title: Progression of human bronchioloalveolar carcinoma to invasive adenocarcinoma is modeled in a transgenic mouse model of K-ras-induced lung cancer by loss of the TGF-β type II receptor.
abstract: Clinical investigations have suggested that repression of the TGF-β type II receptor (TβRII) may be an important step in progression of lung adenocarcinoma from an indolent in situ state to a frank invasive carcinoma. To test this hypothesis, we compared the effects of deleting the murine homolog of this receptor (Tgfbr2) in a mouse model of mutant K-ras-induced lung carcinoma, which normally induces the formation of multifocal tumors of low invasive potential. In this model, loss of Tgfbr2 induced a highly invasive phenotype associated with lymph node metastasis and reduced survival. Tumor-associated stromal cells displayed an immunosuppressive profile marked by increased numbers of B and T cells. Moreover, tumor stromal cell profiling revealed a developmental TGF-β response profile that associated with a collagenized extracellular matrix and increased invasion of TGF-β nonresponsive tumor cells. Together, these results suggest that our KrasTgfbr2(-/-) mouse model of invasive lung carcinoma mirrors the genomic response and clinical progression of human lung adenocarcinoma, recapitulating changes in lung stromal pathways that occur in the tumor microenvironment during malignant progression in this disease.
authors.affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Borczuk
authors.forename: Marieta
authors.initials: M
authors.lastname: Sole
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Jinli
authors.initials: J
authors.lastname: Chen
authors.forename: May-Lin
authors.initials: ML
authors.lastname: Wilgus
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Charles A
authors.initials: CA
authors.lastname: Powell
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008207:Lymphatic Metastasis; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II