Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells

Kawaguchi, Koji; Murakami, Hideki; Taniguchi, Tetsuo; Fujii, Makiko; Kawata, Shigehisa; Fukui, Takayuki; Kondo, Yutaka; Osada, Hiroyuki; Usami, Noriyasu; Yokoi, Kohei; Ueda, Yuichi; Yatabe, Yasushi; Ito, Masafumi; Horio, Yoshitsugu; Hida, Toyoaki; Sekido, Yoshitaka

doi:10.1093/carcin/bgp097

Cited by 76 publications

(84 citation statements)

References 31 publications

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“…29,30 Activation of ERBB2 is reported in human mesothelioma cell lines. 31 Our present study demonstrated that oxidative stress is a cause of ERBB2 amplification. Inactivation of CDKN2A/2B is the second most common genetic event in human cancers next to p53 tumor suppressor gene alterations.…”

Section: Discussionsupporting

confidence: 53%

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Akatsuka

Yamashita

et al. 2010

Laboratory Investigation

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In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2 0 -deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

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Section: Discussionsupporting

confidence: 53%

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Akatsuka

Yamashita

et al. 2010

Laboratory Investigation

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“…ACC-MESO-1, ACC-MESO-4, Y-MESO-8A, Y-MESO-9, Y-MESO-12, and Y-MESO-14 were established in Aichi Cancer Research Center Institute (35). EHMES-1 was provided by Dr. Hironobu Hamada (Ehime University, Matsuyama, Japan) (36).…”

Section: Cell Linesmentioning

confidence: 99%

A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

Abe

Morita

Kaneko

et al. 2013

The Journal of Immunology

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Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a+) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.

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“…NF2 expression vectors were described previously (28). RNA interference vectors to generate lentiviruses that transcribe short hairpin (sh)-RNA were prepared as described previously (32). sh-LATS2-RNA interference vector (sh-LATS2) contained a target sequence of the hairpin loop of LATS2 (5 0 -GGACCTCACTGCATTAAA-3 0 ).…”

Section: Plasmid and Lentiviral Vectormentioning

confidence: 99%

“…sh-LATS2-RNA interference vector (sh-LATS2) contained a target sequence of the hairpin loop of LATS2 (5 0 -GGACCTCACTGCATTAAA-3 0 ). A control shRNA vector for luciferase (Sh-Luc), which contained a target sequence for luciferase (5 0 -CGTACGCGGAA-TACTTCGA-3 0 ), was described previously (32).…”

Section: Plasmid and Lentiviral Vectormentioning

confidence: 99%

LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

et al. 2011

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Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation.

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Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells

Cited by 76 publications

References 31 publications

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

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