Lung adenocarcinoma global profiling identifies type II transforming growth factor-beta receptor as a repressor of invasiveness.
BACKGROUND
Lung adenocarcinoma histology and clinical outcome are heterogeneous and associated with tumor invasiveness.


OBJECTIVE
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.


RESULTS
Microarray analysis of microdissected noninvasive bronchioloalveolar carcinoma (BAC) and invasive adenocarcinoma and adenocarcinoma-mixed type with BAC features identified transcriptional profiles of lung adenocarcinoma invasiveness. Among the signature set that was lower in adenocarcinoma-mixed compared with BAC was the type II transforming growth factor beta (TGF-beta) receptor, suggesting downregulation of TGFbetaRII is an early event in lung adenocarcinoma metastasis. Immunostaining in independently acquired specimens demonstrated a correlation between TbetaRII expression and length of tumor invasion. Repression of TGFbetaRII in lung cancer cells increased tumor cell invasiveness and activated p38 mitogen-activated protein kinases. Microarray analysis of invasive cells identified potential downstream mediators of TGFbetaRII with differential expression in lung adenocarcinomas.


CONCLUSIONS
The repression of type II TGF-beta receptor may act as a significant determinant of lung adenocarcinoma invasiveness, an early step in tumor progression toward metastasis.
Borczuk
Alain C
AC
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Kim
Han K
HK
Yegen
Hilary A
HA
Friedman
Richard A
RA
Powell
Charles A
CA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II