Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter

Curr Opin Oncol. 2005 Jan;17(1):49-54. doi: 10.1097/01.cco.0000143682.45316.ae.


Purpose of review: Transforming growth factor beta type I (TGF-beta) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-beta signal transduction pathway are found in many gastrointestinal cancers, confirming its importance as a tumor suppressor. In contrast, many nongastrointestinal epithelial malignancies lack these somatic alterations, yet these cancers still acquire resistance to the growth-inhibitory effects of TGF-beta. In many instances, this resistance is part of a signaling switch whereby TGF-beta loses its growth inhibitory effects and is then used by the epithelial cell in a growth-promoting fashion. The mechanisms that underlie this change in the phenotypic growth response to TGF-beta are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-beta pathway as it relates to human carcinogenesis.

Recent findings: Elucidating the molecular basis that enables epithelial cells to change from a growth-suppressive to growth-stimulatory phenotype on TGF-beta exposure is an area of active research. Besides enhancing cancer cell growth, TGF-beta is also thought to promote a malignant cell's ability to metastasize by mediating changes in the cytoskeletal architecture, known as an epithelial-to-mesenchymal transition. This process enables a cancer cell to invade and spread to distal sites. Strong evidence has now emerged suggesting that the ability of a cell to use TGF-beta as a growth-promoting/invasive cytokine is a result of a number of different cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates a cell's response to TGF-beta as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-beta signaling.

Summary: Current studies are beginning to shed light on the mechanisms that allow some nongastrointestinal epithelial cancers to evade the growth inhibitory effects of TGF-beta while simultaneously using this cytokine for growth advantage. By dissecting this phenotypic switch during tumor development, important genes, proteins, and pathways that are involved with TGF-beta signaling continue to be discovered. Knowledge of how premalignant cells and tumor cells respond to the growth promoting effects of TGF-beta and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Cell Transformation, Neoplastic*
  • Cytokines / pharmacology
  • Epithelial Cells / physiology
  • Genes, Tumor Suppressor
  • Humans
  • Neoplasms / genetics*
  • Neoplasms / physiopathology*
  • Phenotype
  • Promoter Regions, Genetic
  • Receptors, Transforming Growth Factor beta / physiology*
  • Signal Transduction
  • Transforming Growth Factor beta / pharmacology*


  • Cytokines
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta