Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

Oncogene. 1998 Jul 9;17(1):25-34. doi: 10.1038/sj.onc.1202161.

Abstract

The role of Transforming growth factor beta (TGF-beta) in carcinogenesis is complex. There are reports on both tumor inhibition and tumor promotion by TGF-beta. To elucidate the complex role of TGF-beta in epithelial carcinogenesis, we generated transgenic mice overexpressing a dominant negative type II TGF-beta receptor in the basal cell compartment and in follicular cells of the skin. Despite the reduced responsiveness of transgenic keratinocytes to TGF-beta, both proliferation and differentiation were normal in non-irritated epidermis of these transgenic mice. Thus, interruption of signaling of all three isoforms of TGF-beta in basal and follicular cells does not disturb tissue homeostasis. However, during tumor promotion transgenic mice showed an elevated level of proliferation in the epidermis. This hyperproliferation correlated with a very early onset of carcinoma development and a malignant conversion frequency of 30% from benign papillomas to carcinomas. By comparison, the conversion frequency in wild-type mice of this strain has previously been reported as 5.5%. Even without induction of hyperproliferation by tumor promoters, transgenic mice developed far more carcinomas as controls when treated with a carcinogen. This result indicates that there is a synergistic effect between loss of TGF-beta responsiveness and mutations caused by initiation with a carcinogen leading to an endogenous tumor promotion in initiated cells only.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / epidemiology
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / physiopathology
  • Cell Division / drug effects
  • Cells, Cultured
  • Humans
  • Incidence
  • Keratinocytes / metabolism
  • Mice
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / biosynthesis
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Skin / metabolism
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / physiopathology
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*

Substances

  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II