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TGF-β and the SMAD Signaling Pathway in Carcinogenesis

  • Wendy Greenwood
  • Alejandra Bruna
Chapter

Abstract

The TGF-β signaling pathway is highly conserved and plays crucial roles in the maintenance of tissue homoeostasis. At the cellular level, TGF-β effects are pleiotropic, regulating pluripotency and differentiation in development but maintaining homeostasis through cytostatic mechanisms in the mature epithelium. Because of the crucial role of TGF-β in controlling cellular programs regulating proliferation, differentiation, and tissue regeneration, deregulation of the pathway is commonly seen in disease, including cancer.

Canonical TGF-β signaling is initiated by ligand-induced oligomerization of the serine/threonine receptor kinase leading to the phosphorylation of intracellular SMAD signaling molecules. Activated SMADs then regulate hundreds of TGF-β target genes through their ability to activate specific transcription factors.

TGF-β signaling is strongly implicated in many aspects of cancer progression mainly functioning as a tumor suppressor in early stages of cancer development. This tumor-suppressive effect is eradicated in many cancers by inactivation or loss of TGF-β pathway components. However, other cancers progress with an intact TGF-β signaling pathway; here evasion of the tumor-suppressive effect occurs downstream of SMAD signaling. Our recent work has demonstrated that in breast cancer, this paradoxical role of TGF-β activity is not necessarily linked to the stage of breast cancer progression.

Because of the important roles of TGF-β signaling in cancer, it has become an increasingly interesting candidate for drug development. However, further understanding of the opposing roles of TGF-β signaling in different tumor types, the role of the tumor microenvironment, and the development of markers of TGF-β activity is crucial for treatment strategies to succeed.

Keywords

TGF-β Pleiotropy Cancer SMAD Tissue homoeostasis 

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK

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