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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differentiating reactive mesothelial cells from malignant mesotheliomas and from adenocarcinomas can be diagnostically challenging when based solely on the morphologic examination of serous fluids. The diagnosis even after the use of standard immunohistochemical stains may at times be inconclusive because of the variable reactivity of mesothelial cells for these markers. Pathologists and cytologists underutilize reactivity for desmin, a feature of mesothelial cells apparently not shared by adenocarcinomas. The purpose of this study was to evaluate the extent to which mesothelial cells express muscle differentiation and to assess the diagnostic utility of muscle markers in distinguishing reactive mesothelial cells from malignant mesotheliomas and adenocarcinomas. Archival paraffin-embedded cell blocks of serous fluids from 24 cases of reactive mesothelial cells, 14 cases of malignant mesothelioma, and 56 cases (14 cases from each) of metastatic adenocarcinoma from the lung, breast, ovary, and gastrointestinal tract were retrieved. Five cases of omentum with unremarkable mesothelial cells were also included in the study. All cases were stained for desmin, actin, myoglobin, and myogenin and evaluated independently by two observers. Strong cytoplasmic reactivity for desmin was noted in 22 of 24 cases (92%) of reactive mesothelial cells. The reactive mesothelial cells did not express actin, myoglobin, or myogenin. All cases of malignant mesothelioma and metastatic adenocarcinoma were negative for the four muscle markers. The mesothelial lining and scattered subserosal cells in the omental sections were positive for desmin. Because desmin was expressed only in benign mesothelial cells, it may serve as a reliable marker in distinguishing reactive mesothelial cells from mesothelioma or from adenocarcinoma. Awareness of this staining pattern is also important to avoid pitfalls when evaluating body fluid specimens from patients with a history of tumors expressing muscle differentiation.
Appl Immunohistochem Mol Morphol 2002 Jun
PMID:Diagnostic use of muscle markers in the cytologic evaluation of serous fluids. 1205 38

Thyroid transcription factor-1 (TTF-1) is a 38-kd homeodomain containing DNA-binding protein originally identified in follicular cells of the thyroid and subsequently in pneumocytes. This review focuses on the utility of antisera in TTF-1 immunohistochemical staining in the diagnosis of neoplastic conditions. Based on published studies to date, anti-TTF-1 is a very useful reagent in distinguishing pulmonary adenocarcinoma from other primary carcinomas, identifying differentiated thyroid neoplasms, distinguishing mesothelioma from pulmonary adenocarcinoma, and distinguishing small cell carcinoma of the lung from Merkel cell carcinoma. It may also be useful in distinguishing neuroendocrine (NE) tumors of the lung from well-differentiated NE tumors from other sites, such as the intestine.
Appl Immunohistochem Mol Morphol 2002 Jun
PMID:Thyroid transcription factor-1: a review. 1205 43

One promising therapeutic approach to intracavitary tumors, such as malignant mesothelioma and ovarian cancer, is immuno-gene therapy. In a previous study, intraperitoneal (i.p.) instillation of an adenoviral vector encoding the mouse interferon-beta gene (Ad.muIFN-beta) was shown to eradicate established mesothelioma tumors in the peritoneal cavity of immune competent, but not immunodeficient mice. The goal of this study was to understand more completely the kinetics and mechanisms of this immune-mediated response. Two days after a single intraperitoneal (i.p.) injection of Ad.muIFN-beta into BALB/c mice with established tumors, the response in the peritoneum was characterized by an influx of activated natural killer (NK) cells, polymorphonuclear (PMN) cells, and macrophages with minimal infiltration into the tumor nodules. However, depletion of PMN or NK cells after Ad.IFN-beta treatment had only minimal effects. At later time points (up to 10 days after Ad.IFN-beta i.p.), a large influx of CD4(+) and activated CD8(+) T cells was present in the peritoneal fluid and within the tumor nodules. The CD8(+) T cells had cytolytic activity, and adoptive transfer of peritoneal exudate cells (obtained by peritoneal lavage) resulted in effective tumor cell killing. Antitumor effects of Ad.IFN-beta may be different in different tumor types or in different anatomic locations. However, these results demonstrate that tumor-specific CD4(+) and CD8(+) T cells are the key effector cells for tumor eradication in this model.
Mol Ther 2002 Aug
PMID:Analysis of the immunologic response generated by Ad.IFN-beta during successful intraperitoneal tumor gene therapy. 1216 Nov 87

