A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma

Our plain-English summary of A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma, by C. Tabata, N. Hirayama, R. Tabata, et al (The European Respiratory Journal, 2010).

The study

• Authors: C. Tabata, N. Hirayama, R. Tabata, A. Yasumitsu, S. Yamada, A. Murakami, S. Iida, K. Tamura, K. Fukuoka, K. Kuribayashi, T. Terada, T. Nakano
• Journal: The European Respiratory Journal
• Published: 2010;36(5):1099-105
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

In plain English

This Japanese study combined laboratory experiments with blood tests in patients. In cell cultures, the authors found that adding the protein angiopoietin-1 (Ang-1) increased the growth and movement of two of four malignant pleural mesothelioma cell lines (MSTO-211H and H2452), but not of a normal mesothelial cell line. They then measured Ang-1 in the blood of 102 people with a documented history of asbestos exposure, seen at Hyogo College of Medicine Hospital from 2000 to 2007. Of these, 62 had malignant pleural mesothelioma and 40 did not (25 with pleural plaques and/or asbestosis, 15 with no asbestos-related lesions). Mean Ang-1 was 44.4 ng/mL in the mesothelioma patients and 28.5 ng/mL in the group without mesothelioma (p less than 0.0001). At a cut-off of 34.5 ng/mL, the test had 71.0% sensitivity and 77.5% specificity. Levels tended to be higher at more advanced stages. Among 50 mesothelioma patients analysed for survival, a level of 34.5 ng/mL or higher was linked to shorter survival (hazard ratio 3.43, 95% CI 1.08 to 10.87). The authors suggested Ang-1 could be a useful prognostic marker. They noted that its diagnostic sensitivity was not high.

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: Laboratory study of human mesothelioma cell lines (in vitro) and a mouse xenograft model, combined with a clinical study comparing serum Ang-1 levels between patient groups, with survival analysis (Kaplan-Meier and Cox regression)
• Who was studied: 102 patients with a documented asbestos exposure history admitted to the Dept of Respiratory Medicine of Hyogo College of Medicine Hospital, Japan, 2000 to 2007. Of these, 62 had malignant pleural mesothelioma and 40 did not: 25 had pleural plaques and/or asbestosis and 15 had no asbestos-related lesions. Samples from 11 patients with lung cancer with malignant pleuritis and five healthy volunteers were also studied. The laboratory work used four human mesothelioma cell lines, one human mesothelial cell line, and SCID mice.
• Exposure: All patients had a documented history of asbestos exposure. Fiber types, jobs and doses were not described. The laboratory exposure was recombinant human Ang-1 at 1 to 100 ng/mL added to cell cultures.
• Main results:
  • In cell culture, Ang-1 stimulated the growth of MSTO-211H and H2452 mesothelioma cells in a dose-dependent manner. At 100 ng/mL the increase was 1.3-fold and 1.1-fold respectively. Ang-1 did not affect the growth of H2052 or H28 cells or the normal mesothelial cell line MeT-5A.
  • Ang-1 increased cell migration in MSTO-211H cells (1.4-fold, p=0.002) and H2452 cells (1.3-fold, p=0.002). It had no effect on migration of MeT-5A mesothelial cells.
  • Mean serum Ang-1 was significantly higher in the 62 mesothelioma patients (44.4 plus or minus 16.1 ng/mL) than in the 40 asbestos-exposed people without mesothelioma (28.5 plus or minus 10.7 ng/mL), p less than 0.0001.
  • For distinguishing mesothelioma patients from asbestos-exposed people without mesothelioma, the area under the ROC curve was 0.7974 (95% CI 0.7261 to 0.8687). At a cut-off of 34.5 ng/mL, sensitivity was 71.0% and specificity was 77.5%. The positive predictive value was 83.0% and the negative predictive value was 63.3%.
  • Serum Ang-1 in the 11 patients with lung cancer with malignant pleuritis (31.9 plus or minus 9.1 ng/mL) was lower than in mesothelioma patients (p=0.0088).
  • Among mesothelioma patients, serum Ang-1 tended to rise with stage: stage I 35.7, stage II 36.1, stage III 40.2 and stage IV 49.3 ng/mL (p=0.049). The authors noted that only stage IV had potentially significantly higher values.
  • Overall survival differed significantly (p=0.029) between mesothelioma patients with serum Ang-1 below 34.5 ng/mL (13 patients) and those at or above that level (37 patients).
  • In Cox regression on 50 mesothelioma patients, serum Ang-1 of 34.5 ng/mL or higher versus below 34.5 had an independent, statistically significant effect on survival (HR 3.43, 95% CI 1.08 to 10.87, p=0.036). Age 65 or older (HR 2.63, 95% CI 1.04 to 6.68) and pemetrexed-based chemotherapy (HR 0.38, 95% CI 0.15 to 0.941) also had significant effects.
  • There were no significant differences in Ang-1 levels between subjects with benign asbestos-related diseases and asbestos-exposed subjects who were healthy.
• The authors' conclusion: The authors proposed that Ang-1 may play a role in mesothelioma tumour growth. They suggested that serum Ang-1 could be a useful prognostic factor and could support the diagnosis of mesothelioma.
• Limitations the authors state:
  • The authors stated that the diagnostic sensitivity of serum Ang-1 for mesothelioma was not high (71.0%).
  • The authors stated that the precise cellular mechanism by which Ang-1 might affect mesothelioma growth was not fully investigated.
  • The authors noted that only stage IV mesothelioma had potentially significantly higher Ang-1 values.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Pulmonary Fibrosis, Fibroblast.

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• Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma — N. Hirayama, C. Tabata, et al. (2011)
• Third-line chemotherapy with carboplatin, gemcitabine and liposomised doxorubicin for malignant pleural mesothelioma — V.A. de Lima, J.B. Sørensen (2015)

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