Duel nature of TGF-β signaling: tumor suppressor vs. tumor... : Current Opinion in Oncology (original) (raw)
Cancer biology
aUniversity of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA, and bSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Dr. Park is an Avon Scholar and also receives generous support from the V Foundation, the Entertainment Industry Foundation, the Department of Defense Breast Cancer Research Program, and the Flight Attendant’s Medical Research Institute.
Correspondence to Ben Ho Park, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA
Tel: 410 502 7399; fax: 410 614 8397; e-mail: [email protected]
Abstract
Purpose of review
Transforming growth factor β type I (TGF-β) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-β 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-β. In many instances, this resistance is part of a signaling switch whereby TGF-β 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-β are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-β 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-β exposure is an area of active research. Besides enhancing cancer cell growth, TGF-β 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-β 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-β as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-β 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-β 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-β signaling continue to be discovered. Knowledge of how premalignant cells and tumor cells respond to the growth promoting effects of TGF-β and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.
© 2005 Lippincott Williams & Wilkins, Inc.