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 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.
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 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.
Authors: Rafael A Irizarry; Benjamin M Bolstad; Francois Collin; Leslie M Cope; Bridget Hobbs; Terence P Speed Journal: Nucleic Acids Res Date: 2003-02-15 Impact factor: 16.971
Authors: Christopher J Moran; Douglas A Arenberg; Chiang-Ching Huang; Thomas J Giordano; Dafydd G Thomas; David E Misek; Guoan Chen; Mark D Iannettoni; Mark B Orringer; Samir Hanash; David G Beer Journal: Clin Cancer Res Date: 2002-12 Impact factor: 12.531
Authors: Elina Azenshtein; Galia Luboshits; Sima Shina; Eran Neumark; David Shahbazian; Miguel Weil; Nely Wigler; Iafa Keydar; Adit Ben-Baruch Journal: Cancer Res Date: 2002-02-15 Impact factor: 12.701
Authors: Rebecca S Muraoka; Nancy Dumont; Christoph A Ritter; Teresa C Dugger; Dana M Brantley; Jin Chen; Evangeline Easterly; L Renee Roebuck; Sarah Ryan; Philip J Gotwals; Victor Koteliansky; Carlos L Arteaga Journal: J Clin Invest Date: 2002-06 Impact factor: 14.808
Authors: Chi-Ming Li; Meirong Guo; Alain Borczuk; Charles A Powell; Michelle Wei; Harshwardhan M Thaker; Richard Friedman; Ulf Klein; Benjamin Tycko Journal: Am J Pathol Date: 2002-06 Impact factor: 4.307
Authors: David G Beer; Sharon L R Kardia; Chiang-Ching Huang; Thomas J Giordano; Albert M Levin; David E Misek; Lin Lin; Guoan Chen; Tarek G Gharib; Dafydd G Thomas; Michelle L Lizyness; Rork Kuick; Satoru Hayasaka; Jeremy M G Taylor; Mark D Iannettoni; Mark B Orringer; Samir Hanash Journal: Nat Med Date: 2002-07-15 Impact factor: 53.440
Authors: Dawn A Kirschmann; Elisabeth A Seftor; Sheri F T Fong; Daniel R C Nieva; Colleen M Sullivan; Elijah M Edwards; Pascal Sommer; Katalin Csiszar; Mary J C Hendrix Journal: Cancer Res Date: 2002-08-01 Impact factor: 12.701
Authors: Binwu Tang; Mary Vu; Timberly Booker; Steven J Santner; Fred R Miller; Miriam R Anver; Lalage M Wakefield Journal: J Clin Invest Date: 2003-10 Impact factor: 14.808
Authors: Sanjib Chowdhury; Gillian M Howell; Carol A Teggart; Aparajita Chowdhury; Jonathan J Person; Dawn M Bowers; Michael G Brattain Journal: J Biol Chem Date: 2011-07-08 Impact factor: 5.157
Authors: Alain C Borczuk; Marieta Sole; Ping Lu; Jinli Chen; May-Lin Wilgus; Richard A Friedman; Steven M Albelda; Charles A Powell Journal: Cancer Res Date: 2011-09-12 Impact factor: 12.701
Authors: Ignacio I Wistuba; Humam Kadara; Mohamed Kabbout; Melinda M Garcia; Junya Fujimoto; Diane D Liu; Denise Woods; Chi-Wan Chow; Gabriela Mendoza; Amin A Momin; Brian P James; Luisa Solis; Carmen Behrens; J Jack Lee Journal: Clin Cancer Res Date: 2013-05-09 Impact factor: 12.531