Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Targeting TGF-b Signaling for Therapeutic Gain Rosemary J. Akhurst Department of Anatomy and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158-9001 Correspondence:
[email protected] Transforming growth factor bs (TGF-bs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-b type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-b ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-b signaling for therapeutic benefit. This review will cover the basics of TGF-b signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-b blockade strategies, and give an update on preclinical and clinical trials for TGF-b blockade in a variety of solid tumor types. he three transforming growth factor bs titude of TGF-b-induced tumor promoting ef- T(TGF-bs), TGF-b1, -b2, and -b3, are closely fects modulate the tumor cells directly through related ligands that act on most cells types of the enhancement of tumor cell invasion and metas- body and have pleiotropic activities. Expression tasis, and induction and maintenance of cells of TGF-b1 is activated by tissue perturbations with tumor initiating properties, sometimes that induce cellular stress, such as cell prolifera- termed cancer stem-like cells (CSCs).