Expression of Bcl-2 Family Members in Malignant Pleural Mesothelioma (original) (raw)
Related papers
Immunoreactivity for bcl-2 protein in malignant mesothelioma and non-neoplastic mesothelium
Virchows Archiv, 1994
Immunohistochemical study of bcl-2 protein immunoreactivity in human non-neoplastic mesothelium (44 cases) and in malignant mesothelioma (62 cases) using a murine monoclonal antibody (clone 124) showed cytoplasmic immunoreactivity for bcl-2 protein in five cases of malignant mesothelioma. Non-neoplastic mesothelium was not immunoreactive. Immunoreactivity for bcl-2 protein does not add useful prognostic information in malignant mesothelioma since survival times of bcl-2 positive and bcl-2 negative cases did not differ. Nevertheless, the detection of bcl-2 protein in malignant mesothelioma might be useful for the differentiation from reactive mesothelium.
Lung Cancer, 2005
Aim: We aimed to identify defects in the programmed cell death pathway that can be related to pleural malignant mesothelioma (MM) unresponsiveness to chemotherapy. Materials and methods: We quantified mRNA levels of the apoptosis regulating genes Survivin, member of the IAP family, Bcl-2 and Bax, members of the Bcl-2 family. We studied 22 non-neoplastic pleural samples, comprising normal and inflammatory tissue specimens, and 42 pleural MMs using real-time RT-PCR. Results: Very low mRNA levels of each apoptotic gene were detected in all normal pleural samples. All three genes displayed increased mRNA levels in inflammatory and tumor specimens. Survivin levels in pleuritis and MMs were significantly increased (333% and 908%, respectively) compared to normal counterparts (p = 0.0147 and 0.00349, respectively). Bcl-2 and Bax levels were increased in inflammatory pleural samples (394%, p = 0.001 and 188%, p = ns, respectively) and in MMs (94%, p = ns and 88%, p = 0.0163, respectively). The Bcl-2/Bax ratio was higher in pleuritis than in MMs, compared to normal pleurae (441%, p = ns and 22%, p = ns, respectively); the difference between Bcl-2/Bax ratio in inflammatory and neoplastic pleural samples was significant (p = 0.00375). Conclusions: These results suggest that apoptotic defects in pleural MMs are linked to increased levels of Survivin, whereas variations in Bcl-2 and Bax expression Abbreviation: MM, malignant mesothelioma
BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study
Journal of the Neurological Sciences, 1998
Malignant gliomas are rather refractory to current therapeutic approaches including surgery, radiotherapy, chemotherapy and immunotherapy. Acquired alterations in the pathways required for apoptotic cell death are thought to be responsible to the failure of glioma to respond to therapy. Here we have examined the expression of several proteins involved in the susceptibility to apoptosis in 20 human gliomas, including the BCL-2 family proteins BCL-2, BCL-X, BAX and MCL-1, as well as p53 and RB. Most gliomas expressed several BCL-2 family proteins. There was good correlation between expression of the functional antagonists, BCL-2 / BCL-X and BAX, suggesting that changes in the BCL-21BCL-X / BAX ratio are not responsible for the differential response of glioma patients to chemotherapy. The immunochemistry data were also analysed in regard to response to therapy and clinical outcome. All patients had cytoreductive surgery and received radiotherapy and nitrosourea-based adjuvant chemotherapy. There was no prominent association of outcome with the expression patterns of p53, RB, BCL-2, BCL-X or BAX. We find, however, that expression of the MCL-1 protein is associated with early tumour recurrence and shorter survival in this group of glioma patients. This preliminary observation will have to be confirmed in a larger independent sample of glioma patients.
BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
Cell Death Discovery, 2020
Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical invest...
Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma
2002
Malignant pleural mesothelioma (MPM) is a highly lethal pleural neoplasm that is often resistant to chemotherapeutic drugs, including cisplatin, and for which little is known regarding carcinogenic pathways. We used differential display to compare gene expression patterns in mesothelioma, normal pleura and normal lung, in order to better understand MPM pathobiology, and to search for genes that may facilitate drug resistance in this cancer. The human inhibitor of apoptosis protein-1 gene (IAP-1/ MIHC/cIAP2) was discovered to be highly expressed in MPM. We confirmed overexpression of IAP-1 mRNA and protein in 39 additional human MPM tumor specimens and 3/5 (60%) MPM cell lines by multiple methods, including real time quantitative reverse transcription-PCR and western blot analysis. Using an antisense targeting approach, we found that attenuation of IAP-1 mRNA levels decreases baseline cell viability and increases the sensitivity of MPM cell lines to cisplatin by nearly 20-fold. Reduced IAP-1 gene expression also results in a concordant increase of the pro-apoptotic cleavage product of caspase 9 and a reduction in the number of viable tumor cells. Our observations strongly suggest that IAP-1 is at least partly responsible for promoting carcinogenesis and mediating resistance to cisplatin in many MPM tumors and that further study of this apoptotic pathway is warranted.
