The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma

Our plain-English summary of The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma, by L.E. Dalton, H.J. Clarke, J. Knight, et al (British Journal of Cancer, 2013).

The study

• Authors: L.E. Dalton, H.J. Clarke, J. Knight, M.H. Lawson, J. Wason, D.A. Lomas, W.J. Howat, R.C. Rintoul, D.M. Rassl, S.J. Marciniak
• Journal: British Journal of Cancer
• Published: 2013;108(6):1340-7
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer.

Method: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters.

Results: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas.

Conclusion: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.

In plain English

The study examined stored biopsy tissue from 135 people diagnosed with malignant mesothelioma at Papworth Hospital, UK, between 2005 and 2010. Of these, 84 had tumour tissue in the small tissue cores taken for testing. Most were male (80.7%), and 69.6% had a history of asbestos exposure; fiber types were not described. The authors stained the tumours for three proteins linked to endoplasmic reticulum (ER) stress, a stress response inside cells: CHOP, GADD34 and BiP. Patients whose tumours stained most strongly for CHOP had a median survival of 145 days, against 486 days for the rest (P = 0.002). Tested in pairs with each other factor (tumour type, smoking, performance status, chemotherapy and a standard prognostic score), CHOP still predicted survival. A model weighing several together, in 46 patients, kept only CHOP and performance status, a measure of daily functioning. GADD34 staining was stronger in epithelioid than in biphasic or sarcomatoid tumours, but did not independently predict survival. The authors concluded that CHOP may be a useful marker of tumour aggressiveness. They noted the GADD34 result might reflect limited statistical power.

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: Retrospective study of archived biopsy tissue blocks, stained for ER stress markers on a tissue microarray, with survival analysis using hospital records
• Who was studied: 135 cases of malignant mesothelioma biopsied at Papworth Hospital, Cambridge, UK, between 2005 and 2010. 84 had tumour tissue on at least one level of the tissue microarray; where cores lacked tumour cells, the original material had come from CT-guided needle biopsies. Patients were 80.7% male, median age 70 years at diagnosis, and 74.1% had epithelioid, 16.3% biphasic and 9.6% sarcomatoid tumours. Clinical data were complete to August 2012.
• Exposure: The study measured tumour staining for the ER stress proteins CHOP, GADD34 and BiP. It did not study asbestos as an exposure, but recorded that 94 of 135 patients (69.6%) had a history of asbestos exposure. No fiber types, products, jobs or doses are given.
• Main results:
  • Among the three markers, only CHOP score groups (quintiles) were associated with survival (P = 0.005).
  • Patients in the highest CHOP-staining group had a median survival of 145 days, against 486 days for the rest of the cohort (P = 0.002).
  • When patients were divided by stage, the CHOP survival difference remained statistically significant for early-stage (stage I and II) disease. The figure shows it was not significant for stages III and IV.
  • Cox regression models paired CHOP score with one other factor at a time (Table 3). In each pairing, CHOP score remained a significant predictor of survival.
  • A forward stepwise model considered CHOP score, performance status, histology, smoking and EORTC prognostic score together. It kept only CHOP score (HR 0.332, P = 0.014) and performance status (HR 2.501, P = 0.000), based on 46 patients.
  • Adding CHOP score to other prognostic factors significantly improved prediction only for radiological staging. For CT stage I to III vs IV, the C-statistic rose from 0.608 to 0.797, a difference of 0.188 (P = 0.011). Other improvements were not statistically significant.
  • GADD34 staining correlated with mesothelial differentiation (Spearman's correlation coefficient 0.513). Staining was stronger in epithelioid tumours than in biphasic tumours (P less than 0.001) or sarcomatoid tumours (P less than 0.005).
  • CHOP staining showed a weak inverse correlation with mesothelial differentiation.
  • GADD34 was not an independent predictor of survival in this study.
• The authors' conclusion: The authors concluded that CHOP may be a useful biomarker of tumour aggressiveness that could help in grouping patients. They suggested that the link between GADD34 and mesothelial differentiation may help in classifying borderline histological cases.
• Limitations the authors state:
  • The authors said the lack of an independent GADD34 survival effect may reflect a lack of statistical power.
  • Because mesothelioma is rare, the cohort could not be split into discovery and validation sets. A possible poor-prognosis group with low GADD34 staining therefore remains speculative and needs validation.
  • The antibody used would not detect a truncated form of GADD34 that the authors discuss, and they did not try to detect it.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells, Pericardial, Glycoprotein, Performance Status, Biphasic Mesothelioma, Sarcomatoid, Histopathology.

Related studies

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• Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death — S. Nozaki, G.W. Sledge, et al. (2001)
• (-)- Epigallocatechin-3-gallate induces GRP78 accumulation in the ER and shifts mesothelioma constitutive UPR into proapoptotic ER stress — S. Martinotti, E. Ranzato, et al. (2018)
• Asbestos-induced disruption of calcium homeostasis induces endoplasmic reticulum stress in macrophages — A.J. Ryan, J.L. Larson-Casey, et al. (2014)
• Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma — D. Xu, S.Q. Liang, et al. (2018)
• Antitumoral effects of Bortezomib in malignant mesothelioma: evidence of mild endoplasmic reticulum stress in vitro and activation of T cell response in vivo — M. Benvenuto, V. Angiolini, et al. (2023)

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