Immunoreactivity for cadherins, HGF/SF, met, and erbB‐2 in pleural malignant mesotheliomas

Thirkettle, I; Harvey, P; Hasleton, Philip; Ball, R. Y.; Warn, R. M.

doi:10.1046/j.1365-2559.2000.00888.x

Cited by 65 publications

(42 citation statements)

References 20 publications

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“…HGF and its receptor Met, a proto-oncogene known to modulate cell growth and morphogenesis, are activated in many human MM cell lines (13,37) and are present in many MMs (38)(39)(40). Our data show that HGF stimulates MM cell proliferation through a PI3K/ERK5/Fra-1 pathway in some MM lines.…”

Section: Discussionmentioning

confidence: 62%

HGF Mediates Cell Proliferation of Human Mesothelioma Cells through a PI3K/MEK5/Fra-1 Pathway

Ramos-Niño

Blumen²,

Sabo‐Attwood³

et al. 2008

Am J Respir Cell Mol Biol

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The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their increased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (Fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in HGF-induced proliferation in human MMs. In three of seven human MM lines evaluated, HGF increased Fra-1 levels and phosphorylation of both extracellular signal-regulated kinase 5 (ERK5) and AKT that were inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY290042. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1, whereas overexpression of Fra-1 blocked the expression of mitogen/extracellular signal-regulated kinase kinases (MEK)5 at the mRNA and protein levels. Stable MM cell lines using a dnMEK5 showed that basal Fra-1 levels were increased in comparison to empty vector control lines. HGF also caused increased MM cell viability and proliferating cell nuclear antigen (PCNA) expression that were abolished by knockdown of MEK5 or Fra-1. Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors.Keywords: hepatocyte growth factor/scatter factor; fos-related antigen 1; phosphatidylinositol 3-kinase; MEK5; mesothelioma Malignant mesothelioma (MM) is an insidious tumor associated historically with occupational exposure to asbestos (2, 3). The average survival of patients with MM is less than 1 year after initial diagnosis, and no successful treatment options exist. Although the mechanisms of development of MM are obscure, the initiation of signaling events after interaction with asbestos fibers may govern transactivation of genes governing cell proliferation and transformation (4). Cell survival, proliferation, and progression of MMs are complex and may be related to overexpression of several autocrine growth factors, including insulin-like growth factor (5, 6), platelet-derived growth factor (7), fibroblast growth factor (8), transforming growth factor b (8), and hepatocyte growth factor/scatter factor (HGF) (9).Increased expression of Fos/Jun family members and activator protein-1 (AP-1) transactivation are observed in mesothelial cells after exposure to asbestos and erionite fibers in contrast to other nonpathogenic fibers and particles (10-12). In comparison to other fos/jun mRNAs, fos-related antigen 1 (fra-1) expression is more protracted and critical to expession of c-met and cd44 in a rat model of mesothelial cell transformation (1).Although HGF and its receptor, c-Met, are known to be involved in chemotaxis, growth, and invasion of a number of tumor types including MMs (13-15), the mechanisms of HGF/ Met signaling and their functional ramifications in MMs remain unclear. We previously reported that HGF stimula...

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Section: Discussionmentioning

confidence: 62%

HGF Mediates Cell Proliferation of Human Mesothelioma Cells through a PI3K/MEK5/Fra-1 Pathway

Ramos-Niño

Blumen²,

Sabo‐Attwood³

et al. 2008

Am J Respir Cell Mol Biol

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“…Several studies investigated the potential involvement of other growth factors, like platelet-derived growth factor A and B (13), insulin-like growth factor-1 (14), transforming growth factor ␤, fibroblast growth factor-2 (15), and hepatocyte growth factor (HGF) (16)(17)(18)(19) in the onset of MM. High levels of HGF, in particular, were detected in pleural effusion from patients with MM (20).…”

Section: Alignant Mesothelioma (Mm) Is An Aggressive and Invasivementioning

confidence: 99%

SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma

Cacciotti

Libener

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

134

137

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“…[6][7][8][9][10] It is known that MM expresses a variety of RTKs, such as epidermal growth factor receptor (EGFR), c-Met, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor. [11][12][13] However, to our knowledge, the possible presence and function of EphA2 and the expression of its ligands in MM are not known. The over-expression of receptor EphA2 has been implicated in tumor growth, angiogenesis, and metastasis.…”

mentioning

confidence: 99%

Silencing the receptor EphA2 suppresses the growth and haptotaxis of malignant mesothelioma cells

Nasreen

Mohammed

Antony

2006

Cancer

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BACKGROUND.The over‐expression of the ephrin‐A1 ligand receptor EphA2 is associated with the growth and metastatic potential of tumors. Although EphA2 is expressed in a variety of tumors, its expression and function in malignant mesothelioma (MM) remain unknown. The authors hypothesized that expression of the receptor EphA2 in MM cells (MMCs) plays a key role in the growth and haptotactic migration of MM. They also hypothesized that silencing EphA2 expression by using small‐interfering RNA (siRNA) inhibits the proliferation and haptotaxis of MMCs and induces apoptosis in MMCs.METHODS.The expression of EphA2 in MMCs and in normal pleural mesothelial cells (PMCs) was studied by using real‐time quantitative polymerase chain reaction analysis and Western blot analysis. The growth of MMCs was determined with the WST‐1 cell‐proliferation assay. The haptotactic migration of MMCs and PMCs was determined with a Boyden chamber assay. Expression of caspases was determined with calorimetric assays.RESULTS.The results demonstrated that silencing the receptor EphA2 by siRNA significantly reduced the proliferation and haptotactic migration of MMCs compared with controls. Over‐expression of EphA2 with plasmid pcDNA/EphA2 enhanced the proliferation and haptotaxis of MMCs significantly. Knocking down EphA2 expression initiated caspase‐9–mediated apoptosis in MMCs.CONCLUSIONS.The current results suggested that constitutive expression of EphA2 may contribute to the aggressive behavior and cellular survival of MMCs. EphA2 may be an effective therapeutic target in patients with mesothelioma. Silencing the receptor EphA2 gene is a novel approach for the containment of growth and migration of tumor in patients with malignant mesothelioma. Cancer 2006. © 2006 American Cancer Society.

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Immunoreactivity for cadherins, HGF/SF, met, and erbB‐2 in pleural malignant mesotheliomas

Cited by 65 publications

References 20 publications

HGF Mediates Cell Proliferation of Human Mesothelioma Cells through a PI3K/MEK5/Fra-1 Pathway

HGF Mediates Cell Proliferation of Human Mesothelioma Cells through a PI3K/MEK5/Fra-1 Pathway

SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma

Silencing the receptor EphA2 suppresses the growth and haptotaxis of malignant mesothelioma cells

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