Iranian Journal of Pathology, 2017
Apoptosis Malignant lymphoproliferative Bcl2 Bax Background & Objective: The current study aimed to perform an immunohistochemical analysis of patterns of apoptotic and cell proliferative related protein expression in different histological grades and immune phenotypes of malignant lymphomas and other lymphoproliferative disorders Methods: This observational study was carried on 60lymph node biopsies of lymphoproliferative disorders. The biopsies were analyzed histologically and immunohistochemically. Results: A total of 60 lymph node biopsies were included in the study, of which 81.6% were of malignant lympho-proliferative lesions. The majority of the biopsies were B-cell (66%) and were grouped in the intermediate grade. Bax and BCL-2 protein expression was presented by percentage of immune positive neoplastic cells per 10fields and graded on a scale of 1 to4. A Bcl-2, Bax Protein Ratio (BBPR) was determined for each case by dividing the estimated Bcl-2 protein (percentage of Bcl-2 positive cells x Bcl-2 staining intensity) by the estimated Bax protein (percentage of Bax positive cells x Bax immunostaining intensity). The mean BBPR was found to be significantly higher in indolent lymphomas (2.64 ± 1.3) as compared to aggressive lymphomas (0.47 ± 0.9) (P<0.01). The expression of P53 and PCNA in 35 biopsies of Non Hodgkin Lymphomas (NHL) was found to increase from low to high grade tumors. Conclusions: A significant correlation was found between BBPR and predicted biological behavior of indolent and aggressive lymphomas. This indicates the important role of Bcl-2 and Bax in biological behavior of lymphomas. Furthermore, P53 and PCNA expression were found to increase from low to high-grade tumors suggesting their prognostic value in NHL.
The role of apoptosis, cell proliferation index, bcl-2, and p53 in glioblastoma prognosis
Arquivos de Neuro-Psiquiatria, 2004
Glioblastoma is the most common neuroectodermic tumor. It is also the most malignant one. Many genetic changes are found in glioblastomas, among them, the presence of oncoproteins p53 and blc-2, as well as a high mitotic level and the presence of apoptosis. The utility of such findings through immunohistochemistry for the prognosis of patients remains uncertain. Our objectives in this study were to verify the presence of apoptosis, blc-2, p53, and the proliferative index (MIB-1), through immunohistochemistry, in 30 glioblastomas obtained by surgical resection between August 2000 and August 2001, as well as correlations between those immunohistochemical variables and the patient's age and survival time. Correlations between immunohistochemical variables themselves were also examined. For correlation calculations, Pearson's and Spermann's correlations were used and the time of survival was calculated with the Kaplan-Meier method. RESULTS: No correlation was found between i...
Apoptosis and expression of bcl-2 ?, ? mRNA isoforms and protein in neuroblastoma
Apoptosis, 1996
We studied apoptosis in 36 neuroblastomas by DNA ladder assay. Expression of bcl2-α and β mRNA isoforms and protein were detected by RT-PCR and by immunohistochemistry, respectively. Internucleosomal DNA fragmentation was found in 20/36 (56%) tumor tissues collected both at onset and relapse of disease. Bcl-2α and β mRNAs and protein were found in almost all examined tumors irrespective of DNA ladder, thus showing lack of correlation with the clinical stage. BCL-2 protein was observed to be expressed at various levels in undifferentiated and in more differentiated neuroblasts, while the stroma and the fibrovascular tissue were negative. Our results show that apoptosis is present in neuroblastoma at all stages and that bcl-2 gene is widely expressed in tumor tissue. In our series of neuroblastomas, bcl-2 expression is not correlated with unfavorable prognosis.
Journal of Thoracic Oncology, 2017
Background: BRCA1-associated protein 1 (BAP1) gene is located at chromosome region 3p21.1, a genomic region that is deleted in several human malignancies, including approximately 30-60% of mesotheliomas(1). In this study, we retrospectively investigated BAP1 status in 41 unrelated patients with mesothelioma who had a history of environmental fibrous mineral exposure (erionite or asbestos). We have also reviewed histological type and clinical characteristics of the analyzed patients. Methods: A total of 41 malignant mesothelioma cases were reviewed histopathologically. Representative areas were selected and 4-mm-diameter tissue microarrays were composed from paraffin blocks. Immunohistochemistry (IHC) was performed on paraffin tissue sections prepared from microarrays with a monoclonal antibody against BAP1. Cases with loss of nuclear staining were considered as loss of BAP1 expression. Results: Satisfactory results were obtained in 37 patients (25 females, 12 males; mean age 56 yrs). Thirtyone cases were pleural, 5 cases were peritoneal and 1 case was paratesticular mesotheliomas. Histologically, 31 cases were epithelioid, and 6 cases were biphasic type. Overall all loss of BAP1 expression was 31/37 [83, 8% (87, 1% pleural, 80% peritoneal, 0 paratesticular)]. Histologically, all biphasic types and 25/31 (80, 6%) epithelioid types showed BAP1 expression loss. Conclusion: Loss of BAP1 expression seems to be a frequent event in Turkish malignant mesotheliomas. However, in our small cohort, no significant correlation was found between tumor type and localization. We need to demonstrate both somatic and germ-like mutations in familial cases especially from erionite villages.