Role of angiopoietins in mesothelioma progression

Our plain-English summary of Role of angiopoietins in mesothelioma progression, by S. Magkouta, A. Kollintza, C. Moschos, et al (Cytokine, 2019).

The study

• Authors: S. Magkouta, A. Kollintza, C. Moschos, M. Spella, I. Skianis, A. Pappas, M.E. Vazakidou, G. Stathopoulos, I. Kalomenidis
• Journal: Cytokine
• Published: 2019;118:99-106
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background And Objective: Anti-angiogenic treatment has been recently shown to be clinically beneficial for mesothelioma patients. Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. Ang-1 is mainly known to promote angiogenesis and vessel stability, while Ang-2 could serve as an antagonist of Ang-1 causing vessel regression and destabilization or enhance angiogenesis in a context-dependent manner. We hypothesized that Ang-1 would promote and Ang2 would halt experimental mesothelioma by affecting tumor angiogenesis.

Methods: To examine the effects of angiopoietins in mesothelioma angiogenesis and in vivo growth we constructed Ang-1 or Ang-2 overexpressing AE17 and AB1 mesothelioma cells and implanted them in the respective syngeneic animals. We also explored the clinical relevance of our observations using the human tumoral mRNAseq data available in the TCGA database.

Results And Conclusions: Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Low Ang-1 levels in human mesotheliomas are associated with the epitheloid subtype. Tumors of high Ang-1, or concurrent high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression, markers of vascularity and vascular stability, respectively. Our results highlight the importance of angiopoietins in mesothelioma pathophysiology and pave the way for the clinical development of novel anti-angiogenic strategies.

Copyright © 2018 Elsevier Ltd. All rights reserved.

In plain English

This laboratory study tested how angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) affect mesothelioma growth and tumour blood vessels. The authors made AE17 and AB1 murine mesothelioma cell clones stably overexpressing Ang-1 or Ang-2 (or empty vector) and injected them into the pleural cavity of syngeneic C57BL/6 and Balb/c mice, euthanising the animals 14 days later. Ang-1 overexpression significantly increased tumour growth in both models, while Ang-2 overexpression reduced AE17 tumour growth and favoured AB1 tumours; mice with AE17 Ang-2 tumours had 90% lower pleural fluid volumes than controls. Vessel density, vessel area and pericyte coverage changed differently in the two models. Using publicly available mRNAseq data from 87 mesothelioma patients in the TCGA database, neither Ang-1 nor Ang-2 expression independently predicted survival; epithelioid type did, and low tumoral Ang-1 was associated with epithelioid type. Tumoral Ang-1 correlated with PECAM-1 and CDH5 expression. The authors concluded Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Asbestos was not studied; the introduction called it the main cause of mesothelioma and noted it is still used in many populous countries.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Experimental animal study using genetically modified mesothelioma cell lines in syngeneic mouse models, combined with analysis of an existing human tumour gene-expression database (TCGA)
• Who was studied: Murine AE17 and AB1 mesothelioma cell clones implanted intrapleurally into 8-10 week-old C57BL/6 and Balb/c mice (5-8 mice per group), plus mRNAseq and survival data from 87 patients with malignant pleural mesothelioma retrieved from TCGA; laboratory in Athens, Greece
• Exposure: Overexpression of angiopoietin-1 or angiopoietin-2 by the tumour cells themselves (3-5 fold overexpression), compared with empty-vector control cells; no asbestos or other fibre exposure was studied
• Main results:
  • In mice, Ang-1 overexpression significantly increased tumour growth in both the AE17 and AB1 models; Ang-2 overexpression reduced AE17 tumour growth but increased AB1 tumour growth
  • Mice bearing AE17 Ang-2 overexpressing tumours had 90% lower pleural fluid volumes than mice bearing control tumours
  • In AE17 tumours, Ang-1 overexpression increased vessel density and pericyte coverage, while Ang-2 overexpression reduced vessel density, area and pericyte coverage
  • In AB1 tumours, Ang-1 overexpression expanded total vessel area without affecting vessel density or maturity, while Ang-2 overexpression increased both vessel area and pericyte coverage
  • In mice, Ang-1 overexpressing AE17 tumours showed higher proliferation and lower apoptosis; AE17 Ang-2 tumours showed higher apoptosis; in AB1 tumours both angiopoietins reduced apoptosis and Ang-2 increased proliferation
  • In the 87 TCGA patients, neither Ang-1 nor Ang-2 expression independently predicted survival; epithelioid type predicted longer survival, and low Ang-1 mRNA was associated with epithelioid type
  • In the TCGA patient tumours, Ang-1 expression correlated significantly with PECAM-1 and with CDH5 expression, whereas no significant association was found for Ang-2 with these genes
  • Among TCGA patients, those with high Ang-2 and high VEGF had higher PECAM-1 than those with low Ang-2/high VEGF or high Ang-2/low VEGF, and higher CDH5 than those with high Ang-2 and low VEGF
• The authors' conclusion: The authors concluded that, in this preclinical evaluation, Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 depends on context, and that this points towards development of new anti-angiogenic strategies
• Limitations the authors state:
  • The authors noted that the Ang-1 effect seen in one mouse model (AE17/C57bl-6) matched the human data better than the other model, and attributed the divergent results to differing background VEGF levels between models

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Angiogenesis.

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