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Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2014 Feb 15; Vol. 20 (4), pp. 1020-8. Date of Electronic Publication: 2013 Dec 13. - Publication Year :
- 2014
-
Abstract
- Purpose: In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biologic and clinical relevance.<br />Experimental Design: In a training and validation set of patients with early-stage (I-III) lung ADC (n = 1,209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models.<br />Results: MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS [HR = 1.78; 95% confidence interval (CI), 1.26-2.50; P < 0.01] and RFS (HR = 1.67; 95% CI, 1.21-2.27; P < 0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P = 0.001).<br />Conclusions: MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.<br /> (©2013 AACR)
- Subjects :
- Adenocarcinoma mortality
Adenocarcinoma pathology
Adenocarcinoma of Lung
Aged
Animals
Biomarkers, Tumor genetics
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease-Free Survival
Female
GPI-Linked Proteins genetics
Gene Expression
Humans
Kaplan-Meier Estimate
Lung Neoplasms mortality
Lung Neoplasms pathology
Male
Mesothelin
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Neoplasm Invasiveness
Neoplasm Transplantation
Adenocarcinoma metabolism
Biomarkers, Tumor metabolism
GPI-Linked Proteins metabolism
Lung Neoplasms metabolism
Neoplasm Recurrence, Local metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 20
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 24334761
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-13-1862