Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solid tumors such as mesothelioma exhibit a stubborn resistance to apoptosis that may derive from survival pathways, such as PI3K/Akt/mTOR, that are activated in many tumors, including mesothelioma. To address the role of PI3K/Akt/mTOR, we used a novel approach to study mesothelioma ex vivo as tumor fragment spheroids. Freshly resected mesothelioma tissue from 15 different patients was grown in vitro as 1- to 2-mm-diameter fragments, exposed to apoptotic agents for 48 hours with or without PI3K/Akt/mTOR inhibitors, and doubly stained for cytokeratin and cleaved caspase 3 to identify apoptotic mesothelioma cells. Mesothelioma cells within the tumor spheroids exhibited striking resistance to apoptotic agents such as TRAIL plus gemcitabine that were highly effective against monolayers. In a majority of tumors (67%; 10 of 15), apoptotic resistance could be reduced by more than 50% by rapamycin, an mTOR inhibitor, but not by LY294002, a PI3K inhibitor. Responsiveness to rapamycin correlated with staining for the mTOR target, p-S6K, in the original tumor, but not for p-Akt. As confirmation of the role of mTOR, siRNA knockdown of S6K reproduced the effect of rapamycin in three rapamycin-responsive tumors. Finally, in 37 mesotheliomas on tissue microarray, p-S6K correlated only weakly with p-Akt, suggesting the existence of Akt-independent regulation of mTOR. We propose that mTOR mediates survival signals in many mesothelioma tumors. Inhibition of mTOR may provide a nontoxic adjunct to therapy directed against malignant mesothelioma, especially in those with high baseline expression of p-S6K.
Am J Respir Cell Mol Biol 2008 Nov
PMID:mTOR mediates survival signals in malignant mesothelioma grown as tumor fragment spheroids. 1851 8

Malignant mesotheliomas occur in the pleura, peritoneum, pericardium, and tunica vaginalis. The majority of tumors are pleural in origin. The typical pattern of spread is usually contiguous or via implantation. Hematogenous or lymphatic metastasis is not uncommon; however, metastasis to bone has rarely been well documented. This is a case report of malignant pleural mesothelioma metastatic to the femur with a pathologic fracture of femoral neck.
Appl Immunohistochem Mol Morphol 2008 Oct
PMID:Malignant pleural mesothelioma with osseous metastases and pathologic fracture of femoral neck. 1858 Apr 95

Pleural effusions are commonly clinical disorders, resulting from the imbalance between pleural fluid turnover and reabsorption. The mechanisms underlying pleural fluid clearance across the mesothelium remain to be elucidated. We hypothesized that epithelial Na(+) channel (ENaC) is expressed and forms the molecular basis of the amiloride-sensitive resistance in human mesothelial cells. Our RT-PCR results showed that three ENaC subunits, namely, alpha, beta, gamma, and two delta ENaC subunits, are expressed in human primary pleural mesothelial cells, a human mesothelioma cell line (M9K), and mouse pleural tissue. In addition, Western blotting and immunofluorescence microscopy studies revealed that alpha, beta, gamma, and delta ENaC subunits are expressed in primary human mesothelial cells and M9K cells at the protein level. An amiloride-inhibitable short-circuit current was detected in M9K monolayers and mouse pleural tissues when mounted in Ussing chambers. Whole-cell patch clamp recordings showed an ENaC-like channel with an amiloride concentration producing 50% inhibition of 12 microM in M9K cells. This cation channel has a high affinity for extracellular Na+ ions (K(m): 53 mM). The ion selectivity of this channel to cations follows the same order as ENaC: Li+ > Na+ > K+. The unitary Li(+) conductance was 15 pS in on-cell patches. Four ENaC subunits form a functional Na+ channel when coinjected into Xenopus oocytes. Furthermore, we found that both forskolin and cGMP increased the short-circuit currents in mouse pleural tissues. Taken together, our data demonstrate that the ENaC channels are biochemically and functionally expressed in human pleural mesothelial cells, and can be up-regulated by cyclic AMP and cyclic GMP.
Am J Respir Cell Mol Biol 2009 May
PMID:Expression and regulation of epithelial Na+ channels by nucleotides in pleural mesothelial cells. 1892 49

