Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

J Clin Invest. 2005 Jul;115(7):1714-23. doi: 10.1172/JCI24399. Epub 2005 Jun 2.

Abstract

In the present study, we demonstrated that human skin cancers frequently overexpress TGF-beta1 but exhibit decreased expression of the TGF-beta type II receptor (TGF-(beta)RII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-beta(1) in keratinocytes expressing a dominant negative TGF-(beta)RII (Delta(beta)RII) in the epidermis. Without Delta(beta)RII expression, TGF-beta1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, Delta(beta)RII expression abrogated TGF-beta1-mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-beta1/Delta(beta)RII compound tumors. Furthermore, expression of molecules thought to mediate TGF-beta1-induced EMT was attenuated in TGF-beta1/Delta(beta)RII-transgenic tumors. However, TGF-beta1/Delta(beta)RII-transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-beta1-transgenic, or Delta(beta)RII-transgenic mice. Abrogation of Smad activation by Delta(beta)RII correlated with the blockade of EMT. However, Delta(beta)RII did not alter TGF-beta1-mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-beta1 induces EMT and invasion via distinct mechanisms. TGF-beta1-mediated EMT requires functional TGF-(beta)RII, whereas TGF-beta1-mediated tumor invasion cooperates with reduced TGF-(beta)RII signaling in tumor epithelia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinoma in Situ / etiology
  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / pathology
  • Carcinoma, Squamous Cell / etiology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / secondary
  • DNA-Binding Proteins / genetics
  • Epithelium / pathology
  • Gene Expression
  • Humans
  • Mesoderm / pathology
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Models, Biological
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Signal Transduction
  • Skin Neoplasms / etiology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Smad2 Protein
  • Trans-Activators / genetics
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1

Substances

  • DNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • Smad2 protein, mouse
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II