Kimura K, Toyooka S, Tsukuda K, Yamamoto H, Suehisa H, Soh J, Otani H, Kubo T, Aoe K, Fujimoto N, Kishimoto T, Sano Y, Pass HI, Date H.

Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata-cho, Okayama, Japan.

Abstract

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-ß superfamily. Recent studies have showed that aberrant methylation of BMP genes is present in several types of human cancer. We examined the expression and methylation status of BMP3b and BMP6 in malignant pleural mesotheliomas (MPMs). The expression status of BMP3b, and BMP6 mRNAs were examined in seven MPM cell lines by RT-PCR assay. The expression of BMP3b was completely suppressed in 2 and partially suppressed in 2 of 7 cell lines and expression of BMP6 was partially suppressed in 2 cell lines. Methylation status of BMP3b in cell lines was determined by methylation-specific assay to find aberrant methylation in 6 cell lines which include 4 cell lines with suppressed BMP3b expression. Partial methylation of BMP6 was found in 2 cell lines whose expression was partially suppressed. Treatment with 5-Aza-dC restored BMP3b expression in methylated cell lines. Next, we examined the methylation status in 57 surgically resected MPM cases and found aberrant methylation of BMP3b in 9 (53%) out of 17 cases from Japan and 3 (8%) of 40 cases from USA and that of BMP6 in 4 (24%) cases from Japan and 12 (30%) cases from USA, showing significant difference in frequency of BMP3b methylation between MPMs of the two countries (P=0.0004). Our study indicated that BMP3b and BMP6 genes were suppressed by DNA methylation and methylation of BMP3b is significantly frequent in Japanese MPMs, suggesting its pathogenic role and the ethnic difference in MPMs.

Glossary

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

DNA

(dee-ok-see-ri-bo-new-CLAY-ic) abbreviation for deoxyribonucleic acid. DNA holds genetic information on cell growth, division, and function.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M.

Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296-359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

Glossary

mutation

a change; a change in a gene.

flow cytometry

(flow cy-tom-uh-tree) a test of tumor tissue to see how fast the tumor cells are reproducing and whether the tumor cells contain a normal or abnormal amount of DNA. This test is used to help predict how aggressive a cancer is likely to be. (See also ploidy, DNA, S-phase fraction.)

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

antibody

a protein in the blood that defends against foreign agents, such as bacteria. These agents contain certain substances called antigens. Each antibody works against a specific antigen. (See also antigen.)

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

Graziani I, Eliasz S, De Marco MA, Chen Y, Pass HI, De May RM, Strack PR, Miele L, Bocchetta M.

Department of Pathology and Oncology Institute, Loyola University Chicago, Cancer Center, Maywood, Illinois 60153, USA.

Abstract

Malignant mesothelioma (MM) is a cancer of the lining of the lungs, heart, and intestine and is known to respond poorly to chemotherapy. Here we show that malignant mesothelial cells have an elevated Notch signaling pathway compared with normal human mesothelial cells. We studied the role of Notch in MM under normoxic and hypoxic conditions, the latter condition best recapitulating the MM microenvironment. Genetic and chemical modulation of the Notch pathway indicated that MM cells are dependent on Notch signaling. More specifically, this signaling was Notch-1 dependent as the result of its negative transcriptional regulation on phosphatase and tensin homologue (PTEN), which led to activation of the prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our study also provides evidence that whereas Notch-1 is elevated in the malignant setting, Notch-2 is diminished. This differential expression of the two Notch isoforms benefits cancer cell survival because reexpression of Notch-2 was toxic to MM cells. The mechanism of Notch-2 toxicity to MM cells countered that of Notch-1, as it was the result of positive transcriptional regulation of PTEN and inhibition of the PI3K/Akt/mTOR signaling pathway. These results provide new insight into the role of Notch in MM and suggest that Notch pathway inhibitors may be useful in the treatment of this deadly disease.

Keywords: Notch signaling, Akt, apoptosis, hypoxia, mesothelioma, γ-secretase inhibitors

Glossary

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Ivanov SV, Miller J, Lucito R, Tang C, Ivanova AV, Pei J, Carbone M, Cruz C, Beck A, Webb C, Nonaka D, Testa JR, Pass HI.

