A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma

Our plain-English summary of A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma, by B.T.V. Duong, L. Wu, B.J. Green, et al (EBioMedicine, 2020).

The study

• Authors: B.T.V. Duong, L. Wu, B.J. Green, F. Bavaghar-Zaeimi, Z. Wang, M. Labib, Y. Zhou, F.J.P. Cantu, T. Jeganathan, S. Popescu, J. Pantea, M. de Perrot, S.O. Kelley
• Journal: EBioMedicine
• Published: 2020;61:103031
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer related to asbestos exposure. Early diagnosis is challenging due to generic symptoms and a lack of biomarkers. We previously demonstrated that mesothelial precursor cells (MPC) characterized by mesothelin (MSLN)+CD90+CD34+ could be implicated in the development of mesothelioma after asbestos exposure. Here, we aimed to determine the clinical significance of detecting MPC in blood for early-stage diagnosis and prognosis of mesothelioma.

Methods: Due to the rarity of MPC in blood, it is challenging to identify this cell population using conventional techniques. Hence, we have developed a microfluidic liquid biopsy platform called MesoFind that utilizes an immunomagnetic, mesothelin capture strategy coupled with immunofluorescence to identify rare populations of cells at high sensitivity and precision. To validate our technique, we compared this approach to flow cytometry for the detection of MPC in murine blood and lavage samples. Upon successful validation of the murine samples, we then proceeded to examine circulating MPC in 23 patients with MPM, 23 asbestos-exposed individuals (ASB), and 10 healthy donors (HD) to evaluate their prognostic and diagnostic value.

Finding: MPC were successfully detected in the blood of murine samples using MesoFind but were undetectable with flow cytometry. Circulating MPC were significantly higher in patients with epithelioid MPM compared to HD and ASB. The MPC subpopulation, MSLN+ and CD90+, were upregulated in ASB compared to HD suggesting an early role in pleural damage from asbestos. The MPC subpopulation, MSLN+ and CD34+, in contrast, were detected in advanced MPM and associated with markers of poor prognosis, suggesting a predominant role during cancer progression.

Interpretation: The identification of circulating MPC presents an attractive solution for screening and early diagnosis of epithelioid mesothelioma. The presence of different subtypes of MPC have a prognostic value that could be of assistance with clinical decisions in patients with MPM.

Funding: Princess Margaret Hospital Foundation Mesothelioma Research Fund, Toronto General & Western Hospital Foundation.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

In plain English

This Toronto study described a new blood test called MesoFind. It is a microfluidic chip that captures mesothelin-carrying cells so 'mesothelial precursor cells' (MPC) and their subtypes can be counted. In mice injected with mesothelioma cells, the chip detected MPC in blood; standard flow cytometry did not. The authors tested blood from 23 patients with malignant pleural mesothelioma, 23 asbestos-exposed people and 10 healthy donors with no known exposure. Average MPC counts in 0.5 mL of blood were 262, 537 and 1664 for healthy donors, exposed people and patients respectively, with standard errors of 43, 137 and 360. One MPC subtype separated exposed people from patients with 81% sensitivity and 70% specificity. Another subtype was higher in exposed people than in healthy donors. Links with PET scan values (p = 0.16) and with whether the tumor could be removed by surgery (p = 0.38) were not statistically significant. The authors concluded that certain MPC subtypes have excellent predictive values for diagnosis and prognosis, and called for prospective studies. They noted that other causes of pleural inflammation were not studied and could give false positives.

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: Development and validation of a microfluidic blood test (MesoFind), first in a mouse model and then in a comparison of clinical blood samples from three groups of people
• Who was studied: 56 people recruited at Princess Margaret Cancer Centre, Toronto: 10 healthy volunteers with no known asbestos exposure, 23 asbestos-exposed individuals recruited from a low-dose CT screening program, and 23 patients with histologically confirmed malignant pleural mesothelioma recruited from a mesothelioma clinic during evaluation for surgery. Mice injected intraperitoneally with RN5 mouse mesothelioma cells or saline were also studied. Dates of recruitment are not given.
• Exposure: Asbestos-exposed individuals had to be over 30 years old and have had asbestos exposure at least 20 years earlier and/or documented pleural plaques on x-ray. Table 2 lists exposure as direct or indirect. The type of asbestos is listed as unknown for most people, with one listed as 'Amphiboles & Chrysotile' and one as 'Chrysotile'. The mice were injected with mesothelioma cells, not asbestos.
• Main results:
  • In mice, MesoFind detected MPC in blood, while flow cytometry detected none in blood samples.
  • Average MPC counts in 0.5 mL of blood (mean with standard error) were 262 plus or minus 43 for healthy donors, 537 plus or minus 137 for asbestos-exposed individuals, and 1664 plus or minus 360 for mesothelioma patients.
  • The MSLN+ CD90- CD34+ CD45- subtype best separated asbestos-exposed individuals (n=23) from mesothelioma patients (n=23), with a clinical sensitivity of 81% and specificity of 70%.
  • The MSLN+ CD90+ CD34- CD45- subtype showed a greater mesothelin level in asbestos-exposed individuals than in healthy donors.
  • Among patients, the MSLN+ CD90+ CD45- subtype distinguished epithelioid (n=16) from biphasic (n=5) mesothelioma with a sensitivity of 95% and specificity of 80% (cut-off value 2650).
  • Between patients with low and high PET scan uptake values (4 and 4 patients), the difference in the MSLN+ CD34+ CD45- subtype was not statistically significant at the usual level (p = 0.16).
  • For telling resectable tumors (n=4) from unresectable tumors (n=19), the MSLN+ CD90+ CD34- CD45- subtype had 100% sensitivity but only 50% specificity. The difference between the groups was not significant (p = 0.38).
  • The MSLN+ CD34+ CD45- subtype differed significantly between patients with lymph node metastasis (n=3) and without it (n=13), with a sensitivity of 67% and specificity of 100% (cut-off value 24500).
• The authors' conclusion: The authors concluded that specific MPC subtypes have excellent predictive values for clinical diagnosis and prognosis of mesothelioma. They added that further investigation and prospective studies are needed before the test could be used clinically.
• Limitations the authors state:
  • Other causes of pleural inflammation, such as pleural infection and pleurodesis, were not included and could produce false positive MPC counts.
  • PET scan data were available for only 8 patients.
  • The number of patients who underwent surgery was small.
  • The authors stated that prospective studies following patients through disease development and treatment are needed.

Topics

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

Medical terms in this study, explained in our Lexicon: Liquid Biopsy, Biomarker, Prognosis, Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Mesothelin, CD34.

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