Epithelial–mesenchymal transition in malignant mesothelioma

Fassina, Ambrogio; Cappellesso, Rocco; Guzzardo, Vincenza; Via, Lisa Dalla; Piccolo, Stefano; Ventura, Laura; Fassan, Matteo

doi:10.1038/modpathol.2011.144

Cited by 133 publications

(133 citation statements)

References 42 publications

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“…Regarding the molecular profile of the epithelioid MPM in the C2 subgroup, it may be suggested that these cells have undergone mesenchymal differentiation and acquired mesenchymal features, while still retaining some epithelial characteristics. Previous studies showed that epithelioid MPM had a higher level of expression of E-cadherin than the biphasic and sarcomatoid subtypes (52)(53)(54). However, the absence of E-cadherin expression in some subgroups of epithelioid MPM tumors despite their epithelial histologic features was previously observed by immunohistochemistry (52,54).…”

Section: Discussionmentioning

confidence: 62%

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Reyniès

Jaurand

Renier

et al. 2014

Clinical Cancer Research

124

156

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Purpose: Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinicobiological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies.Experimental Design: Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels.Results: Unsupervised hierarchical clustering on transcriptomic data defined two robust MPM subgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype.Conclusions: A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established. Clin Cancer Res; 20(5); 1323-34. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 62%

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Reyniès

Jaurand

Renier

et al. 2014

Clinical Cancer Research

124

156

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“…Whether this was due to apoptosis or detachment, and the explanation for why STK1 did not induce as many floating cells with HSC-3, could not be elucidated. STK1 may also possibly affect MSTO cell adhesion molecules, including β-catenin, claudins and E-cadherin (18,19).…”

Section: Discussionmentioning

confidence: 99%

Cell culture of human gingival fibroblasts, oral cancer cells and mesothelioma cells with serum-free media, STK1 and STK2

et al. 2014

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Abstract. The majority of cells are cultured with Dulbecco's modified Eagle's medium (DMEM) or RPMI supplemented with fetal bovine serum (FBS), which contains numerous factors, including cytokines, nutrients and unknown growth factors. These factors may affect cell growth, apoptosis and differentiation. The serum-free medium, STK2, has been previously reported as suitable for the cell culture of human mesenchymal stem cells. However, how STK1 or STK2 affect the cell proliferation of normal and cancer cells remains unknown. The present study examined the growth of the human gingival fibroblast (HGF-1) cell-line and the HSC-3, CA9-22 and MSTO cancer cell-lines, cultured with STK1 and STK2. STK1 increased the cell proliferation of HGF-1 compared to DMEM by assessment with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, whereas STK1 and STK2 markedly inhibited the cell proliferation of HSC-3 and MSTO. The cell proliferation rate of CA9-22 cultured with STK1 or STK2 for 96 h was ~2-fold higher than the rate for 24 h culture. The shape of the HSC-3 cells was also found to have changed to round when cultured with STK2. These results indicate that STK1 increased the cell proliferation of HGF-1 compared to DMEM, whereas the proliferation of HSC-3 and MSTO was inhibited by STK1 and STK2. Thus, STK1 and STK2 had different affects on the cell growth of HGF-1, CA9-22, HSC-3 and MSTO.

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“…HER2 immunohistochemical staining was performed using the automated Leica Microsystems Bondmax (Leica, Wetzlar, Germany) according to the manufacturer's instructions. 20 Sections were then lightly counterstained with hematoxylin.…”

Section: Methodsmentioning

confidence: 99%

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Stewart¹,

James

McCluggage

et al. 2015

Modern Pathology

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The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P ¼ 0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2. Modern Pathology (2015) 28, 428-436; doi:10.1038/modpathol.2014 published online 26 September 2014 The molecular mechanisms controlling the maturation and secretion of WNT proteins in the cells responsible for their production are attracting considerable attention. Wntless (WLS) (also known as GPR177 and Evi) was recently discovered as a key modulator of WNT protein secretion. [1][2][3] This multipass transmembrane protein localizes to compartments of the secretory pathway including the Golgi apparatus, endosomes, and plasma membrane. WLS acts as a WNT cargo receptor, shuttling palmitoylated Wnts from the endoplasmic reticulum to the plasma membrane, and it is required for exocytosis of WNT proteins from the WNT-producing cells. 4 In contrast to most other components of the WNT signaling pathway, only a single WLS gene exists in vertebrate genomes. WLS appears to be required for the secretion of all WNT proteins in both the canonical and noncanonical WNT pathways. 5 Augustin et al 6 recently demonstrated that WLS is highly overexpressed in malignant astrocytomas, indicating that the aberrant release of canonical and noncanonical WNT is a potential driver of glioma tumorigenesis required for proliferation, survival, and migration of glioma cells. Their work raises the question of whether WLS has a similar role in other cancers known to have aberrant activation of WNT signaling, including ovarian, gastric, and breast cancers. [7][8][9][10][11][12][13][14][15]

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Epithelial–mesenchymal transition in malignant mesothelioma

Cited by 133 publications

References 42 publications

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Cell culture of human gingival fibroblasts, oral cancer cells and mesothelioma cells with serum-free media, STK1 and STK2

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

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