title: TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer.
abstract: Lung cancer is the most frequent and one of the most deadly cancer types and is classified into small cell lung cancer and non-small cell lung cancer (NSCLC). Transforming growth factor beta (TGFβ) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFβ signals through the complex of TGFβ type I and type II receptors, triggering Smad and non-Smad signaling pathways such as PI3K/Akt and MEK1/ERK. We investigated the role of TGFβ1 on the progression of the murine lung adenocarcinoma cell line LP07. Furthermore, we undertook a retrospective study with tissue samples from stage I and II NSCLC patients to assess the clinical pathologic role and prognostic significance of TβRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFβ1 anti-mitogenic effects and TGFβ1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFβ1 treatment was observed at the metastatic site. In our model, TGFβ1 modulated in vitro clonogenicity, protected against stress-induced apoptosis and increased adhesion, spreading, lung retention and metastatic outgrowth. PI3K and MEK1 signaling pathways were involved in TGFβ1-mediated metastasis stimulation. Several of these TGFβ responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TβRI in human lung tumors is associated with poor patient's overall survival by univariate analysis, while multivariate analysis did not reach statistical significance. Although additional detailed analysis of the endogenous signaling in vivo and in vitro is needed, these studies may provide novel molecular targets for the treatment of lung cancer.
authors.affiliation: Research Area, Institute of Oncology "Ángel H. Roffo", Av. San Martín 5481, C1417DTB, Buenos Aires, Argentina.
authors.forename: Paula Fernanda
authors.initials: PF
authors.lastname: Vázquez
authors.forename: María José
authors.initials: MJ
authors.lastname: Carlini
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Daroqui
authors.forename: Lucas
authors.initials: L
authors.lastname: Colombo
authors.forename: Mercedes Liliana
authors.initials: ML
authors.lastname: Dalurzo
authors.forename: David Eduardo
authors.initials: DE
authors.lastname: Smith
authors.forename: Julieta
authors.initials: J
authors.lastname: Grasselli
authors.forename: María Guadalupe
authors.initials: MG
authors.lastname: Pallotta
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
authors.forename: Elisa Dora
authors.initials: ED
authors.lastname: Bal de Kier Joffé
authors.forename: Lydia
authors.initials: L
authors.lastname: Puricelli
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta