TGF-beta signaling in cancer treatment.
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-β 1 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.
Isabel
I
Fabregat
Joan
J
Fernando
Jessica
J
Mainez
IDIBELL. Gran Via de Hospitalet, 199. Hospitalet de Llobregat, 08908 Barcelona, Spain. ifabregat@idibell.cat.
Patricia
P
Sancho
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta