scholarly journals Cytogenomic characterization of three murine malignant mesothelioma tumor cell lines

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Eva Wahlbuhl ◽  
Thomas Liehr ◽  
Martina Rincic ◽  
Shaymaa Azawi
Keyword(s):  
Cell Lines ◽  
Malignant Mesothelioma ◽  
Asbestos Exposure ◽  
Molecular Genetic ◽  
Copy Number Variants ◽  
Molecular Cytogenetics ◽  
Latency Period ◽  
Molecular Karyotyping ◽  
Tumor Type ◽  
Genomic Imbalances

Abstract Background Malignant mesothelioma (MM) is a rare aggressive cancer primary located in pleura and lung. MMs can be divided into biphasic, epithelioid and sarcomatoid subtypes. In majority of cases MMs are induced by asbestos fiber exposure. As latency period after asbestos exposure ranges between ~ 10 and 60 years MMs are mainly observed in elder people. Human MM, being a rare tumor type, lacks detailed cytogenetic data, while molecular genetic studies have been undertaken more frequently. However, murine MM cell lines are also regularly applied to get more insight into MM biology and to test new therapy strategies. Results Here the murine MM cell lines AB1, AB22 and AC29 were studied by molecular cytogenetics and molecular karyotyping. Interestingly, yet there were no genetic or genomic studies undertaken for these already in 1992 established cell lines. The obtained data on genomic imbalances in these murine cell lines was translated into the human genome as previously reported based on human and murine genomic browsers. Conclusions It turned out that all three cell lines showed high similarities in copy number variants as observed typically in human MM. Also, all three cell lines were most similar to human epithelioid MMs, and should be used as models therefore.

scholarly journals Cytoskeletal Organization Correlates to Motility and Invasiveness of Malignant Mesothelioma Cells

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 685
Author(s):  
Maureen Keller ◽  
Katarina Reis ◽  
Anders Hjerpe ◽  
Katalin Dobra ◽  
Pontus Aspenström
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Actin Filament ◽  
Malignant Mesothelioma ◽  
Nuclear Localization ◽  
Asbestos Exposure ◽  
Cytoskeletal Organization ◽  
Direct Invasion ◽  
Aggressive Cancer ◽  
And Function

Malignant mesothelioma (MM) is a rare but highly aggressive cancer that primarily originates from the pleura, peritoneum or pericardium. There is a well-established link between asbestos exposure and progression of MM. Direct invasion of the surrounding tissues is the main feature of MM, which is dependent on dysregulated communication between the mesothelium and the microenvironment. This communication is dependent on the dynamic organization of the cytoskeleton. We have analyzed the organization and function of key cytoskeletal components in MM cell lines of increasing malignancies measured as migratory and invasive properties, and we show that highly malignant and invasive MM cells have an organization of the actin filament and vimentin systems that is distinct from the less malignant MM cell lines. In addition, the Hippo tumor suppressor pathway was inactivated in the invasive MM cells, which was seen as increased YAP nuclear localization.

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 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 Genomic imbalances in the placenta are associated with poor fetal growth

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Giulia F. Del Gobbo ◽  
Yue Yin ◽  
Sanaa Choufani ◽  
Emma A. Butcher ◽  
John Wei ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Sex Chromosome ◽  
Copy Number Variants ◽  
Placental Insufficiency ◽  
Potential Contribution ◽  
Genomic Imbalances ◽  
Significant Difference ◽  
Underlying Causes ◽  
Risk Of Disease ◽  
The Impact

Abstract Background Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth. Methods We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR. Results Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5–107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3. Conclusions We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.

scholarly journals Predicting tumor response to drugs based on gene-expression biomarkers of sensitivity learned from cancer cell lines

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuanyuan Li ◽  
David M. Umbach ◽  
Juno M. Krahn ◽  
Igor Shats ◽  
Xiaoling Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Predictive Models ◽  
Drug Sensitivity ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
The Cancer Genome Atlas ◽  
Differential Sensitivity ◽  
Tumor Type

Abstract Background Human cancer cell line profiling and drug sensitivity studies provide valuable information about the therapeutic potential of drugs and their possible mechanisms of action. The goal of those studies is to translate the findings from in vitro studies of cancer cell lines into in vivo therapeutic relevance and, eventually, patients’ care. Tremendous progress has been made. Results In this work, we built predictive models for 453 drugs using data on gene expression and drug sensitivity (IC50) from cancer cell lines. We identified many known drug-gene interactions and uncovered several potentially novel drug-gene associations. Importantly, we further applied these predictive models to ~ 17,000 bulk RNA-seq samples from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database to predict drug sensitivity for both normal and tumor tissues. We created a web site for users to visualize and download our predicted data (https://manticore.niehs.nih.gov/cancerRxTissue). Using trametinib as an example, we showed that our approach can faithfully recapitulate the known tumor specificity of the drug. Conclusions We demonstrated that our approach can predict drugs that 1) are tumor-type specific; 2) elicit higher sensitivity from tumor compared to corresponding normal tissue; 3) elicit differential sensitivity across breast cancer subtypes. If validated, our prediction could have relevance for preclinical drug testing and in phase I clinical design.

