TGF-beta signaling in cancer treatment

Curr Pharm Des. 2014;20(17):2934-47. doi: 10.2174/13816128113199990591.

Abstract

The transforming growth factor-beta (TGF-β ) belongs to a superfamily of cytokines that act on protein kinase receptors at the plasma membrane to induce a plethora of biological signals that regulate cell growth and death, differentiation, immune response, angiogenesis and inflammation. Dysregulation of its pathway contributes to a broad variety of pathologies, including cancer. TGF-β is an important regulatory tumor suppressor factor in epithelial cells, where it early inhibits proliferation and induces apoptosis. However, tumor cells develop mechanisms to overcome the TGF-β -induced suppressor effects. Once this occurs, cells may respond to this cytokine inducing other effects that contribute to tumor progression. Indeed, TGF-β induces epithelial-mesenchymal transition (EMT), a process that is favored in tumor cells and facilitates migration and invasion. Furthermore, TGF-β mediates production of mitogenic growth factors, which stimulate tumor proliferation and survival. Finally, TGF-β is a well known immunosuppressor and pro-angiogenic factor. Many studies have identified the overexpression of TGF-β 1 in various types of human cancer, which correlates with tumor progression, metastasis, angiogenesis and poor prognostic outcome. For these reasons, different strategies to block TGF-β pathway in cancer have been developed and they can be classified in: (1) blocking antibodies and ligand traps; (2) antisense oligos; (3) TβRII and/or ALK5 inhibitors; (4) immune response-based strategies; (5) other inhibitors of the TGF-β pathway. In this review we will overview the two faces of TGF-β signaling in the regulation of tumorigenesis and we will dissect how targeting the TGF-β pathway may contribute to fight against cancer.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Epithelial-Mesenchymal Transition / drug effects
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Signal Transduction / drug effects*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antineoplastic Agents
  • Transforming Growth Factor beta