Title:TGF-beta Signaling in Cancer Treatment
Volume: 20
Issue: 17
Author(s): Isabel Fabregat, Joan Fernando, Jessica Mainez and Patricia Sancho
Affiliation:
Keywords:
TGF-beta, Smads, EMT, tumor progression, cancer treatment.
Abstract: The transforming growth factor-beta (TGF-β) belongs to a superfamily of cytokines that act on protein kinase receptors at the
plasma membrane to induce a plethora of biological signals that regulate cell growth and death, differentiation, immune response, angiogenesis
and inflammation. Dysregulation of its pathway contributes to a broad variety of pathologies, including cancer. TGF-β is an important
regulatory tumor suppressor factor in epithelial cells, where it early inhibits proliferation and induces apoptosis. However, tumor
cells develop mechanisms to overcome the TGF-β-induced suppressor effects. Once this occurs, cells may respond to this cytokine inducing
other effects that contribute to tumor progression. Indeed, TGF-β induces epithelial-mesenchymal transition (EMT), a process that is
favored in tumor cells and facilitates migration and invasion. Furthermore, TGF-β mediates production of mitogenic growth factors,
which stimulate tumor proliferation and survival. Finally, TGF-β is a well known immunosuppressor and pro-angiogenic factor. Many
studies have identified the overexpression of TGF-β1 in various types of human cancer, which correlates with tumor progression, metastasis,
angiogenesis and poor prognostic outcome. For these reasons, different strategies to block TGF-β pathway in cancer have been developed
and they can be classified in: (1) blocking antibodies and ligand traps; (2) antisense oligos; (3) TβRII and/or ALK5 inhibitors;
(4) immune response-based strategies; (5) other inhibitors of the TGF-β pathway. In this review we will overview the two faces of TGF-β
signaling in the regulation of tumorigenesis and we will dissect how targeting the TGF-β pathway may contribute to fight against cancer.