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, whose main etiology is exposure to asbestos fibers. The incidence of MPM is anticipated to increase worldwide during the first half of this century. For various reasons, MPM is difficult to diagnose and is notoriously refractory to most treatments. However, recently two active chemotherapy regimens have been demonstrated to significantly increase survival in patients with MPM, and several therapeutic agents and strategies are currently under evaluation.Researchers have actively sought MPM biomarkers for more than 20 years. Biomarkers would be helpful in managing three clinical aspects of MPM: early diagnosis, prognosis, and treatment outcome prediction. The aims of the present review are to summarize the published and recently presented data on MPM biomarkers and to identify the prospects for future translational research projects.Among the 'classical' diagnostic biomarkers measured in biological fluids, such as cytokeratins and cell surface antigens, none discriminate patients with MPM from those with other malignancies and nonmalignant diseases. Osteopontin, soluble mesothelin, and megakaryocyte potentiating factor (MPF) appear to be the most promising of the recent biomarkers, but are still subject to some limitations. Osteopontin lacks specificity for mesothelioma, while both soluble mesothelin and MPF lack sensitivity for detecting non-epithelial subtypes. Panels consisting of a small set of biomarkers do not improve the diagnostic yield, and results from molecular profiling are too preliminary to be brought into daily clinical practice. While a large number of biomarkers have been assessed in biological fluids and tumor tissue for their prognostic value, none have had a widespread impact on clinical practice. In contrast, data concerning predictive biomarkers are very limited, even though they are most interesting from the perspective of clinicians.Additional prospective studies, in large and independent samples of patients, with rigorous statistical methodology and standardized laboratory techniques are now warranted to validate and define the precise value of diagnostic and prognostic MPM biomarkers. Future research efforts should focus on biomarkers predictive of the efficacy and toxicity of standard chemotherapy. Translational research should be systematically incorporated into the design of clinical trials assessing new targeted agents in MPM.
Mol Diagn Ther 2008
PMID:Biomarkers for malignant pleural mesothelioma: current status. 1903 24

Mesothelin is a potential new target for cancer immunotherapy because it is present at relatively low levels only in mesothelial cells of pleura, peritoneum, and pericardium of healthy people, but is significantly elevated in a number of tumors, including mesothelioma, ovarian, pancreatic, and lung cancers. However, all currently available antibodies against mesothelin are either murine or chimeric, which could limit their use because of increased likelihood of immunogenicity compared with fully human antibodies. Here, we report the identification and characterization of a novel fully human monoclonal antibody, m912, which was isolated from a human Fab library by panning against recombinant mesothelin. This antibody in scFv, Fab, and IgG1 formats bound specifically and with high affinity (equilibrium dissociation constant in the nmol/L range) to cell surface-associated human mesothelin and to recombinant mesothelin. It specifically lysed cancer cells engineered to express mesothelin in the presence of peripheral blood mononuclear cells isolated from healthy donors most likely by antibody-dependent cellular cytotoxicity. M912 is the first reported fully human monoclonal antibody to mesothelin, which has potential for cancer treatment and diagnosis.
Mol Cancer Ther 2009 May
PMID:A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity. 1941 59

The TP53 tumor suppressor gene is the most frequently inactivated gene in human cancer identified to date. However, TP53 mutations are rare in human mesotheliomas, as well as in many other types of cancer, suggesting that aberrant TP53 function may be due to alterations in its regulatory pathways. Mouse double minute 4 (MDM4) has been shown to be a key regulator of TP53 activity, both independently as well as in concert with its structural homolog, Mouse Double Minute 2 (MDM2). The purpose of this study was to characterize the effects of MDM4 suppression on TP53 and other proteins involved in cell cycle control before and after ultraviolet (UV) exposure in MeT5a cells, a nonmalignant human mesothelial line. Short hairpin RNA (shRNA) was used to investigate the impact of MDM4 on TP53 function and cellular transcription. Suppression of MDM4 was confirmed by Western blot. MDM4 suppressed cells were analyzed for cell cycle changes with and without exposure to UV. Changes in cell growth as well as differences in the regulation of direct transcriptional targets of TP53, CDKN1A (cyclin-dependent kinase 1alpha, p21) and BAX, suggest a shift from cell cycle arrest to apoptosis upon increasing UV exposure. These results demonstrate the importance of MDM4in cell cycle regulation as well as a possible role inthe pathogenesis of mesothelioma-type cancers.
Environ Mol Mutagen 2009 Dec
PMID:Suppression of the mouse double minute 4 gene causes changes in cell cycle control in a human mesothelial cell line responsive to ultraviolet radiation exposure. 1947 17

