Transforming growth factor-β enhances invasion and metastasis in Ras-transfected human malignant epidermal keratinocytes

Int J Exp Pathol. 2012 Apr;93(2):148-56. doi: 10.1111/j.1365-2613.2011.00806.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / secondary
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Genes, ras
  • Humans
  • Keratinocytes / drug effects*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Skin Neoplasms / drug therapy*
  • Transfection
  • Transforming Growth Factor beta1 / biosynthesis
  • Transforming Growth Factor beta1 / pharmacology*
  • Transforming Growth Factor beta2 / biosynthesis
  • Transforming Growth Factor beta2 / pharmacology*

Substances

  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2