Several tumors, including mesothelioma and ovarian cancer, can overexpress mesothelin, a glycosylphosphatidylinositol-linked differentiation glycoprotein. The membrane-bound type of mesothelin is found in the blood of cancer patients at a very low level, which makes mesothelin a good candidate for targeted therapy of certain cancers. An antimesothelin disulfide-linked Fv (SS1 Fv) was fused to a truncated mutant of Pseudomonas exotoxin A to produce the recombinant immunotoxin SS1(dsFv)-PE38, which has a high binding affinity to mesothelin (Kd = 0.7 nM). Our studies in vitro showed that SS1(dsFv)-PE38 is significantly more cytotoxic to the high-mesothelin-producing NCI-H226 human non-small cell lung cancer cells than to human lung adenocarcinoma PC14PE6 cells, which do not express mesothelin. When administered at a nontoxic dose of 500 microg/kg on days 7, 9, and 11 to nude mice injected i.v. with the two human lung cancer cell lines, SS1(dsFv)-PE38 selectively inhibited experimental lung metastases produced by the mesothelin-producing NCI-H226 cells. Our data indicate that mesothelin-producing squamous cell carcinoma of the lung may be a good target for this immunotoxin.
Mol Cancer Ther 2002 Jun
PMID:Targeted therapy against human lung cancer in nude mice by high-affinity recombinant antimesothelin single-chain Fv immunotoxin. 1247 19

Malignant pleural mesothelioma is a rare and aggressive tumor characterized by rapid progression, late metastases, and poor prognosis. In this study, we investigated the expression of survivin, a member of the inhibitors of apoptosis protein gene family, in mesothelioma and an antisense oligonucleotide-based gene therapy for mesothelioma using survivin as a target. Initially, we documented the expression of survivin in human mesothelioma cell lines and fresh tissues using reverse transcription-PCR and Western blot analysis. Our results showed that survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed. To investigate the use of survivin as a therapeutic target on mesothelioma, we carried out transfections with antisurvivin oligonucleotides to induce apoptosis in mesothelioma cell lines MS-1 and H28. Results from cellular transfection and subsequent analysis using the flow cytometry demonstrated that antisurvivin oligonucleotides induced significantly greater apoptosis rates in the survivin-positive mesothelioma cell line H28 (42.5%) as compared with the control oligonucleotides (16.2%; P < 0.001). The survivin-negative cell line LRK1A (survivin-/-) did not apoptose with antisense oligonucleotides. Furthermore, time course evaluation by Western blot analysis showed that survivin was inhibited by antisurvivin oligonucleotides within 12 h after transfection. Our results show, for the first time, that survivin, an inhibitors of apoptosis protein family gene member, is highly overexpressed in malignant pleural mesothelioma. Down-regulation of survivin by a targeted antisense oligonucleotide appears to be an effective gene therapy approach to the treatment of mesothelioma.
Mol Cancer Ther 2002 Jul
PMID:Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides. 1247 65

The epidemiologic association between asbestos exposure and human malignant mesothelioma is well established. However, the molecular mechanisms linking asbestos exposure of humans and the subsequent mesothelioma formation is not well understood. The most frequent genetic changes found so far in human malignant mesothelioma (HMM) are deletions and point mutations in the tumor suppressor genes p16INK4a and NF2. Whereas homozygous deletions appear to be the predominant mechanism leading to p16/CDKN2A inactivation, inactivating point mutations coupled with allelic loss mainly occur at the NF2 locus. In the present study, asbestos-treated human mesothelial cells (HMC), SV40-transformed human mesothelial cells (MeT-5A) and a human mesothelioma cell line (COLO) were investigated for genetic changes of cell cycle genes (cyclin D1, p16INK4a, RB1, CDK2) using multicolor fluorescence in situ hybridization (mFISH) in interphase cells. The results show that cyclin D1 is unaffected in all investigated cells. The p16INK4a gene locus was shown to be mutated in COLO cells but not in HMC. After labeling of CDK2 and RB1, hemizygous loss of one allele of each gene was observed in asbestos-treated HMC whereas gene amplification of these genes was detectable in MeT-5A and COLO cells. Our data indicate that disarrangement of the RB1 dependent pathway seems to be involved in mesothelioma formation.
Cell Mol Biol (Noisy-le-grand) 2002
PMID:Interphase fish analysis of cell cycle genes in asbestos-treated human mesothelial cells (HMC), SV40-transformed HMC (MeT-5A) and mesothelioma cells (COLO). 1264 44

Gene delivery of CD40 Ligand (CD40L) has shown promise in murine models of melanoma and adenocarcinoma; however, its potential for thoracic malignancies such as malignant mesothelioma remains unclear. In this study, we investigated the hypothesis that CD40L gene therapy would be effective in local and distant tumor suppression in mesothelioma using an immunocompetent murine model. Using a recombinant adenovirus encoding murine CD40L (AdCD40L), we demonstrated no suppression of in vitro cell growth for the AC29 (mesothelioma) cell line. However, inoculation of immunocompetent CBA/J mice with AC29 cells treated ex vivo with AdCD40L resulted in significant suppression of tumor formation in vivo when compared with controls (P < 0.001). Intratumoral inoculation of AdCD40L into previously established AC29 tumors yielded similar antitumor results and was associated with increased recruitment of intratumoral CD8+ T cells. Adoptive transfer of CD8+ T cells from AdCD40L-treated tumor bearing mice conferred protection to naive mice given an AC29 tumor challenge. Finally, in mice with two synchronous tumors, treatment of one of the tumors with AdCD40L resulted in a regression of both tumors. These findings demonstrate the development of tumor specific CD8+ T cells by AdCD40L and support the further development of AdCD40L for the treatment of malignant mesothelioma.
Am J Respir Cell Mol Biol 2003 Sep
PMID:Efficacy of CD40 ligand gene therapy in malignant mesothelioma. 1267 4

