TGF-beta antiproliferative effects in tumor suppression
Stephan Christopher Jahn1, Mary Elizabeth Law1, Patrick Evan Corsino1, Brian Keith Law1
1
Department of Pharmacology and Therapeutics, Shands Cancer Center, University of Florida, Gainesville, FL 32610, United States
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. TGF-beta mediated cell cycle arrest of nontransformed epithelial cells
- 4. Mechanisms by which carcinomas become resistant to TGF-beta cytostatic actions
- 4.1. Mutation or loss of TGF-beta receptors
- 4.2. Aberrant Smad activity
- 4.3. Dysregulation of cell cycle effectors
- 4.4. Tumor microenvironment
- 5. Evidence for TGF-beta antiproliferative effects from intact in vivo systems
- 5.1. Allelic variations in the TGF-beta signaling cascade
- 5.2. The TGF-beta-/- mouse
- 5.3. Targeted expression of TGF-beta
- 5.4. Expression of mutant TGF-beta receptors
- 5.5. Studies with altered Smad signaling
- 5.6. The use of TGF-beta decoy receptors
- 6. Directions for future studies
- 6.1. Abrogating TGF-beta signaling to block promotion of tumor invasion and metastasis
- 6.2. Restoring TGF-beta antiproliferative actions in tumors using rapalogs
- 7. Acknowledgements
- 8. References
1. ABSTRACT
The TGF-beta signaling pathway controls multiple functions of cancer cells and the surrounding stromal tissue. Some TGF-beta actions suppress cancer formation, while others contribute to tumor progression. Evidence supporting a tumor suppressive role for the TGF-beta/Smad signaling axis is presented here. These data are compiled from cell culture studies, animal models, analyses of human tumors, and investigations of polymorphisms of TGF-beta pathway components and their associated cancer risk. Therapeutic strategies for cancer treatment involving either restoring or potentiating TGF-beta tumor suppressive activities, or blocking TGF-beta tumor promoting functions are considered.
