Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis

Smeele, Patrick; D'Almeida, Sènan Mickael; Meiller, Clément; Chêne, Anne-Claire; Liddell, Charly; Cellerin, L.; Montagne, François; Deshayes, Sophie; Benziane, Sarah; Copin, Marie‐Christine; Hofman, Paul; Pimpec‐Barthes, Françoise Le; Porte, Henri; Scherpereel, Arnaud; Grégoire, Marc; Jean, Didier; Blanquart, Christophe

doi:10.1186/s12943-018-0891-0

Cited by 10 publications

(8 citation statements)

References 10 publications

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“…The collection of MPM tumor samples and normal pleura was previously described. 14 Transcriptome microarray data were available from 63 tumor samples of the same collection 15 ; ArrayExpress database: accession codes E-MTAB-6877.…”

Section: Collection Of Mesothelioma Cell Lines and Pleural Effusionsmentioning

confidence: 99%

Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma

Blondy

D'Almeida

Briolay

et al. 2020

J Immunother Cancer

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BackgroundMalignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The tumor microenvironment content, particularly the presence of macrophages, was described as crucial for the development of the disease. This work aimed at studying the involvement of the M-CSF (CSF-1)/IL-34/CSF-1R pathway in the formation of macrophages in MPM, using samples from patients.MethodsPleural effusions (PEs), frozen tumors, primary MPM cells and MPM cell lines used in this study belong to biocollections associated with clinical databases. Cytokine expressions were studied using real-time PCR and ELISA. The Cancer Genome Atlas database was used to confirm our results on an independent cohort. An original three-dimensional (3D) coculture model including MPM cells, monocytes from healthy donors and a tumor antigen-specific cytotoxic CD8 T cell clone was used.ResultsWe observed that high interleukin (IL)-34 levels in PE were significantly associated with a shorter survival of patients. In tumors, expression of CSF1 was correlated with ‘M2-like macrophages’ markers, whereas this was not the case with IL34 expression, suggesting two distinct modes of action of these cytokines. Expression of IL34 was higher in MPM cells compared with primary mesothelial cells. Particularly, high expression of IL34 was observed in MPM cells with an alteration of CDKN2A. Finally, using 3D coculture model, we demonstrated the direct involvement of MPM cells in the formation of immunosuppressive macrophages, through activation of the colony stimulating factor-1 receptor (CSF1-R) pathway, causing the inhibition of cytotoxicity of tumor antigen-specific CD8+ T cells.ConclusionsThe M-CSF/IL-34/CSF-1R pathway seems strongly implicated in MPM and could constitute a therapeutic target to act on immunosuppression and to support immunotherapeutic strategies.

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Section: Collection Of Mesothelioma Cell Lines and Pleural Effusionsmentioning

confidence: 99%

Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma

Blondy

D'Almeida

Briolay

et al. 2020

J Immunother Cancer

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“…The advantages and limitations of the mesothelioma preclinical models are presented in Table 1. (62,67,68). One study discussed the limits of these cell models.…”

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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“…Notably, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival in a cohort of 79 MPM tumor samples and 26 normal pleura. Moreover, BDNF activation is implicated in the PE-induced angiogenesis: this observation has potentially strong clinical implication and supports rationale of targeting angiogenesis in MPM [122]. Circulating cell-free RNA (MirRNA) fragments might serve as biomarkers in several diseases.…”

Section: Serologymentioning

confidence: 69%

Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

Abbott

Bortolotto

Benvenuti

et al. 2020

Cancers

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Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches.

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Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis

Cited by 10 publications

References 10 publications

Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma

Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

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