Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia

Cancer Cell. 2007 Oct;12(4):313-27. doi: 10.1016/j.ccr.2007.08.020.

Abstract

Although TGFbeta is a potent inhibitor of proliferation, epithelia lacking the essential receptor (TbetaRII) for TGFbeta signaling display normal tissue homeostasis. By studying asymptomatic TbetaRII-deficient stratified epithelia, we show that tissue homeostasis is maintained by balancing hyperproliferation with elevated apoptosis. Moreover, rectal and genital epithelia, which are naturally proliferative, develop spontaneous squamous cell carcinomas with age when TbetaRII is absent. This progression is associated with a reduction in apoptosis and can be accelerated in phenotypically normal epidermis by oncogenic mutations in Ras. We show that TbetaRII deficiency leads to enhanced keratinocyte motility and integrin-FAK-Src signaling. Together, these mechanisms provide a molecular framework to account for many of the characteristics of TbetaRII-deficient invasive SQCCs.

Publication types

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

MeSH terms

  • Animals
  • Anus Neoplasms / metabolism
  • Anus Neoplasms / pathology
  • Apoptosis*
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Movement
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Extracellular Matrix / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Homeostasis
  • Humans
  • Integrins / metabolism
  • Keratin-14 / genetics
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Neoplasm Invasiveness
  • Papilloma / metabolism
  • Papilloma / pathology
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / deficiency
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction*
  • Skin / metabolism
  • Skin / pathology
  • Skin / physiopathology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Time Factors
  • Transforming Growth Factor beta / metabolism*
  • Urogenital Neoplasms / metabolism
  • Urogenital Neoplasms / pathology
  • Wound Healing
  • ras Proteins / genetics
  • ras Proteins / metabolism
  • src-Family Kinases / metabolism

Substances

  • Integrins
  • KRT14 protein, human
  • Keratin-14
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Focal Adhesion Protein-Tyrosine Kinases
  • src-Family Kinases
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • ras Proteins