The TGF-beta paradox in human cancer: an update

Abstract

TGF-beta plays an essential role in maintaining tissue homeostasis through its ability to induce cell cycle arrest, differentiation and apoptosis, and to preserve genomic stability. Thus, TGF-beta is a potent anticancer agent that prohibits the uncontrolled proliferation of epithelial, endothelial and hematopoietic cells. Interestingly, tumorigenesis typically elicits aberrations in the TGF-beta signaling pathway that engenders resistance to the cytostatic activities of TGF-beta, thereby enhancing the development and progression of human malignancies. Moreover, these genetic and epigenetic events conspire to convert TGF-beta from a suppressor of tumor formation to a promoter of their growth, invasion and metastasis. The dichotomous nature of TGF-beta during tumorigenesis is known as the 'TGF-beta paradox', which remains the most critical and mysterious question concerning the physiopathological role of this multifunctional cytokine. Here we review recent findings that directly impact our understanding of the TGF-beta paradox and discuss their importance to targeting the oncogenic activities of TGF-beta in developing and progressing neoplasms.

Figure 1. Cellular Targets of TGF-β During the Development and Progression of Human Cancers

TGF-β is a multifunctional cytokine that normally suppresses cell proliferation, differentiation, and apoptosis, as well as regulates cell and tissue homeostasis. Under normal physiological conditions, TGF-β functions as a tumor suppressor by preventing the ability of cells to progress through the cell cycle, or by stimulating the ability of cells to undergo apoptosis or differentiation. However, genetic and epigenetic events that transpire during tumorigenesis can convert TGF-β from a tumor suppressor to a tumor promoter, particularly the ability of cancer cells to acquire invasive and metastatic phenotypes. The oncogenic activities of TGF-β also are coordinated by dysregulated autocrine and paracrine signaling networks that take place between epithelial, fibroblasts, endothelial, and immune cells, that collectively promote tumor angiogenesis, invasion, and metastasis, and inhibit host immunosurveillance within tumor microenvironments. See text for specific examples of how TGF-β signaling becomes dysregulated during tumorigenesis