scholarly journals Three newly established immortalized mesothelial cell lines exhibit morphological phenotypes corresponding to malignant mesothelioma epithelioid, intermediate, and sarcomatoid types, respectively

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tatsuhiro Sato ◽  
Hayao Nakanishi ◽  
Ken Akao ◽  
Maho Okuda ◽  
Satomi Mukai ◽  
...  
Keyword(s):  
Cell Lines ◽  
Malignant Mesothelioma ◽  
Cell Transformation ◽  
Asbestos Exposure ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Histological Subtypes ◽  
Human Telomerase Reverse Transcriptase ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells

Abstract Background Malignant mesothelioma (MM) is a very aggressive tumor that develops from mesothelial cells, mainly due to asbestos exposure. MM is categorized into three major histological subtypes: epithelioid, sarcomatoid, and biphasic, with the biphasic subtype containing both epithelioid and sarcomatoid components. Patients with sarcomatoid mesothelioma usually show a poorer prognosis than those with epithelioid mesothelioma, but it is not clear how these morphological phenotypes are determined or changed during the oncogenic transformation of mesothelial cells. Methods We introduced the E6 and E7 genes of human papillomavirus type 16 and human telomerase reverse transcriptase gene in human peritoneal mesothelial cells and established three morphologically different types of immortalized mesothelial cell lines. Results HOMC-B1 cells exhibited epithelioid morphology, HOMC-A4 cells were fibroblast-like, spindle-shaped, and HOMC-D4 cells had an intermediate morphology, indicating that these three cell lines closely mimicked the histological subtypes of MM. Gene expression profiling revealed increased expression of NOD-like receptor signaling-related genes in HOMC-A4 cells. Notably, the combination treatment of HOMC-D4 cells with TGF-β and IL-1β induced a morphological change from intermediate to sarcomatoid morphology. Conclusions Our established cell lines are useful for elucidating the fundamental mechanisms of mesothelial cell transformation and mesothelial-to-mesenchymal transition.

scholarly journals Gastric cancer derived exosomes induce peritoneal mesothelial cell EMT through TGF-β1/Smads pathway to promote peritoneal metastasis

2021 ◽  
Author(s):  
Jungang Dong ◽  
Zhongbo Zhu ◽  
Guoning Cui ◽  
Zhixuan Zhang ◽  
Juan Yue ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Peritoneal Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Metastatic Microenvironment ◽  
Tgf Β1

Epithelial-mesenchymal transition (EMT) plays an important role in peritoneal metastasis of Gastric cancer (GC). Tumor exosomes can mediate tumor directed metastasis, and TGF-β1 is an important factor in inducing tumor Epithelial mesenchymal transition. However, it is not clear whether GC derived exosomes can induce peritoneal mesothelial cells through the TGF-β1/ Smads pathway and the effect of injured peritoneal mesothelial cells on the biological characteristics of GC cells. In this study, we demonstrated that GC-derived exosomes can activate the TGF-β1/Smads pathway in peritoneal mesothelial cells and induce the corresponding EMT process, and that the injured peritoneal mesothelial cells can improve the migration and adhesion of GC cells. Taken together, these data further support the critical role of exosomes in the remodeling of the pre-metastatic microenvironment.

scholarly journals miRNA589 Regulates Epithelial-Mesenchymal Transition in Human Peritoneal Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ke Zhang ◽  
Hao Zhang ◽  
Xun Zhou ◽  
Wen-bin Tang ◽  
Li Xiao ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
E Cadherin

Background. microRNA (miRNA, miR) are thought to interact with multiple mRNAs which are involved in the EMT process. But the role of miRNAs in peritoneal fibrosis has remained unknown.Objective. To determine if miRNA589 regulates the EMT induced by TGFβ1 in human peritoneal mesothelial cell line (HMrSV5 cells).Methods. 1. Level of miR589 was detected in both human peritoneal mesothelial cells (HPMCs) isolated from continuous ambulatory peritoneal dialysis (CAPD) patients’ effluent and HMrSV5 cells treated with or without TGFβ1. 2. HMrSV5 cells were divided into three groups: control group, TGFβ1 group, and pre-miR-589+TGFβ1 group. The level of miRNA589 was determined by realtime PCR. The expressions of ZO-1, vimentin, and E-cadherin in HPMCs were detected, respectively.Results. Decreased level of miRNA589 was obtained in either HPMCs of long-term CAPD patients or HMrSV5 cells treated with TGFβ1. In vitro, TGFβ1 led to upregulation of vimentin and downregulation of ZO-1 as well as E-cadherin in HMrSV5 cells, which suggested EMT, was induced. The changes were accompanied with notably decreased level of miRNA589 in HMrSV5 cells treated with TGFβ1. Overexpression of miRNA589 by transfection with pre-miRNA589 partially reversed these EMT changes.Conclusion. miRNA589 mediates TGFβ1 induced EMT in human peritoneal mesothelial cells.

scholarly journals Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event

2019 ◽  
Vol 20 (1) ◽  
pp. 150 ◽  
Author(s):  
Stefano Turini ◽  
Loredana Bergandi ◽  
Elena Gazzano ◽  
Mauro Prato ◽  
Elisabetta Aldieri
Keyword(s):  
Zinc Finger ◽  
Cancer Progression ◽  
Malignant Mesothelioma ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Zinc Finger Protein ◽  
Asbestos Exposure ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)—an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the E-cadherin gene. Since SNAIL-1, Twist, and ZEB-1 have been shown to be overexpressed in MM, these genes could be considered possible predictive or diagnostic markers of MM development.

