p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma

Hirabayashi, Hirohisa; Fujii, Yoshitaka; Sakaguchi, Masahiro; Tanaka, Hisashi; Yoon, Hyungeun; Komoto, Yoshiko; Inoue, M.; Miyoshi, Shinichiro; Matsuda, Hikaru

doi:10.1002/(sici)1097-0215(19971127)73:5<639::aid-ijc5>3.3.co;2-9

Cited by 20 publications

(41 citation statements)

References 12 publications

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“…Correspondingly, previous reports have shown that inactivation of p16 INK4A , which results in higher CDK4 activity (35), is involved in the progression of TEMs (36). Regarding EGFR, which is frequently overexpressed in TEMs (23), mutations that alter its susceptibility towards different inhibitors are rare in this cancer (37)(38)(39).…”

Section: Discussionmentioning

confidence: 88%

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

Breinig

Mayer

Harjung

et al. 2011

Clinical Cancer Research

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Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.Experimental Design: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.Results: Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R-signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.Conclusions: We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials.

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Section: Discussionmentioning

confidence: 88%

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

Breinig

Mayer

Harjung

et al. 2011

Clinical Cancer Research

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“…52 Abnormal expression of RB1 based on immunohistochemistry has been reported in few cases of thymoma. 53 In one case of type B3 thymoma, a high-level amplification was detected involving chromosomal band 8p12. This chromosomal region harbors a potential oncogene, namely the fibroblast growth factor receptor I, which has been reported to be amplified in other epithelial neoplasms, eg, in breast cancer and ovarian cancer.…”

Section: Discussionmentioning

confidence: 98%

Recurrent Genetic Aberrations in Thymoma and Thymic Carcinoma

Zettl

Ströbel

Wagner

et al. 2000

The American Journal of Pathology

159

140

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Apart from single reported aberrant karyotypes, genetic alterations in thymic epithelial neoplasms have not been investigated so far. In this study, 12 World Health Organization classification type A thymomas (medullary thymomas), 16 type B3 thymomas (welldifferentiated thymic carcinomas), and nine type C thymomas, all of them primary thymic squamous cell carcinomas, were analyzed by comparative genomic hybridization and fluorescence in situ hybridization. With the exception of one single case, type A thymomas did not reveal chromosomal gains or losses in comparative genomic hybridization. In contrast, all type B3 thymomas showed chromosomal imbalances, with gain of 1q, loss of chromosome 6, and loss of 13q occurring in 11 (69%), six (38%), and five (31%) of 16 cases, respectively. In primary thymic squamous cell carcinoma, the most frequent chromosomal losses were observed for 16q (six of nine cases, 67%), 6 (4 of 9, 44%), and 3p and 17p (three of nine each, 33%), whereas recurrent gains of chromosomal material were gains of 1q (5 of 9, 56%), 17q, and 18 (three of nine each, 33%). This study shows that the distinct histological thymoma types A and B3 exhibit distinct genetic phenotypes, whereas type B3 thymoma and primary thymic squamous cell carcinoma partially share genetic aberrations. In addition to the possible tumorigenic role, the deletion in type B3 thymoma of chromosome 6, harboring the HLA locus, might play a role in the pathogenesis of paraneoplastic autoimmunity characteristic of thymoma. 1 classification, several types of thymomas are distinguished based on histological criteria: 1) type A thymomas (also called medullary or spindle-cell thymoma); 2) type AB thymomas (also called mixed thymoma); 3) type B thymomas which are subclassified as type B1 thymomas (also called lymphocyte-rich thymoma, lymphocytic thymoma, predominantly cortical thymoma, or organoid thymoma), type B2 thymomas (also called cortical thymoma) and type B3 thymomas (also called epithelial, atypical, or squamoid thymoma or well-differentiated thymic carcinoma, respectively) and; 4) type C thymomas (thymic carcinomas) which exhibit morphological similarities to corresponding neoplasms in organs other than the thymus (eg, primary thymic squamous cell carcinoma).

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“…Few of the factors involved in regulating cell cycle control have been investigated in thymomas; even fewer studies have examined multiple factors in the same tumor series (7,8). The aim of this study was therefore to evaluate the expression of p53, p21, and p27 proteins in a homogeneous series of samestage thymomas to assess the integrity of cell cycle checkpoints in these tumors, to evaluate the coexpression of these proteins, and, finally, to examine the relationship between these cell cycle regulators and the clinicopathologic features of thymomas, including their ability to predict recurrence, and therefore necessity, of more accurate follow-up and supplemental therapy.…”

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confidence: 99%

Analysis of Cell Cycle Regulator Proteins in Encapsulated Thymomas

Baldi¹,

Ambrogi

Mineo

et al. 2005

Clinical Cancer Research

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Purpose: Although survival of encapsulated thymomas is usually good, some patients present a higher incidence rate of recurrence and a shorter long-term survival. Abnormalities in the components of cell cycle checkpoints are extremely common among virtually all neoplasms. In this study, three components of the cell cycle machinery (i.e., p21, p27 and p53) were examined in a series of well-characterized encapsulated thymoma specimens to analyze coregulation and influence on recurrence and survival. Experimental Design: Sixty-eight consecutive patients with thymoma were operated in our center from 1987 to 2000. Expression of p53, p21, and p27 was studied in specimens from 25 encapsulated thymomas using immunohistochemistry. Generic factors and gene expression influencing the probability of recurrence were studied. Positive expression was dichotomized defining positive when present in more than 5% of tumor cells. Mean follow up was 85.9 months; clinical data about recurrence were recorded.Results: Univariate analysis suggests that positive p53 (P < 0.05), negative p21 (P = 0.01), and especially negative p27 expressions (P = 0.001) significantly correlate with poor prognosis for disease-free survival. Multivariate Cox regression analysis suggests that negative p27 immunohistology is the only significant variable for poor prognosis (P = 0.03; odds ratio, 0.08; 95% confidence interval, 0.01-0.88). Conclusions: These results show that loss of control of cell cycle checkpoints is a common occurrence in thymomas and support the idea that functional cooperation between different cell cycle inhibitor proteins constitutes another level of regulation in cell growth control and tumor suppression.

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p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma

Cited by 20 publications

References 12 publications

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

Recurrent Genetic Aberrations in Thymoma and Thymic Carcinoma

Analysis of Cell Cycle Regulator Proteins in Encapsulated Thymomas

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