scholarly journals Mesothelioma in Agriculture in Lombardy, Italy: An Unrecognized Risk

2021 ◽  
Vol 18 (1) ◽  
pp. 358
Author(s):  
Carolina Mensi ◽  
Barbara Dallari ◽  
Marco Polonioli ◽  
Luciano Riboldi ◽  
Dario Consonni ◽  
...  
Keyword(s):  
Cohort Studies ◽  
Malignant Mesothelioma ◽  
Asbestos Exposure ◽  
Agricultural Workers ◽  
Wine Production ◽  
Maintenance And Repair ◽  
Lombardy Region ◽  
Frequent Exposure ◽  
Agricultural Setting ◽  
Jute Bags

Cohort studies showed consistently low risks for malignant mesothelioma (MM) among agricultural workers, however the investigated exposures did not include asbestos. Our aim is to describe sources of asbestos exposure of MM in agriculture. Twenty-six MM cases in agricultural or seed trades workers were identified through the MM registry of the Lombardy region, Italy in 2000–2016. Asbestos exposures were investigated through a standardized questionnaire. The most frequent exposure circumstances were recycled jute bags previously containing asbestos (11 cases) and maintenance and repair of asbestos roofs (12 subjects). Three subjects performed maintenance and repair of tractor asbestos brakes and two used asbestos filters for wine production. Our data suggest asbestos exposure opportunities in the agricultural setting, underlining the need to look for this exposure in subjects affected with mesothelioma.

Bioelectronic Sensor Technology for Detection of Cystic Fibrosis and Hereditary Hemochromatosis Mutations

2003 ◽  
Vol 127 (12) ◽  
pp. 1565-1572
Author(s):  
Susan H. Bernacki ◽  
Daniel H. Farkas ◽  
Wenmei Shi ◽  
Vivian Chan ◽  
Yenbou Liu ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Cell Lines ◽  
Molecular Genetic ◽  
Hereditary Hemochromatosis ◽  
The Other ◽  
Molecular Diagnostic ◽  
Molecular Genetic Testing ◽  
Diagnostic Applications ◽  
Lymphocyte Cell

Abstract Context.—Bioelectronic sensors, which combine microchip and biological components, are an emerging technology in clinical diagnostic testing. An electronic detection platform using DNA biochip technology (eSensor) is under development for molecular diagnostic applications. Owing to the novelty of these devices, demonstrations of their successful use in practical diagnostic applications are limited. Objective.—To assess the performance of the eSensor bioelectronic method in the validation of 6 Epstein-Barr virus–transformed blood lymphocyte cell lines with clinically important mutations for use as sources of genetic material for positive controls in clinical molecular genetic testing. Two cell lines carry mutations in the CFTR gene (cystic fibrosis), and 4 carry mutations in the HFE gene (hereditary hemochromatosis). Design.—Samples from each cell line were sent for genotype determination to 6 different molecular genetic testing facilities, including the laboratory developing the DNA biochips. In addition to the bioelectronic method, at least 3 different molecular diagnostic methods were used in the analysis of each cell line. Detailed data were collected from the DNA biochip output, and the genetic results were compared with those obtained using the more established methods. Results.—We report the successful use of 2 applications of the bioelectronic platform, one for detection of CFTR mutations and the other for detection of HFE mutations. In all cases, the results obtained with the DNA biochip were in concordance with those reported for the other methods. Electronic signal output from the DNA biochips clearly differentiated between mutated and wild-type alleles. This is the first report of the use of the cystic fibrosis detection platform. Conclusions.—Bioelectronic sensors for the detection of disease-causing mutations performed well when used in a “real-life” situation, in this case, a validation study of positive control blood lymphocyte cell lines with mutations of public health importance. This study illustrates the practical potential of emerging bioelectronic DNA detection technologies for use in current molecular diagnostic applications.

scholarly journals Scalp Metastasis of Mesothelioma

2021 ◽  
Author(s):  
İlkin Yetişkin ◽  
Berna Eren Kömürcüoğlu ◽  
Eylem Yıldırım
Keyword(s):  
Adrenal Gland ◽  
Malignant Mesothelioma ◽  
Malignant Tumor ◽  
Late Stage ◽  
Poor Prognosis ◽  
Early Stage ◽  
Asbestos Exposure ◽  
Distant Metastases ◽  
Rare Neoplasm ◽  
Scalp Metastasis

Mesothelioma is a primary malignant tumor of the mesothelial cells lining the pleura, pericardium and peritoneum, which is frequently seen between the ages of 40-60. Malignant mesothelioma (MM) is a rare neoplasm with a poor prognosis, usually associated with asbestos exposure. It is characterized by aggressive local invasion and metastatic spread. Extrathoracic lymphogenous-hematogenous metastases are rare at the time of diagnosis and in the early stage. However, metastases develop in at least half of the cases in the late stage of the disease. After the spread of serous membranes, distant metastases to the bone, adrenal gland, and liver are frequently observed. Skin and scalp metastases are rarely observed. Our case MPM is presented because it is a rare scalp metastasis.

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