al. (1996) Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor. Oncogene 13, 577-587Google Scholar
202Basciani, S. et al. (2002) Expression of platelet-derived growth factor-A (PDGF-A), PDGF-B, and PDGF receptor-alpha and -beta during human testicular development and disease. Journal of Clinical Endocrinology and Metabolism 87, 2310-2319Google Scholar
203Castillo-Avila, W. et al. (2009) Sunitinib inhibits tumor growth and synergizes with cisplatin in orthotopic models of cisplatin-sensitive and cisplatin-resistant human testicular germ cell tumors. Clinical Cancer Research 15, 3384-3395Google Scholar
204Oechsle, K. et al. (2011) Preclinical and clinical activity of sunitinib in patients with cisplatin-refractory or multiply relapsed germ cell tumors: a Canadian Urologic Oncology Group/German Testicular Cancer Study Group cooperative study. Annals of Oncology 22, 2654-2660Google Scholar
205Roth, B.J. et al. (1993) 5-Azacytidine (NSC 102816) in refractory germ cell tumors. A phase II trial of the Eastern Cooperative Oncology Group. Investigational New Drugs 11, 201-202Google Scholar
206Fang, F. et al. (2010) A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer 116, 4043-4053Google Scholar
207Timmer-Bosscha, H. et al. (1993) cis-diamminedichloroplatinum(ii) resistance in vitro and in vivo in human embryonal carcinoma cells. Cancer Research 53, 5707-5713Google Scholar
208Berger, D.P. et al. (1990) Preclinical phase II study of ifosfamide in human tumour xenografts in vivo. Cancer Chemotherapy and Pharmacology 26(Suppl), S7-S11Google Scholar