An in vivo platform for tumor biomarker assessment

Our plain-English summary of An in vivo platform for tumor biomarker assessment, by E.L. Servais, K. Suzuki, C. Colovos, et al (PloS One, 2011).

The study

• Authors: E.L. Servais, K. Suzuki, C. Colovos, L. Rodriguez, C. Sima, M. Fleisher, V.W. Rusch, M. Sadelain, P.S. Adusumilli
• Journal: PloS One
• Published: 2011;6(10):e26722
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers--serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response--a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.

In plain English

This laboratory study in mice did not study asbestos exposure. The authors implanted human malignant pleural mesothelioma cells (MSTO-211H), engineered to express human mesothelin and GFP-luciferase, in the chest lining of immunodeficient mice and tracked tumors by bioluminescence imaging and MRI. In 14 mice, imaging signal matched MRI tumor volume (r = 0.86). Blood levels of soluble mesothelin-related peptide (SMRP) rose with tumor growth, correlating with imaging signal (r = 0.92) and MRI volume (r = 0.87). Osteopontin (OPN) did not track tumor burden. During chemoradiation cycles (days 0 to 11), SMRP rose more slowly than in untreated controls (slope 0.04 versus 0.21). Elevated SMRP was associated with higher risk of death (hazard ratio 4.5, 95% CI 1.53 to 13.1). Response meant less than a twofold rise in imaging signal, and tumors still grew in all standard-treatment groups. SMRP rose 10-fold in responders and 17-fold in non-responders. Mice with a below-median SMRP increase survived longer. With an experimental MPM-targeted T-cell therapy versus control, response was associated with SMRP change (0.62-fold decrease versus 11-fold increase). The authors concluded that serum SMRP, but not OPN, was a sensitive disease biomarker in this model.

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: orthotopic (intrapleural) mouse model of human malignant pleural mesothelioma, with imaging and serum biomarker measurements
• Who was studied: Female SCID/beige and male athymic nude mice, 6 to 10 weeks old, from Taconic Farms, NY. The imaging correlation used 14 mice. The total number of mice is not stated.
• Exposure: No asbestos exposure was studied. The mice were injected intrapleurally with the human MPM cell line MSTO-211H, engineered to express GFP-luciferase and human mesothelin. Treatment groups received cisplatin (4 mg/kg IP weekly), isolated thoracic radiation (20 Gy total in 5 fractions), combination chemoradiation, or no treatment. A separate experiment used an experimental targeted T-cell therapy.
• Main results:
  • Bioluminescence signal correlated with pleural tumor volume measured by MRI (r = 0.86) in a group of 14 mice.
  • Serum SMRP correlated with bioluminescence signal (r = 0.92) and with MRI tumor volume (r = 0.87).
  • Serum OPN levels did not correlate with tumor burden or with SMRP level, so later experiments evaluated only SMRP.
  • During chemoradiation treatment cycles (days 0 to 11), SMRP still increased, but the rate of increase was lower than in controls (slope 0.04 versus 0.21 for controls; Wilcoxon test, p = 0.01).
  • Elevated serum SMRP was associated with an increased risk of death (hazard ratio 4.5, 95% CI 1.53 to 13.1).
  • Response to therapy was defined as less than a 2-fold increase in bioluminescence signal over the treatment period. All standard-treatment groups still had growing tumors.
  • After standard treatment, the increase in SMRP was lower in mice that responded to therapy than in non-responders (10-fold versus 17-fold increase, p = 0.009).
  • Mice with a lower percent increase in SMRP (less than the group median) had improved survival compared with mice with a higher increase (p less than 0.001).
  • With MPM-targeted T-cell therapy versus control, treatment response (same definition) was associated with the percentage change in SMRP (0.62-fold decrease versus 11-fold increase, p = 0.002).
  • All treatment groups had growing tumors despite standard therapy, so 'response' was a relative category.
• The authors' conclusion: The authors concluded that the orthotopic mouse model allows accurate quantitative imaging, and that serum SMRP, but not OPN, is a sensitive biomarker of disease in MPM, paralleling published clinical observations.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Histopathology, Mesothelin, Soluble Mesothelin-Related Peptides (SMRP), Osteopontin.

Related studies

• Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma — K. Shiomi, Y. Hagiwara, et al. (2008)
• Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos — M. Gube, D. Taeger, et al. (2011)
• Serum and pleural fluid biomarkers for mesothelioma — J. Creaney, B.W. Robinson (2009)
• Hyaluronan and N-ERC/mesothelin as key biomarkers in a specific two-step model to predict pleural malignant mesothelioma — F. Mundt, G. Nilsonne, et al. (2013)
• Serum biomarkers in patients with mesothelioma and pleural plaques and healthy subjects exposed to naturally occurring asbestos — M. Bayram, I. Dongel, et al. (2014)
• A liquid biopsy for detecting circulating mesothelial precursor cells: A new biomarker for diagnosis and prognosis in mesothelioma — B.T.V. Duong, L. Wu, et al. (2020)

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