title: TGF-beta receptor I conditional knockout mice develop spontaneous squamous cell carcinoma.
abstract: We generated a mouse model with a conditional deletion of TGF-beta signaling in the neurons by crossing TGF-beta receptor I (TbetaRI) floxed mice with neurofilament-H (NF-H) Cre mice. 35% of F1 conditional knockout (COKO) mice developed spontaneous squamous cell carcinomas (SCCs) in periorbital and/or perianal regions. Transplantation of these tumors into athymic nude mice resulted in 62% tumorigenicity. To determine whether evasion of the immune response plays any role in this tumorigenesis, we analyzed the expression levels of receptors for interleukin-13 (mIL-13R), a key negative regulator of tumor immunosurveillance, and found that 33% of COKO tumors expressed the IL-13R alpha2 chain. Primary cultures of the SCCs expressing IL-13R alpha2 were sensitive to the cytotoxic effect of IL-13R-directed cytotoxin treatment. This is the first demonstration that loss of TbetaRI can lead to spontaneous tumor formation. These mice can serve as a unique mouse model of SCC to evaluate the tumorigenicity and effect of anti-cancer therapeutics.
authors.affiliation: Functional Genomics Section, Laboratory of Cellular and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Honjo
authors.forename: Yansong
authors.initials: Y
authors.lastname: Bian
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Glenn
authors.initials: G
authors.lastname: Longenecker
authors.forename: Ramanamurthy
authors.initials: R
authors.lastname: Boppana
authors.forename: Jonas
authors.initials: J
authors.lastname: Larsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001005:Anus Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D003433:Crosses, Genetic; D004354:Drug Screening Assays, Antitumor; D005098:Exotoxins / Q000494:pharmacology; D005260:Female; D005813:Genes, Synthetic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D018793:Interleukin-13 / Q000494:pharmacology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D016900:Neurofilament Proteins / Q000235:genetics; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005098:Exotoxins; C521502:IL13-PE38; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D009363:Neoplasm Proteins; D016900:Neurofilament Proteins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C051774:neurofilament protein H; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C045073:Cre recombinase; D019426:Integrases