Published ahead of print on June 23, 2005, doi:10.1164/rccm.200504-615OC
Am. J. Respir. Crit. Care Med., Volume 172, Number 6, September 2005, 729-737
A more recent version of this article appeared on September 15, 2005
Submitted on April 19, 2005
Accepted on June 13, 2005
Lung Adenocarcinoma Global Profiling Identifies Type II TGF- Receptor as a Repressor of Invasiveness
Alain C Borczuk1, Han K Kim2, Hilary A Yegen2, Richard A Friedman3, and Charles A Powell4*
1 Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA,
2 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA,
3 Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, New York, NY, USA,
4 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, New York, NY, USA
* To whom correspondence should be addressed. E-mail: cap6{at}columbia.edu.
Rationale: Lung adenocarcinoma histology and clinical outcome are heterogeneous and associated with tumor invasiveness. Objectives: We hypothesized that invasiveness is associated with a distinct molecular signature and that genes differentially expressed in tumor or adjacent stroma will identify cell surface signal transduction and matrix remodeling pathways associated with the acquisition of invasiveness in lung adenocarcinoma. Main Results: Microarray analysis of microdissected non-invasive bronchioloalveolar carcinoma (BAC) and invasive AC and AC-mixed type with BAC features (AC-mixed) identified transcriptional profiles of lung adenocarcinoma invasiveness. Among the signature set that was lower in AC-mixed compared with BAC was the type II TGF- receptor, suggesting downregulation of TGFRII is an early event in lung adenocarcinoma metastasis. Immunostaining in independently acquired specimens demonstrated a correlation between TRII expression and length of tumor invasion. Repression of TGFRII in lung cancer cells increased tumor cell invasiveness and activated p38MAPK. Microarray analysis of invasive cells identified potential downstream mediators of TGFRII with differential expression in lung adenocarcinomas. Conclusions: The repression of type II TGF- receptor may act as a significant determinant of lung adenocarcinoma invasiveness, an early step in tumor progression towards metastasis.
Key words: lung cancer,adenocarcinoma,neoplasm invasiveness,microarray analysis,
Transforming growth factor-beta
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