Role of P53 and MDM2 in Treatment Response of Human Germ Cell Tumors

Kersemaekers, A.-M. F.

doi:10.1200/jco.20.6.1551

Cited by 79 publications

(78 citation statements)

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“…Most of the genes analysed, however, were either not detectable (no signal) or only weakly expressed in NCCIT cells (weak signals) and did not reveal any down-or upregulation after drug treatment. p53, the p53-regulated gene mdm-2 and genes from the Bcl-2 family belonged to this group, as reported by others (Burger et al, 1997;Kersemaekers et al, 2002) (Table 1). The expression level of five genes including IGFBP-2, AP-1, CDC25A, GADD45 and ID-1 was decreased in treated cells compared to the levels in untreated cells (Table 1).…”

Section: Analysis Of Apoptosis-regulating Genes Following Cddp Treatmentsupporting

confidence: 81%

“…Although Chresta et al (1996) postulated that a hypersensitivity of human TGCT to drug-dependent apoptosis may also be associated with functional p53 , Burger et al (1999) showed that abrogation of the p53 function does not affect the hypersensitivity of human TGCT cell lines to chemotherapy. Thus in human TGCT, apoptotic signalling pathways including those activated by CDDP seem to be -at least partly -p53 independent (Burger et al, 1997;Kersemaekers et al, 2002).…”

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confidence: 97%

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Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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Testicular germ cell tumours (TGCT) represent the most common malignancies in young males. Whereas in 1970s, the survival rate in patients with metastatic testicular tumours was only 5%, these days, 80% of the patients treated by modern chemotherapy will survive their disease. The drug that revolutionised the cure rate for patients with metastatic testicular tumours was cisdiamminedichloroplatinum (cisplatin, CDDP). In vitro experiments on neoplastic germ cell lines showed that their exquisite sensitivity to CDDP could be attributed to p53-dependent and -independent pathways. Applying cDNA macroarray, semiquantitative RT -PCR and Western blot analyses, blocking experiments, caspase activity assays, and morphological methods, we sought here to define the p53-independent pathway(s) involved in the CDDP-induced apoptosis. For this purpose, we used the human TGCT cell line NCCIT, the mutated p53 of which is known to remain inactive during the course of CDDP-induced apoptosis. Our experiments showed that within hours of CDDP application, two prototype members of the 'mitogen-activated protein kinase' (MAPK) family, designated 'MAPK ERK kinase' (MEK) and 'extracellular signal-regulated kinase' (ERK), were dually phosphorylated and caspase-3 became active. Functional assays using MEK inhibitors demonstrated that the phosphorylation of MEK and ERK was required for the activation of caspase-3 as the executing caspase. Interestingly, experiments with the human malignant germ cell line NTERA, which is known to possess wild-type p53, revealed the same results. Thus, our data suggest that CDDP mediates its p53-independent apoptosis-inducing effect on the malignant human testicular germ cells -at least partially -through activation of the MEK -ERK signalling pathway.

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Section: Analysis Of Apoptosis-regulating Genes Following Cddp Treatmentsupporting

confidence: 81%

mentioning

confidence: 97%

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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“…Chemoresistance has been linked to P53 gene mutations by some investigators 14 but not others. 15 By comparative genomic hybridization analysis, Rao et al 16 identified possible amplified regions involving multiple chromosomes (1q, 2p, 7q, 9q, 9q, 15q, and 20q) in cisplatin-resistant germ cell tumors. Identification of amplified/overexpressed genes may elucidate genetic pathways of chemotherapy resistance in germ cell tumors and may help in the development of novel treatments targeted at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor protein expression and gene amplification in the chemorefractory metastatic embryonal carcinoma

