A Conditional Mouse Model for Malignant Mesothelioma

Jongsma, Johan; Montfort, Erwin van; Vooijs, Marc; Zevenhoven, John; Krimpenfort, Paul; Valk, Martin van der; Vijver, Marc J. van de; Berns, Anton

doi:10.1016/j.ccr.2008.01.030

Cited by 121 publications

(159 citation statements)

References 76 publications

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“…Evidence from in vivo studies indicates that MPE formation is dictated by a complex tumour-host interplay which through paracrine and autocrine effects stimulates pleural inflammation, tumour angiogenesis and vascular hyperpermeability [7]. To trigger these events, tumour cells execute pro-inflammatory and pro-angiogenic transcriptional programmes which are controlled, at least in part, by transcription factors nuclear factor (NF)-κB [27] and signal transducer and activator of transcription (STAT) 3 [28,29]. Autocrine tumour necrosis factor (TNF), interleukin (IL)-6 and osteopontin (OPN) participate in positive feedback loops regulating tumour NF-κB/STAT3 activation to promote MPE [29][30][31].…”

Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

Malignant pleural effusion: from bench to bedside

et al. 2016

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Malignant pleural effusion (MPE) is a common but serious condition that is related with poor quality of life, morbidity and mortality. Its incidence and associated healthcare costs are rising and its management remains palliative, with median survival ranging from 3 to 12 months. During the last decade there has been significant progress in unravelling the pathophysiology of MPE, as well as its diagnostics, imaging, and management. Nowadays, formerly bed-ridden patients are genotyped, phenotyped, and treated on an ambulatory basis. This article attempts to provide a comprehensive overview of current advances in MPE from bench to bedside. In addition, it highlights unanswered questions in current clinical practice and suggests future directions for basic and clinical research in the field. @ERSpublications This review provides up to date knowledge for malignant pleural effusion covering aspects from bench to bedside http://ow.ly/10w7vN

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Section: Formation Of Mpe: General Aspectsmentioning

confidence: 99%

Malignant pleural effusion: from bench to bedside

et al. 2016

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“…Both CDKN2A and NF2 encode for tumorsuppressor genes and when either gene is inactivated within a murine model, the mice rarely develop mesothelioma. 28,42 However, concomitant loss of both CDKN2A and NF2 results in a high incidence of mesothelioma with a relatively short latency. 42 Taken together, these observations indicate alterations in both CDKN2A and NF2 define an aggressive subtype of mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n = 25, 29%), hemizygous NF2 loss (n = 30, 35%), and/or loss of BAP1 protein expression (n = 49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progressionfree survival (Po 0.02) and poor overall survival (Po 0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (Po 0.01) and overall survival rate of 18% with a median of 8 months (Po 0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

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“…Several genetically engineered mesothelioma models demonstrated the essential role of NF2, CDKN2A/ARF, and P53 in mesothelial carcinogenesis. 64,65 However, it remains elusive how oxidative DNA damage catalyzed by iron leads to specific homozygous deletion of CDKN2A/2B. In this sense, this model is appropriate for the further study of mesothelial carcinogenesis and its preventive intervention.…”

Section: Discussionmentioning

confidence: 99%

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Akatsuka

Yamashita

et al. 2010

Laboratory Investigation

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In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2 0 -deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

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A Conditional Mouse Model for Malignant Mesothelioma

Cited by 121 publications

References 76 publications

Malignant pleural effusion: from bench to bedside

Malignant pleural effusion: from bench to bedside

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

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