Expression of FGFR1–4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity

Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1–FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1–4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1–4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.

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Influence of Methallothionein Expression on Sensitivity Against Platin Compounds in Human Malignant Pleural Mesothelioma Cell Lines – Knock-Down of Gene Expression as New Therapeutic Approach?

10.1055/s-0039-1678402 ◽

2019 ◽

Author(s):

Sabrina Borchert ◽

Pia Suckrau ◽

Michael Wessolly ◽

Jan Schmeller ◽

Elena Mairinger ◽

...

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Malignant Pleural Mesothelioma ◽

Therapeutic Approach ◽

Pleural Mesothelioma ◽

Knock Down ◽

Malignant Pleural Mesothelioma Cell ◽

Mesothelioma Cell

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Prognostic significance of nuclear grade in malignant pleural mesothelioma: A single institution experience

10.26226/morressier.578f37fdd462b8028d8902e7 ◽

2016 ◽

Author(s):

Simge Erbil

Keyword(s):

Malignant Pleural Mesothelioma ◽

Prognostic Significance ◽

Nuclear Grade ◽

Pleural Mesothelioma ◽

Single Institution

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Prognostic significance of Bax and Fas Ligand in erionite and asbestos induced Turkish malignant pleural mesothelioma

Lung Cancer ◽

10.1016/j.lungcan.2005.05.025 ◽

2005 ◽

Vol 50 (2) ◽

pp. 189-198 ◽

Cited By ~ 18

Author(s):

Nurdan Kokturk ◽

Pinar Firat ◽

Hadi Akay ◽

Cem Kadilar ◽

Can Ozturk ◽

...

Keyword(s):

Malignant Pleural Mesothelioma ◽

Fas Ligand ◽

Prognostic Significance ◽

Pleural Mesothelioma

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Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma

Cancers ◽

10.3390/cancers12113460 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3460

Author(s):

Mayura Meerang ◽

Jessica Kreienbühl ◽

Vanessa Orlowski ◽

Seraina L. C. Müller ◽

Michaela B. Kirschner ◽

...

Keyword(s):

Cell Lines ◽

Malignant Pleural Mesothelioma ◽

Ubiquitin Ligase ◽

Tumor Model ◽

Progression Free Survival ◽

Neurofibromatosis Type ◽

Resistant Cell ◽

Pleural Mesothelioma ◽

G2 Cell Cycle Arrest

Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.

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Real-Time RT-PCR Quantification of Human Telomerase Reverse Transcriptase Splice Variants in Tumor Cell Lines and Non–Small Cell Lung Cancer

Clinical Chemistry ◽

10.1373/clinchem.2006.073015 ◽

2007 ◽

Vol 53 (1) ◽

pp. 53-61 ◽

Cited By ~ 29

Author(s):

Eleni Mavrogiannou ◽

Areti Strati ◽

Aliki Stathopoulou ◽

Emily G Tsaroucha ◽

Loukas Kaklamanis ◽

...

Keyword(s):

Tumor Cell ◽

Real Time ◽

Cell Lines ◽

Splice Variant ◽

Splice Variants ◽

Telomerase Activity ◽

Tumor Cell Lines ◽

Rt Pcr ◽

Human Telomerase Reverse Transcriptase ◽

Tissue Samples

Abstract Background: We developed and validated a real-time reverse transcription (RT)–PCR for the quantification of 4 individual human telomerase reverse transcriptase (TERT) splice variants (α+β+, α−β+, α+β−, α−β−) in tumor cell lines and non–small cell lung cancer (NSCLC). Methods: We used in silico designed primers and a common TaqMan probe for highly specific amplification of each TERT splice variant, PCR transcript–specific DNA external standards as calibrators, and the MCF-7 cell line for the development and validation of the method. We then quantified TERT splice variants in 6 tumor cell lines and telomerase activity and TERT splice variant expression in cancerous and paired noncancerous tissue samples from 28 NSCLC patients. Results: In most tumor cell lines, we observed little variation in the proportion of TERT splice variants. The α+β− splice variant showed the highest expression and α−β+ and α−β− the lowest. Quantification of the 4 TERT splice variants in NSCLC and surrounding nonneoplastic tissues showed the highest expression percentage for the α+β− variant in both NSCLC and adjacent nonneoplastic tissue samples, followed by α+β+, with the α−β+ and α−β− splice variants having the lowest expression. In the NSCLC tumors, the α+β+ variant had higher expression than other splice variants, and its expression correlated with telomerase activity, overall survival, and disease-free survival. Conclusions: Real-time RT-PCR quantification is a specific, sensitive, and rapid method that can elucidate the biological role of TERT splice variants in tumor development and progression. Our results suggest that the expression of the TERT α+β+ splice variant may be an independent negative prognostic factor for NSCLC patients.

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