title: Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma.
abstract: Although the etiology of squamous cell carcinomas of the oral mucosa is well understood, the cellular origin and the exact molecular mechanisms leading to their formation are not. Previously, we observed the coordinated loss of E-cadherin (CDH1) and transforming growth factor beta receptor II (TGFBR2) in esophageal squamous tumors. To investigate if the coordinated loss of Cdh1 and Tgfbr2 is sufficient to induce tumorigenesis in vivo, we developed two mouse models targeting ablation of both genes constitutively or inducibly in the oral-esophageal epithelium. We show that the loss of both Cdh1 and Tgfbr2 in both models is sufficient to induce squamous cell carcinomas with animals succumbing to the invasive disease by 18 months of age. Advanced tumors have the ability to invade regional lymph nodes and to establish distant pulmonary metastasis. The mouse tumors showed molecular characteristics of human tumors such as overexpression of Cyclin D1. We addressed the question whether TGFβ signaling may target known stem cell markers and thereby influence tumorigenesis. From our mouse and human models, we conclude that TGFβ signaling regulates key aspects of stemness and quiescence in vitro and in vivo. This provides a new explanation for the importance of TGFβ in mucosal homeostasis.
authors.affiliation: Division of Dermatology, Department of Medicine, Department of Surgery, Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt Digestive Disease Center and Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Andl
authors.affiliation: Department of Surgery.
authors.forename: Grégoire F
authors.initials: GF
authors.lastname: Le Bras
authors.affiliation: Department of Surgery.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Richards
authors.affiliation: Department of Surgery.
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Allison
authors.affiliation: Department of Cancer Biology.
authors.forename: Holli A
authors.initials: HA
authors.lastname: Loomans
authors.affiliation: Vanderbilt Ingram Cancer Center, Vanderbilt Digestive Disease Center and Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Vanderbilt Ingram Cancer Center, Vanderbilt Digestive Disease Center and Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Revetta
authors.affiliation: Department of Surgery.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Lee
authors.affiliation: Department of Surgery.
authors.forename: Chase
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Department of Cancer Biology, Vanderbilt Ingram Cancer Center.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Department of Surgery, Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt Digestive Disease Center and Claudia.andl@vanderbilt.edu.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Andl
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D015703:Antigens, CD; C530104:CCND1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D018125:Receptors, Transforming Growth Factor beta; D013629:Tamoxifen; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II