期刊
EUROPEAN JOURNAL OF CANCER
卷 47, 期 2, 页码 326-332出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2010.09.044
关键词
Malignant pleural mesothelioma; DNA-damaging chemotherapy; Accelerated senescence; Senescence markers; PAI-1; Apoptosis; Clinical outcome
类别
资金
- Oncosuisse
- Zurich Krebsliga
- Stiftung fur angewandte Krebsforschung Zurich
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), PM-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. (C) 2010 Elsevier Ltd. All rights reserved.
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