Evaluation of imaging techniques for the assessment of tumour progression in an orthotopic rat model of malignant pleural mesothelioma†

Meerang, Mayura; Boss, Andreas; Kenkel, David; Broggini-Tenzer, Angela; Bérard, Karima; Lauk, Olivia; Arni, Stephan; Weder, Walter; Opitz, Isabelle

doi:10.1093/ejcts/ezu393

Cited by 5 publications

(5 citation statements)

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“…By immunohistochemistry, the immunoreactivity of Merlin was also detected in both cytoplasmic and nuclear fractions of Met5A and was negative in Mero‐82 cells (Supplementary Figure 1C). Tumors derived from orthotopic implantation of rat MPM cells (IL45; Merlin positive) collected in our previous study (Meerang et al., 2015) were positively stained, mainly in the cytoplasm. Xenograft tumors, derived from a human MPM cell line negative for Merlin (ZL55), show very weak‐negative staining in both nuclear and cytoplasmic fractions (Supplementary Figure 1C).…”

Section: Resultsmentioning

confidence: 84%

“…By immunohistochemistry, the immunoreactivity of Merlin was also detected in both cytoplasmic and nuclear fractions of Met5A and was negative in Mero-82 cells (Supplementary Figure 1C). Tumors derived from orthotopic implantation of rat MPM cells (IL45; Merlin positive) collected in our previous study (Meerang et al, 2015) were positively stained, mainly in the cytoplasm.…”

Section: Markers Expression and Their Association With Clinical And P...mentioning

confidence: 83%

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Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma

et al. 2016

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Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.

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Section: Resultsmentioning

confidence: 84%

Section: Markers Expression and Their Association With Clinical And P...mentioning

confidence: 83%

Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma

et al. 2016

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“…Different analytical methods have been developed for in situ tumor visualization. Firefly luciferase (luc)-engineered cells can be detected by a non-invasive bioluminescence imaging method, as in rats injected with luc-MM cells in the pleural cavity (57). However, data have shown that magnetic resonance imaging (MRI) is a more reliable method for MPM tumor burden measurement compared to bioluminescence (57).…”

Section: Preclinical Modelsmentioning

confidence: 99%

“…Firefly luciferase (luc)-engineered cells can be detected by a non-invasive bioluminescence imaging method, as in rats injected with luc-MM cells in the pleural cavity (57). However, data have shown that magnetic resonance imaging (MRI) is a more reliable method for MPM tumor burden measurement compared to bioluminescence (57). Computed tomography scanning may be also of interest, as shown with a lung cancer cell line in mice (58).…”

Section: Preclinical Modelsmentioning

confidence: 99%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra-and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

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“…MR data sets were acquired applying T2-weighted fast spin-echo sequences in transverse/sagittal/ coronal orientation (repetition time TR 3,500 ms, echo time TE 45 ms). The tumor volume (mm 3 ) was quantified blindly with ImageJ software (NIH, Bethesda, MD) by two observers as we described previously (23).…”

Section: Tumor Imagingmentioning

confidence: 99%

Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

Meerang

Bérard

Felley-Bosco

et al. 2016

Molecular Cancer Therapeutics

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An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma-associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg orally). Daily treatment with vismodegib efficiently downregulated Hh target genes Gli1, Hedgehog Interacting Protein (Hhip), and Ptch1, and caused a significant reduction of tumor volume and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa. Primary cells isolated from the rat model cultured in 3% O 2 continued to express Dhh but did not respond to vismodegib in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts, which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM. Mol Cancer Ther; 15(5); 1095-105. Ó2016 AACR.

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Evaluation of imaging techniques for the assessment of tumour progression in an orthotopic rat model of malignant pleural mesothelioma†

Abstract: MRI is a reliable and reproducible noninvasive in vivo imaging method for MPM tumour burden assessment for the present MPM model.

Cited by 5 publications

References 24 publications

Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma

Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

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