title: Transforming growth factor-β enhances invasion and metastasis in Ras-transfected human malignant epidermal keratinocytes.
abstract: Transforming growth factor-β (TGF-β) is known to act as a tumour suppressor early in carcinogenesis, but then switches to a pro-metastatic factor in some late stage cancers. However, the actions of TGF-β are context dependent, and it is currently unclear how TGF-β influences the progression of human squamous cell carcinoma (SCC). This study examined the effect of overexpression of TGF-β1 or TGF-β2 in Ras-transfected human malignant epidermal keratinocytes that represent the early stages of human SCC. In vitro, the proliferation of cells overexpressing TGF-β1 or TGF-β2 was inhibited by exogenous TGF-β1; cells overexpressing TGF-β1 also grew more slowly than controls, but the growth rate of TGF-β2 overexpressing cells was unaltered. However, cells that overexpressed either TGF-β1 or TGF-β2 were markedly more invasive than controls in an organotypic model of SCC. The proliferation of the invading TGF-β1 overexpressing cells in the organotypic assays was higher than controls. Similarly, tumours formed by the TGF-β1 overexpressing cells following transplantation to athymic mice were larger than tumours formed by control cells and proliferated at a higher rate. Our results demonstrate that elevated expression of either TGF-β1 or TGF-β2 in cells that represent the early stages in the development of human SCC results in a more aggressive phenotype.
authors.affiliation: School of Oral and Dental Science, University of Bristol, Bristol, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Davies
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Prime
authors.forename: John W
authors.initials: JW
authors.lastname: Eveson
authors.forename: Nicky
authors.initials: N
authors.lastname: Price
authors.forename: Anu
authors.initials: A
authors.lastname: Ganapathy
authors.forename: Anita
authors.initials: A
authors.lastname: D'Mello
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D011905:Genes, ras; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000188:drug therapy*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000494:pharmacology*
chemical_list: D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2