Lung adenocarcinoma global profiling identifies type II transforming growth factor-β receptor as a repressor of invasiveness

Alain C. Borczuk, Han K. Kim, Hilary A. Yegen, Richard A. Friedman, Charles A. Powell

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

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 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 β (TGF-β) receptor, suggesting downregulation of TGFβRII is an early event in lung adenocarcinoma metastasis. Immunostaining in independently acquired specimens demonstrated a correlation between TβRII expression and length of tumor invasion. Repression of TGFβRII in lung cancer cells increased tumor cell invasiveness and activated p38 mitogen-activated protein kinases. Microarray analysis of invasive cells identified potential down-stream mediators of TGFβRII with differential expression in lung adenocarcinomas. Conclusions: The repression of type II TGF-β receptor may act as a significant determinant of lung adenocarcinoma invasiveness, an early step in tumor progression toward metastasis.

Original languageEnglish
Pages (from-to)729-737
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume172
Issue number6
DOIs
StatePublished - 15 Sep 2005
Externally publishedYes

Keywords

  • Adenocarcinoma
  • Lung cancer
  • Microarray analysis
  • Neoplasm invasiveness
  • Transforming growth factor-β

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