PURPOSE OF REVIEW: Transforming growth factor beta type I (TGF-beta) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-beta 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-beta. In many instances, this resistance is part of a signaling switch whereby TGF-beta 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-beta are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-beta 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-beta exposure is an area of active research. Besides enhancing cancer cell growth, TGF-beta 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-beta 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-beta as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-beta 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-beta 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-beta signaling continue to be discovered. Knowledge of how premalignant cells and tumor cells respond to the growth promoting effects of TGF-beta and the genes that regulate this process will aid in the development of novel therapeutics and treatment strategies.
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Bachman et al. (2004) studied this question.