scholarly journals The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target

2021 ◽  
Vol 22 (21) ◽  
pp. 11452
Author(s):  
Pınar Çakılkaya ◽  
Rikke Raagaard Sørensen ◽  
Henrik Jessen Jürgensen ◽  
Oliver Krigslund ◽  
Henrik Gårdsvoll ◽  
...  
Keyword(s):  
Cell Lines ◽  
Malignant Mesothelioma ◽  
Asbestos Exposure ◽  
Mesothelial Cell ◽  
Tissue Microarrays ◽  
Antibody Drug Conjugate ◽  
Tissue Samples ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Collagen Receptor

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients’ asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.

scholarly journals Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy

2020 ◽  
Vol 117 (41) ◽  
pp. 25543-25552 ◽  
Author(s):  
Jiaming Xue ◽  
Simone Patergnani ◽  
Carlotta Giorgi ◽  
Joelle Suarez ◽  
Keisuke Goto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Malignant Transformation ◽  
Cell Transformation ◽  
Asbestos Exposure ◽  
Mesothelial Cell ◽  
High Mobility ◽  
Mesothelial Cells ◽  
Wild Type ◽  
Hmgb1 Protein

Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.

scholarly journals S100A4 Is a Biomarker of Tumorigenesis, EMT, Invasion, and Colonization of Host Organs in Experimental Malignant Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 939 ◽  
Author(s):  
Joëlle S. Nader ◽  
Jordan Guillon ◽  
Coralie Petit ◽  
Alice Boissard ◽  
Florence Franconi ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Cell Lines ◽  
Malignant Mesothelioma ◽  
Primary Tumor ◽  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cell ◽  
Mesenchymal Transition ◽  
Multistep Process

Recent findings suggest that S100A4, a protein involved in communication between stromal cells and cancer cells, could be more involved than previously expected in cancer invasiveness. To investigate its cumulative value in the multistep process of the pathogenesis of malignant mesothelioma (MM), SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra), an advanced and robust technique of quantitative proteomics, was used to analyze a collection of 26 preneoplastic and neoplastic rat mesothelial cell lines and models of MM with increasing invasiveness. Secondly, proteomic and histological analyses were conducted on formalin-fixed paraffin-embedded sections of liver metastases vs. primary tumor, and spleen from tumor-bearing rats vs. controls in the most invasive MM model. We found that S100A4, along with 12 other biomarkers, differentiated neoplastic from preneoplastic mesothelial cell lines, and invasive vs. non-invasive tumor cells in vitro, and MM tumors in vivo. Additionally, S100A4 was the only protein differentiating preneoplastic mesothelial cell lines with sarcomatoid vs. epithelioid morphology in relation to EMT (epithelial-to-mesenchymal transition). Finally, S100A4 was the most significantly increased biomarker in liver metastases vs. primary tumor, and in the spleen colonized by MM cells. Overall, we showed that S100A4 was the only protein that showed increased abundance in all situations, highlighting its crucial role in all stages of MM pathogenesis.

Mesothelial Cells

2007 ◽  
Vol 27 (2_suppl) ◽  
pp. 110-115 ◽  
Author(s):  
Susan Yung ◽  
Chan Tak Mao
Keyword(s):  
Mesothelial Cell ◽  
In Vitro Models ◽  
Mesothelial Cells ◽  
Dynamic Membrane ◽  
Peritoneal Mesothelial Cells ◽  
Immunohistochemical Markers ◽  
Vitro Model ◽  
And Function

♦ Background The introduction of peritoneal dialysis (PD) as a modality of renal replacement therapy has provoked much interest in the biology of the peritoneal mesothelial cell. Mesothelial cells isolated from omental tissue have immunohistochemical markers that are identical to those of mesothelial stem cells, and omental mesothelial cells can be cultivated in vitro to study changes to their biologic functions in the setting of PD. ♦ Method The present article describes the structure and function of mesothelial cells in the normal peritoneum and details the morphologic changes that occur after the introduction of PD. Furthermore, this article reviews the literature of mesothelial cell culture and the limitations of in vitro studies. ♦ Results The mesothelium is now considered to be a dynamic membrane that plays a pivotal role in the homeostasis of the peritoneal cavity, contributing to the control of fluid and solute transport, inflammation, and wound healing. These functional properties of the mesothelium are compromised in the setting of PD. Cultures of peritoneal mesothelial cells from omental tissue provide a relevant in vitro model that allows researchers to assess specific molecular pathways of disease in a distinct population of cells. Structural and functional attributes of mesothelial cells are discussed in relation to long-term culture, proliferation potential, age of tissue donor, use of human or animal in vitro models, and how the foregoing factors may influence in vitro data. ♦ Conclusions The ability to propagate mesothelial cells in culture has resulted, over the past two decades, in an explosion of mesothelial cell research pertaining to PD and peritoneal disorders. Independent researchers have highlighted the potential use of mesothelial cells as targets for gene therapy or transplantation in the search to provide therapeutic strategies for the preservation of the mesothelium during chemical or bacterial injury.

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