MicroRNAs (miRNAs) post-transcriptionally regulate the expression of target genes, and may behave as oncogenes or tumor suppressors. Human malignant mesothelioma is an asbestos-related cancer, with poor prognosis and low median survival. Here we report, for the first time, a cross-evaluation of miRNA expression in mesothelioma (MPP-89, REN) and human mesothelial cells (HMC-telomerase reverse transcriptase). Microarray profiling, confirmed by real-time quantitative RT-PCR, revealed a differential expression of miRNAs between mesothelioma and mesothelial cells. In addition, a computational analysis combining miRNA and gene expression profiles allowed the accurate prediction of genes potentially targeted by dysregulated miRNAs. Several predicted genes belong to terms of Gene Ontology (GO) that are associated with the development and progression of mesothelioma. This suggests that miRNAs may be key players in mesothelioma oncogenesis. We further investigated miRNA expression on a panel of 24 mesothelioma specimens, representative of the three histotypes (epithelioid, biphasic, and sarcomatoid), by quantitative RT-PCR. The expression of miR-17-5p, miR-21, miR-29a, miR-30c, miR-30e-5p, miR-106a, and miR-143 was significantly associated with the histopathological subtypes. Notably, the reduced expression of two miRNAs (miR-17-5p and miR-30c) correlated with better survival of patients with sarcomatoid subtype. Our preliminary analysis points at miRNAs as potential diagnostic and prognostic markers of mesothelioma, and suggests novel tools for the therapy of this malignancy.
Am J Respir Cell Mol Biol 2010 Mar
PMID:MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications. 1950 86

Malignant pleural mesothelioma (MPM) is known to mimic the morphology of a number of diverse neoplastic conditions. WT-1 protein is conventionally used as a positive mesothelioma marker. Recently, a new monoclonal antibody clone WT49 has recently become commercially available. To compare specificity and sensitivity of the conventionally used clone 6F-H2 for the diagnosis of MPM to those of the new clone WT49. Forty cases of MPM, and 55 cases of lung carcinoma, 10 cases of synovial sarcoma of the intrathoracic region were analyzed. Of the 40 cases of MPM tested, clone WT49 and 6F-H2 stained 30 (75.0%) and 26 (65.0%) cases, respectively. Nuclear staining of clone WT49 was observed in 4 (7.2%) cases of lung carcinomas and in 1 (10.0%) case of synovial sarcoma. However, there was no nuclear staining of clone 6F-H2 in lesions other than MPM. There was no cytoplasmic staining of clone WT49 in any tumor. However, cytoplasmic staining of clone 6F-H2 was observed in 7 (17.5%) cases of MPM, 17 (30.1%) cases of lung carcinomas, and 5 (50.0%) cases of synovial sarcoma. The main advantage of WT49 is its higher reactivity with the sarcomatoid area of biphasic mesothelioma, but the results also indicate 1 drawback, that this clone was seen to react with a small percentage of lung carcinomas when it is used to distinguish epithelioid mesotheliomas from lung carcinomas. Furthermore, the positive reaction of clone WT49 was restricted to nucleus without cytoplasmic staining, which is seen in conventionally used WT-1 antibodies.
Appl Immunohistochem Mol Morphol 2009 Mar
PMID:Comparison of different clones (WT49 versus 6F-H2) of WT-1 antibodies for immunohistochemical diagnosis of malignant pleural mesothelioma. 1951 97

Malignant pleural mesothelioma (MPM) is a lethal neoplasm for which current therapy is unsatisfactory. The urokinase plasminogen activator receptor (uPAR) is associated with increased virulence of many solid neoplasms, but its role in the pathogenesis of MPM is currently unclear. We found that REN human pleural MPM cells expressed 4- to 10-fold more uPAR than MS-1 or M9K MPM cells or MeT5A human pleural mesothelial cells. In a new orthotopic murine model of MPM, we found that the kinetics of REN cell tumorigenesis is accelerated versus MS-1 or M9K cells, and that REN instillates generated larger tumors expressing increased uPAR, were more invasive, and caused earlier mortality. While REN, MS-1, and M9K tumors were all associated with prominent extravascular fibrin deposition, excised REN tumor homogenates were characterized by markedly increased uPAR at both the mRNA and protein levels. REN cells exhibited increased thymidine incorporation, which was attenuated in uPAR-silenced cells (P < 0.01). REN cells traversed three-dimensional fibrin gels while MS-1, M9K, and MeT5A cells did not. uPAR siRNA or uPAR blocking antibodies decreased REN cell migration and invasion, while uPA and fetal bovine serum augmented the effects. Transfection of relatively low uPAR expressing MS-1 cells with uPAR cDNA increased proliferation and migration in vitro and tumor formation in vivo. These observations link overexpression of uPAR to the pathogenesis of MPM, demonstrate that this receptor contributes to accelerated tumor growth in part through interactions with uPA, and suggest that uPAR may be a promising target for therapeutic intervention.
Am J Respir Cell Mol Biol 2010 Jun
PMID:The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells. 1963 32

Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC(50) and LD(50) values were in the low nmol/L range (4-470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD(50) values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X(L). These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC.
Mol Cancer Ther 2009 Aug
PMID:The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. 1967 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>