Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications

Our plain-English summary of Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications, by S. Magkouta, A. Pappas, I.S. Pateras, et al (Oncotarget, 2018).

The study

• Authors: S. Magkouta, A. Pappas, I.S. Pateras, A. Kollintza, C. Moschos, M.E. Vazakidou, V. Karavana, V.G. Gorgoulis, I. Kalomenidis
• Journal: Oncotarget
• Published: 2018;9(31):21783-21796
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is resistant to currently used treatment. Angiopoieitn-1 directly promotes mesothelioma cell growth in a Tie-2-dependent fashion. Angiopoietin/Tie-2 axis may thus be valid targets for therapeutic interventions against mesothelioma. We hypothesized that a soluble angiopoietin inhibitor (Murine Tek-deltaFc) would halt mesothelioma progression in vivo by enhancing mesothelioma cell proliferation and inhibiting tumor angiogenesis. Our hypothesis was challenged on two syngeneic mesothelioma in vivo models (AB1 cells-Balb/c mice and AE17 cells-C57BL/6 mice. Even though both mesothelioma cell lines express the Angiopoietin-1/-2 and Tie-2, murine Tek-deltaFc hampered AB1 but not AE17 mesothelioma growth in vivo by enhancing tumor cell apoptosis and limiting tumor angiogenesis. Neither angiopoietins (Angs)-1 and -2 nor the inhibitor affected mesothelioma cell growth in vitro. AB1 (responding) tumors were more vascularized and displayed higher endothelial Tie-2 and lower tumor Ang-1 expression than the (non-responding) AE17 tumors. Angiopoietins-1 and -2 are expressed in tumors and pleural cavity of mesothelioma patients demonstrating the clinical relevance of our experimental observations. In conclusion, disrupting Ang-Tie-2 signaling limits mesothelioma angiogenesis and halts tumor progression. Tumor vascularity, endothelial Tie-2 expression and tumor Ang-1 expression may predict mesothelioma response to Tek-deltaFc.

In plain English

This laboratory study tested whether a drug that blocks angiopoietins, proteins involved in blood-vessel growth, slowed mesothelioma in mice. It did not study asbestos exposure. Two types of mouse mesothelioma cells (AB1 and AE17) were injected into the chest cavity of two strains of mice. The mice then received the inhibitor Murine Tek-deltaFc or an inactive vehicle three times a week. The inhibitor significantly reduced tumor growth and pleural fluid build-up in the AB1 model but not in the AE17 model. In AB1 tumors it increased tumor cell death and reduced blood-vessel area. In AE17 tumors it did not change these. Neither the drug nor angiopoietins changed cell survival in lab dishes. Before any treatment, AB1 tumors had more blood vessels, less oxygen shortage and more of the receptor Tie-2 on vessel cells than AE17 tumors. Both angiopoietins were found in tumor samples from 14 mesothelioma patients and in pleural fluid from 14 patients. The authors concluded that the findings support clinical testing of anti-angiopoietin treatment. They suggested that tumor vascularity, endothelial Tie-2 and tumor Ang-1 could be investigated as markers predicting response.

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: Animal experiment (two syngeneic mouse models of pleural mesothelioma), with in vitro cell studies and analysis of human mesothelioma tumor, pleural fluid and serum samples
• Who was studied: Male mice aged 8-10 weeks: Balb/c mice injected in the pleura with AB1 mouse mesothelioma cells and C57BL/6 mice injected with AE17 cells (10-13 animals per group in the growth experiments), Athens, Greece. Human samples: archived tumor tissue from 14 mesothelioma patients (all epithelioid subtype), plus pleural fluid and serum from 14 mesothelioma patients and 16 heart failure patients.
• Exposure: Asbestos exposure was not studied. The exposure was treatment with the angiopoietin inhibitor Murine Tek-deltaFc, 40 mg/kg body weight given into the abdomen three times per week, starting four days after tumor cell implantation. The animals were euthanized 14 days after the cells were placed in the pleura. Controls received vehicle.
• Main results:
  • The inhibitor significantly reduced tumor growth and pleural fluid accumulation in the Balb/c (AB1) model but not in the C57BL/6 (AE17) model.
  • Treated AB1 tumors, but not treated AE17 tumors, showed higher apoptosis (tumor cell death) rates than controls. Tumor cell proliferation was not affected in either model.
  • In the lab dish, Ang-1, Ang-2 or Murine Tek-deltaFc had no direct effect on the viability of either cell line. These data were not shown.
  • In AB1 tumors the inhibitor significantly reduced total vascular area and lowered vessel pericyte coverage and endothelial Tie-2 expression. In AE17 tumors it did not affect vascularity, pericyte coverage or endothelial Tie-2 expression.
  • Compared with untreated AE17 tumors, untreated AB1 tumors had more blood vessels, less hypoxia and higher endothelial Tie-2 expression.
  • Treatment significantly reduced active Ang-1 and Ang-2 in AB1 tumors. In AE17 tumors it reduced active Ang-2 but not active Ang-1. Tumor VEGF levels were not altered in either model.
  • In mesothelioma patients, Ang-1 was expressed by a larger proportion of tumor cells than Ang-2 and prevailed in the stroma and in pleural fluid. In every patient with malignant pleural mesothelioma, Ang-2 was higher in pleural fluid than in serum, and Ang-1 was higher in serum than in pleural fluid.
• The authors' conclusion: The authors concluded that this preclinical work highlights a central role of the angiopoietin/Tie-2 axis in mesothelioma blood-vessel formation and growth and supports clinical testing of anti-angiopoietin treatment. They suggested that tumor vascularity, endothelial Tie-2 expression and tumor Ang-1 expression could be investigated as markers predicting patient response.

Topics

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

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