Department of Cardiothoracic Surgery, Thoracic Surgery Laboratory, NYU Langone Medical Center, New York, NY, USA. Sergey.Ivanov@med.nyu.edu

Abstract

Pleural malignant mesothelioma (MM) is an aggressive cancer with a very long latency and a very short median survival. Little is known about the genetic events that trigger MM and their relation to poor outcome. The goal of our study was to characterize major genomic gains and losses associated with MM origin and progression and assess their clinical significance. We performed Representative Oligonucleotide Microarray Analysis (ROMA) on DNA isolated from tumors of 22 patients who recurred at variable interval with the disease after surgery. The total number of copy number alterations (CNA) and frequent imbalances for patients with short time (<12 months from surgery) and long time to recurrence were recorded and mapped using the Analysis of Copy Errors algorithm. We report a profound increase in CNA in the short-time recurrence group with most chromosomes affected, which can be explained by chromosomal instability associated with MM. Deletions in chromosomes 22q12.2, 19q13.32 and
17p13.1 appeared to be the most frequent events (55-74%) shared between MM patients followed by deletions in 1p, 9p, 9q, 4p, 3p and gains in 5p, 18q, 8q and 17q (23-55%). Deletions in 9p21.3 encompassing CDKN2A/ARF and CDKN2B were characterized as specific for the short-term recurrence group. Analysis of the minimal common areas of frequent gains and losses identified candidate genes that may be involved in different stages of MM: OSM (22q12.2), FUS1 and PL6 (3p21.3), DNAJA1 (9p21.1) and CDH2 (18q11.2-q12.3). Imbalances seen by ROMA were confirmed by Affymetrix genome analysis in a subset of samples. © 2008 Wiley-Liss, Inc.

Keywords: mesothelioma, ROMA, CGH, copy number alterations, tumor suppressors, oncogenes

Glossary

recurrence

cancer that has come back after treatment. Local recurrence is when the cancer comes back at the same place as the original cancer. Regional recurrence is when the cancer appears in the lymph nodes near the first site. Distant recurrence is when it appears in organs or tissues (such as the lungs, liver, bone marrow, or brain) farther from the original site than the regional lymph nodes. Metastasis means that the disease has recurred at a distant site.

DNA

(dee-ok-see-ri-bo-new-CLAY-ic) abbreviation for deoxyribonucleic acid. DNA holds genetic information on cell growth, division, and function.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Zhao H, Ardelt B, Ardelt W, Shogen K, Darzynkiewicz Z.

Department of Pathology, Brander Cancer Research Institute, New York Medical College, Valhalla, New York 10595, USA.

Abstract

Onconase (Onc), a ribonuclease from oocytes of Northern Leopard frogs (Rana pipiens) is cytostatic and cytotoxic to a variety of tumor lines in vitro, inhibits growth of tumors in animal in vivo models and enhances sensitivity of tumor cells to a number of other cytotoxic agents with diverse mechanism of action. In Phase III clinical trials Onc demonstrated significant efficacy in patients with malignant mesothelioma that failed prior chemotherapy. We previously postulated that the antitumor activity of Onc and the observed synergisms with other antitumor modalities at least in part may be mediated by targeting RNA interference (RNAi). In the present study we observed that the silencing of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene in human lung adenocarcinoma A549 cells by siRNA was effectively prevented by Onc. While transfection of cells with GAPDH siRNA reduced expression of this protein by nearly 70%, the expression was restored in the cells exposed to 0.8 muM Onc for 48 or 72 h. The data thus provide evidence that one of the targets of Onc is siRNA, likely within the RNA-induced silencing complex (RISC). In light of the findings that microRNAs are involved in tumor pathogenesis as well as in enhancing cell resistance to anticancer therapy the present data may provide explanation for both, the antitumor Onc activity and its propensity to enhance effectiveness of cytotoxic drugs.

Keywords: microRNAs, ranpirnase, gene regulation, RISC, glyceraldehyde 3-phosphate dehydrogenase, laser scanning cytometry, mesothelioma

Glossary

adenocarcinoma

(add-en-o car-sin-o-muh). Cancer that starts in the glandular tissue, such as in the ducts or lobules of the breast.

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

gene

a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.

cytotoxic

(site-o-tox-ik) toxic to cells; cell-killing.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Kashiwakura Y, Ochiai K, Watanabe M, Abarzua F, Sakaguchi M, Takaoka M, Tanimoto R, Nasu Y, Huh NH, Kumon H.

Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. yu-kashi@cj9.so-net.ne.jp

Abstract

REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH₂ kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional down-regulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed down-regulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM.

Keywords: REIC/Dkk-3, malignant mesothelioma, gene therapy

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

prostate

(pros-tate)  a gland found only in men. It is just below the bladder and in front of the rectum. The prostate makes a fluid that is part of semen. The tube that carries urine, the urethra, runs through the prostate.

gene therapy

a new type of treatment in which defective genes are replaced with normal ones. The new genes are delivered into the cells by viruses or proteins. (Mesothelioma gene therapy treatment options.)

gene

a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.

differentiation

(dif-er-en-she-A-shun) the normal process through which cells mature so they can carry out the jobs they were meant to do. Cancer cells are poorly differentiated.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

tissue

a collection of cells, united to perform a particular function.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Okamoto J, Mikami I, Tominaga Y, Kuchenbecker KM, Lin YC, Bravo DT, Clement G, Yagui-Beltran A, Ray MR, Koizumi K, He B, Jablons DM.

Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.

Abstract

Introduction: Heat shock protein 90 (Hsp90) is an abundant molecular chaperone that mediates the maturation and stability of a variety of proteins associated with the promotion of cell growth and survival. Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins. Recently, Hsp90 has emerged as being of prime importance to the growth and survival of cancer cells and its inhibitors have already been used in phase I and II clinical trials.

Methods: We investigated how 17-allylamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is implicated in human malignant pleural mesothelioma (MM).

Results: We found that 17-AAG led to significant G1 or G2/M cell cycle arrest, inhibition of cell proliferation, and decrease of AKT, AKT1, and survivin expression in all human malignant pleural mesothelioma cell lines examined. We also observed significant apoptosis induction in all MM cell lines treated with 17-AAG. Furthermore, 17-AAG induced apoptosis in freshly cultured primary MM cells and caused signaling changes identical to those in 17-AAG treated MM cell lines.

Conclusion: These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.

Glossary

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Fukazawa T, Matsuoka J, Naomoto Y, Maeda Y, Durbin ML, Tanaka N.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. FukazawaT@aol.com

Abstract

Gene therapy and virotherapy are one of the approaches used to treat malignant pleural mesothelioma. To improve the efficiency of targeting malignant mesothelioma cells, we designed a novel system using the promoter of the CREBBP/EP300 inhibitory protein 1 (CRI1), a gene specifically expressed in malignant pleural mesothelioma. Four tandem repeats of the CRI1 promoter (CRI1(-138 4x)) caused significantly high promoter activity in malignant pleural mesothelioma cells but little promoter activity in normal mesothelial cells and normal fibroblasts. The recombinant adenoviral vector expressing proapoptotic BH3-interacting death agonist or early region 1A driven by the CRI1(-138 4x) promoter induced cell death in malignant mesothelioma cells but not in normal cells. Moreover, these viruses showed antitumor effects in a mesothelioma xenograft mouse model. Here, we describe a novel strategy to target malignant mesothelioma using the CRI1(-138 4x) promoter system.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

gene therapy

a new type of treatment in which defective genes are replaced with normal ones. The new genes are delivered into the cells by viruses or proteins. (Mesothelioma gene therapy treatment options.)

gene

a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Ramalingam SS, Belani CP.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA.

Abstract

Malignant pleural mesothelioma clinically manifests after decades of initial exposure to etiologic agents, such as asbestos, and presents with nonspecific symptoms such as dyspnea, pain, or weight loss. In patients with limited, resectable disease, surgical therapy with extrapleural pneumonectomy or pleurectomy is recommended, although, it is unclear which approach is superior. Radiation has a limited role and is used primarily for palliation. The palliative efficacy of traditional chemotherapeutic agents and combination regimens is modest at best. The combination of cisplatin and pemetrexed, a novel multitargeted antifolate agent, is the approved "standard of care" for patients with unresectable malignant pleural mesothelioma. A number of molecularly targeted agents are currently under evaluation for mesothelioma such as the Histone deacetylase (HDAC) inhibitors that have demonstrated promising anticancer activity. Vorinostat, a small molecule inhibitor of HDAC, which targets select members of class I and II HDACs, has shown early evidence of activity and is currently being evaluated in a randomized study for patients who progress with standard therapy for advanced mesothelioma. It is hoped that the HDAC inhibitors and other novel targeted agents will pave the way for improved outcomes for patients with this disease.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

extrapleural pneumonectomy

(EPP) surgery to remove the pleura, diaphragm, pericardium, and entire lung involved with the tumor. You can view a web cast from Brigham and Women's Hospital in Boston of this procedure being done by Dr. David Sugarbaker: see the extrapleural pneumonectomy (EPP) web cast here.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y, Hida T, Sekido Y.

Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.

Abstract

We previously reported the results of bacterial artificial chromosome array comprehensive genomic hybridization of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional coactivator was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene, which is frequently mutated in MPMs. YAP1-RNA interference suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, whereas YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at serine 127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S 127A mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth and that the transcriptional coactivator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies.

Abbreviations: BAC, bacterial artificial chromosome; CGH, comprehensive genomic hybridization; EGFP, enhanced green fluorescent protein; GST, glutathione S-transferase; MPM, malignant pleural mesothelioma; NF2, neurofibromatosis type 2; NHERF1, Na(+)/H(+) exchanger regulatory factor 1; PCR, polymerase chain reaction; RNAi, RNA interference; SDS, sodium dodecyl sulfate; sh, short hairpin

Glossary

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

oncogene

(on-ko-gene) a type of gene. Normally inactive, when these genes are "turned on" (activated), they cause normal cells to change into cancer cells.

gene

a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.