30 TGF-β and the Tumor Microenvironment

Abstract

Transforming growth factor-β (TGF-β) signaling in cancer has been studied in great detail since observations more than two decades ago suggested that TGF-β may have a role in tumor suppression in epithelial cells, from which a majority of cancers arise (Tucker et al. 1984; Moses et al. 1985; Roberts et al. 1985). TGF-β also demonstrated the ability to contribute to transformation of fibroblast cell types, further confirming the importance for this pathway in cancer (Roberts and Sporn 1985). The early years of TGF-β research led to identification of pathways potentially regulated by TGF-β signaling in the cancer microenvironment, including immune evasion, angiogenesis, and modification of other central stromal components that contribute to disease progression (Roberts et al. 1988). These early postulates have been confirmed in many cancer models and clinical studies. It is now clear that TGF-β is a central signaling component in the tumor microenvironment. In cancer, the TGF-β1 ligand is expressed at higher levels than TGF-β2 or TGF-β3 (Derynck et al. 1987; Dickson et al. 1987). This preferential expression has resulted in a focus on the TGF-β1 ligand in a majority of the current literature. It is possible that there are unique roles for each isoform in the cancer microenvironment, but we herein focus on the TGF-β1 ligand to generalize signaling through this pathway. Up-regulation of TGF-β1 expression is common in cancer, and this increase in expression can be readily detected in tumors (Wojtowicz-Praga 2003). In addition, the increase in TGF-β abundance in tumor tissue is often accompanied...