Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma Journal Article
| Authors: | Kachala, S. S.; Bograd, A. J.; Villena-Vargas, J.; Suzuki, K.; Servais, E. L.; Kadota, K.; Chou, J.; Sima, C. S.; Vertes, E.; Rusch, V. W.; Travis, W. D.; Sadelain, M.; Adusumilli, P. S. |
| Article Title: | Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma |
| 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. 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. 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). 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. © 2014 American Association for Cancer Research. |
| Keywords: | human tissue; protein expression; aged; gene mutation; major clinical study; overall survival; cancer recurrence; cancer risk; nonhuman; validation process; cancer staging; cell proliferation; mouse; animal tissue; disease association; animal experiment; animal model; smoking; in vivo study; in vitro study; tumor xenograft; tumor marker; lung adenocarcinoma; cell migration; tumor model; metastasis potential; tissue microarray; tumor growth; gender; mesothelin; recurrence free survival; disease activity; tumor invasion; isograft; cancer prognosis; human; male; female; priority journal; article |
| Journal Title: | Clinical Cancer Research |
| Volume: | 20 |
| Issue: | 4 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-02-15 |
| Start Page: | 1020 |
| End Page: | 1028 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-13-1862 |
| PROVIDER: | scopus |
| PMCID: | PMC3944669 |
| PUBMED: | 24334761 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2014 -- CODEN: CCREF -- Source: Scopus |
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