et al. 2009

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Testicular cancer is the most common cancer in young male patients. The combination of cisplatin-based chemotherapy and surgery has resulted in high cure rates. However, a small percentage of patients have cancers that are refractory to chemotherapy; treatment options for these patients are limited, and their prognosis is generally poor. Further studies are needed to explore the molecular pathogenesis pathways and potential targets of therapy for this group of highly aggressive tumors. We analyzed 21 patients who presented with metastatic embryonal carcinoma, were treated with chemotherapy, and subsequently underwent retroperitoneal lymph node dissection. Immunostaining for epidermal growth factor receptor (EGFR) was performed on paraffin-embedded tissue sections containing tumor from these specimens, using the avidinbiotin-peroxidase method. EGFR gene amplification was performed by interphase fluorescence in situ hybridization (FISH). Immunohistochemically, 9 of 21 cases (43%) demonstrated positive EGFR staining; 12 of 21 cases (57%) had absent or very limited EGFR expression. FISH revealed EGFR amplification in 1 case (5%), polysomy in 15 of 21 cases (71%), and normal disomy pattern in 5 of 21 cases (24%). A significant correlation between EGFR protein expression level and its chromosome polysomy/amplification was established (P ¼ 0.02). Our study showed that EGFR protein is frequently expressed in a subset of patients with chemorefractory metastatic embryonal carcinoma. EGFR chromosomal polysomy/amplification may be one of the mechanisms that cause increased EGFR protein expression, and could potentially be used as indication for anti-EGFR therapy.

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“…One of the unsolved issues in the pathogenesis of type-II GCTs is the overall presence of wild-type P53 protein [74][75][76] , the most frequently inactivated gene in solid cancers. 77 The requirement to inactivate P53 is (partly) due to the role the P53 protein plays in overruling the mechanism of cellular senescence, induced for example by oncogenic stress.…”

Section: Additional Malignant 'Intrinsic' Characteristics Of Embryonimentioning

confidence: 99%

Tumor risk in disorders of sex development (DSD)

Looijenga¹,

Hersmus²,

Oosterhuis

et al. 2007

Best Practice & Research Clinical Endocrinology & Metab

194

139

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Disorders of sex development (DSD), previously referred to as intersex disorders, comprise a variety of anomalies defined by congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Besides issues such as gender assignment, clinical and diagnostic evaluation, surgical and psychosocial management, and sex steroid replacement, the significantly increased risk for developing specific types of malignancies is both clinically and biologically relevant. This relates to germ-cell tumors specifically in DSD patients with hypovirilization or gonadal dysgenesis. The presence of a well-defined part of the Y chromosome (known as the GBY region) is a prerequisite for malignant transformation, for which the testis-specific protein on the Y chromosome (TSPY ) is a likely candidate gene. The precursor lesions of these cancers are carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU) in testicular tissue and gonadoblastoma in those without obvious testicular differentiation. Most recently, undifferentiated gonadal tissue (UGT) has been identified as the likely precursor for gonadoblastoma. The availability of markers for the different developmental stages of germ cells allows detailed investigation of the characteristics of normal and (pre)malignant germ cells. Although informative in a diagnostic setting for adult male patients, these markers -such as OCT3/4 -cannot easily distinguish (pre)malignant germ cells from germ cells showing delayed maturation. This latter phenomenon is frequently found in gonads of DSD patients, and may be related to the risk of malignant transformation. Thus, the mere application of these markers might result in over-diagnosis and unnecessary gonadectomy. It is proposed that morphological and histological evaluation of gonadal tissue, in combination with OCT3/4 and TSPY double immunohistochemistry and clinical parameters, is most informative in estimating the risk for germ-cell tumor development in the individual patient, and might in future be used to develop a decision tree for optimal management of patients with DSD.

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Role of P53 and MDM2 in Treatment Response of Human Germ Cell Tumors

Abstract: Although our results are in line with previous findings of the presence of wild-type P53 in TGCTs, they show that a high level of P53 does not relate directly to treatment sensitivity of these tumors, and inactivation of P53 is not a common event in the development of cisplatin resistance.

Cited by 79 publications

References 0 publications

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Epidermal growth factor receptor protein expression and gene amplification in the chemorefractory metastatic embryonal carcinoma

Tumor risk in disorders of sex development (DSD)

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