The "don't eat me" signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma

Our plain-English summary of The "don't eat me" signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma, by C.M. Schürch, S. Forster, F. Brühl, et al (Oncoimmunology, 2017).

The study

• Authors: C.M. Schürch, S. Forster, F. Brühl, S.H. Yang, E. Felley-Bosco, E. Hewer
• Journal: Oncoimmunology
• Published: 2017;7(1):e1373235
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Diffuse malignant mesothelioma (DMM) is one of the prognostically most discouraging cancers with median survivals of only 12-22 months. Due to its insidious onset and delayed detection, DMM is often at an advanced stage at diagnosis and is considered incurable. Combined chemo- and radiotherapy followed by surgery only marginally affect outcome at the cost of significant morbidity. Because of the long time period between exposure to asbestos and disease onset, the incidence of DMM is still rising and predicted to peak around 2020. Novel markers for the reliable diagnosis of DMM in body cavity effusion specimens as well as more effective, targeted therapies are urgently needed. Here, we show that the "don't eat me" signalling molecule CD47, which inhibits phagocytosis by binding to signal regulatory protein α on macrophages, is overexpressed in DMM cells. A two-marker panel of high CD47 expression and BRCA1-associated protein 1 (BAP-1) deficiency had a sensitivity of 78% and specificity of 100% in discriminating DMM tumour cells from reactive mesothelial cells in effusions, which is superior to the currently used four-marker combination of BAP-1, glucose transporter type 1, epithelial membrane antigen and desmin. In addition, blocking CD47 inhibited growth and promoted phagocytosis of DMM cell lines by macrophages in vitro. Furthermore, DMM tumours in surgical specimens from patients as well as in a mouse DMM model expressed high levels of CD47 and were heavily infiltrated by macrophages. Our study demonstrates that CD47 is an accurate novel diagnostic DMM biomarker and that blocking CD47 may represent a promising therapeutic strategy for DMM.

In plain English

This laboratory and diagnostic study from the University of Bern asked whether the cell-surface protein CD47 could help tell diffuse malignant mesothelioma (DMM) apart from benign reactive mesothelial cells in fluid (effusions) from the chest or abdomen, and whether blocking CD47 could act against the cancer. It did not examine asbestos exposure. In archived effusion samples collected from 2010 to 2014, high CD47 staining was found in 24/38 (63%) DMM samples and in none of 87 benign samples. Combining high CD47 with loss of the protein BAP-1 identified 28/36 (78%) DMM samples, with no benign samples flagged (0/87). The authors reported that this two-marker panel outperformed an established four-marker panel. In laboratory cultures, cell numbers were up to two-fold higher with a control antibody than with a CD47-blocking antibody. Blocking CD47 also gave a two-fold increase in engulfment of one mesothelioma cell line by macrophages (immune cells). Surgical tumour samples and mouse tumours expressed CD47 and contained many macrophages. Sarcomatoid tumours tended to stain only faintly. The authors concluded that CD47 is a diagnostic marker and a basis for further research into therapy. They noted that their findings mainly apply to the epithelioid subtype.

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 and diagnostic marker study: analysis of a public gene-expression dataset, immunostaining of archived effusion cell blocks and surgical specimens, experiments on mesothelioma cell lines, and a mouse mesothelioma model
• Who was studied: Archived cell blocks from pleural and peritoneal effusions collected 2010 to June 2014 at the Institute of Pathology, University of Bern, Switzerland. 45 DMM cases were included in the tissue microarray, and up to 87 to 103 benign/reactive samples were analysed depending on the marker. The study also used a public microarray dataset (40 pleural DMM, 5 normal pleura), five DMM cell lines, surgical resection specimens and mice (n=5).
• Exposure: No asbestos exposure was studied. The study measured CD47 expression and tested a CD47-blocking monoclonal antibody against an IgG control in DMM cell lines.
• Main results:
  • In the public microarray dataset, CD47 mRNA expression was significantly higher in pleural DMM than in normal pleura.
  • All 5 DMM cell lines tested showed strong surface CD47 protein.
  • In effusion cell blocks, CD47 was high in 24/38 (63%) DMM samples and low in all 87 benign samples.
  • BAP-1 was deficient in 21/37 (57%) DMM samples and in 0/103 non-neoplastic samples.
  • High CD47 and/or BAP-1 deficiency was 78% sensitive (28/36 DMM samples) and 100% specific (0/87 reactive samples).
  • The authors stated that the two-marker panel was easier to perform and showed greater sensitivity and specificity than the combination of BAP-1, EMA, GLUT-1 and desmin.
  • In culture, DMM cell numbers were up to two-fold higher with control IgG than with anti-CD47 antibody after three days.
  • Blocking CD47 gave a two-fold increase in phagocytosis of ACC-MESO-1 cells by human macrophages compared with control IgG.
  • Surgical tissue sections from all patients analysed expressed moderate to high CD47, including patients with low or negative CD47 in cytology. Sarcomatoid tumours tended to show only faint staining.
  • Mouse DMM tumours showed high CD47 and heavy macrophage infiltration.
• The authors' conclusion: The authors concluded that CD47 is a diagnostic marker for DMM and that the study provides a foundation for further research into CD47 as a therapeutic target.
• Limitations the authors state:
  • The findings mainly apply to the epithelioid subtype, because the analysis focused on cytology samples and malignant cells are usually absent from effusions of sarcomatoid DMM.
  • CD47 may be less sensitive for diagnosing sarcomatoid DMM in histological samples.
  • Calreticulin levels overlapped heavily between DMM and benign samples, limiting its diagnostic use.
  • The mechanism by which CD47 promotes tumour cell growth was not analysed.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Mesothelioma, Median Overall Survival, Phagocytosis, Macrophage, Reactive Mesothelial Hyperplasia, Epithelial Membrane Antigen (EMA), Desmin.

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