Exosomes are membrane vesicles from endosomal origin secreted by various cells such as hematopoietic, epithelial, and tumor cells. Exosomes secreted by tumor cells contain specific antigens potentially useful for immunotherapeutic purposes. Our aim was to determine if exosomes are present in human cancerous pleural effusions and to identify their proteomic content. Exosomes were purified by sucrose gradient ultracentrifugation, and electron microscopy was used to check both concentration and purity of exosomes. Proteins were separated by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and protein bands were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and Western blotting. Exosomes were present in pleural fluid obtained from patients suffering from mesothelioma (n = 4), lung cancer (n = 2), breast cancer (n = 2), and ovarian cancer (n = 1). As previously reported by others, antigen-presenting molecules, cytoskeletal proteins, and signal transduction-involved proteins were present. Proteins not previously reported were identified (SNX25, BTG1, PEDF, thrombospondin 2). Different types of immunoglobulins and complement factors were abundantly present in the sucrose fractions containing exosomes. Exosome-directed specificity of these immunoglobulins was not observed. In conclusion, sucrose gradient ultracentrifugation allows isolation of exosomes from malignant pleural effusions. However, pleural fluid proteins and especially immunoglobulins are coisolated and may hamper the use of exosomes isolated from malignant effusion for immunotherapy programs.
Am J Respir Cell Mol Biol 2004 Jul
PMID:Proteomic analysis of exosomes isolated from human malignant pleural effusions. 1497 38

Mesothelioma represents an aggressive tumor type with high resistance to all treatment modalities. Its pathogenesis is strongly associated with exposure to asbestos fibers and probably with free radicals. One of the most important free radical scavenging enzymes, mitochondrial manganese superoxide dismutase (MnSOD), has been shown to be elevated in mesothelioma (K. Kahlos et al., 1998, Am. J. Respir. Cell Mol. Biol. 18:570-580). In the present study, we could detect intense ultrastructural accumulation of MnSOD in the mitochondrial compartment of malignant mesothelioma cells. There was no association between the immunohistochemical reactivity and the most common and functional polymorphic variant of MnSOD, the Ala to Val amino acid change at 9 position (16th amino acid from the beginning of the signal sequence), in the 31 mesothelioma cases investigated. Comparative genomic hybridization and fluorescence in situ hybridization did not reveal any changes in chromosome 6, where the MnSOD gene is located. Sequencing of the MnSOD promoter region in four mesothelioma cell lines showed similar nucleotide variables in the malignant and nonmalignant cells. Therefore, the intense expression of MnSOD in the mitochondria of mesothelioma cells does not appear be associated with any major chromosomal alterations or the polymorphism of MnSOD gene. Association with oxidative/nitrosative stress in mesothelioma using nitrotyrosine immunostaining pointed to a tendency for more intense reactivity in those mesotheliomas with higher MnSOD expression (P = 0.069).
Am J Respir Cell Mol Biol 2004 Aug
PMID:Ultrastructural and chromosomal studies on manganese superoxide dismutase in malignant mesothelioma. 1503 38

The small leucine-rich proteoglycan biglycan (BGN) is abundantly expressed in mesenchymal tissues. Its expression level is related to the phenotypic differentiation of cells. A dysregulation in BGN expression occurs under several pathological conditions, including glomerulonephritis, mesothelioma, pancreatic cancer and a mouse model of osteoporosis. Since the extracellular concentration of BGN is regulated both by secretion and endocytosis, we performed mechanistic studies on BGN endocytosis in human skin fibroblasts in vitro, using inhibitors of different endocytic routes. Chlorpromazine, an inhibitor of the clathrin-coated pit-pathway reduced endocytosis of BGN in human skin fibroblasts by 40%, and decreased degradation of BGN by 66% Filipin, an inhibitor of the caveolae pathway, and Tyrphostin AG 1478, a specific inhibitor of EGF-receptor phosphorylation that partially inhibits endocytosis of the structurally related proteoglycan decorin, had no influence on BGN internalization and degradation. Our data indicates that the classical clathrin-mediated endocytic pathway is a major route for the internalization of BGN. Based on the differential susceptibility to pharmacological inhibition, it appears that BGN endocytosis seems to be at least in part mechanistically different from decorin uptake.
Cell Mol Biol Lett 2004
PMID:Biglycan is internalized via a chlorpromazine-sensitive route. 1533 24


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