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Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis


Sidi, R; Pasello, G; Opitz, I; Soltermann, A; Tutic, M; Rehrauer, H; Weder, W; Stahel, R A; Felley-Bosco, E (2011). Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis. European Journal of Cancer, 47(2):326-332.

Abstract

The aim of this study was to assess the induction of senescence markers versus apoptosis pathways in malignant pleural mesothelioma (MPM) tumour samples before and after neo-adjuvant platinum-based chemotherapy and to investigate their relationship with clinical outcome. Specific senescence pathways were assessed by quantifying the expression of p21 and plasminogen activator inhibitor-1 (PAI-1) for the p21-p53 pathway, IGFBP7 for the IGF pathway and ALDH1A3 for the IFN pathway. p21 and PAI-1 expression were also assessed by immunohistochemistry. In addition, beta-galactosidase activity staining at pH 6.0 was performed. Apoptosis was determined by TUNEL assay. Clinical outcome was assessed by modified RECIST criteria, progression-free and overall survival. In a training set (n=9 patients) paired comparison demonstrated a significant increase in p21 (p<0.05), PAI-1 (p<0.01) and apoptosis (p<0.01) after neo-adjuvant chemotherapy. The patients with the highest increase in PAI-1 had stable disease, whilst patients with little change in senescence markers accompanied by a high increase in apoptosis had an objective response after chemotherapy. The hypothesis that stable disease might be associated with an increase in senescence markers was confirmed in a tissue microarray (n=26 patients) using p21 and PAI-1 immunohistochemistry as readouts. For patients where survival and time to progression data were available, increased PAI-1 levels were significantly associated with a worst outcome. Our results demonstrate induction of senescence markers by neo-adjuvant chemotherapy in a proportion of patients with MPM and its potential association with a poor outcome.

Abstract

The aim of this study was to assess the induction of senescence markers versus apoptosis pathways in malignant pleural mesothelioma (MPM) tumour samples before and after neo-adjuvant platinum-based chemotherapy and to investigate their relationship with clinical outcome. Specific senescence pathways were assessed by quantifying the expression of p21 and plasminogen activator inhibitor-1 (PAI-1) for the p21-p53 pathway, IGFBP7 for the IGF pathway and ALDH1A3 for the IFN pathway. p21 and PAI-1 expression were also assessed by immunohistochemistry. In addition, beta-galactosidase activity staining at pH 6.0 was performed. Apoptosis was determined by TUNEL assay. Clinical outcome was assessed by modified RECIST criteria, progression-free and overall survival. In a training set (n=9 patients) paired comparison demonstrated a significant increase in p21 (p<0.05), PAI-1 (p<0.01) and apoptosis (p<0.01) after neo-adjuvant chemotherapy. The patients with the highest increase in PAI-1 had stable disease, whilst patients with little change in senescence markers accompanied by a high increase in apoptosis had an objective response after chemotherapy. The hypothesis that stable disease might be associated with an increase in senescence markers was confirmed in a tissue microarray (n=26 patients) using p21 and PAI-1 immunohistochemistry as readouts. For patients where survival and time to progression data were available, increased PAI-1 levels were significantly associated with a worst outcome. Our results demonstrate induction of senescence markers by neo-adjuvant chemotherapy in a proportion of patients with MPM and its potential association with a poor outcome.

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17 citations in Web of Science®
18 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:27 Jan 2011 19:22
Last Modified:05 Apr 2016 14:39
Publisher:Elsevier
ISSN:0959-8049
Publisher DOI:https://doi.org/10.1016/j.ejca.2010.09.044
PubMed ID:21036600

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