TGF-beta Signaling in 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-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.

Hispolon as an inhibitor of TGF-β-induced epithelial-mesenchymal transition in human epithelial cancer cells by co-regulation of TGF-β-Snail/Twist axis

“…As previously reported, TGF-β induces EMT in various types of cancer cells, increasing their invasion and migration and resulting in enhanced metastasis (22,23,29). The present study demonstrated that MCF-7 and A549 human cancer cells may be induced by TGF-β to undergo a stimulated EMT, reducing E-cadherin expression level in cancer cells and increasing their invasiveness and migration.…”

“…reported that drugs may inhibit the invasion and migration of cancer cells by suppressing TGF-β activation and Snail/Twist induction, which results in recovering E-cadherin expression (22,23). It was suggested that the TGF-β signaling pathway is critically involved in the acquisition of EMT by its downstream target, the transcription factor Snail and Twist (24).…”

Nestin suppression attenuates invasive potential of endometrial cancer cells by downregulating TGF-β signaling pathway

“…A plethora of data indicate that TGF-β signaling has tumor suppressive effects in early-stages of cancer and a tumor-promoting effect in more advanced stages [36, 37]. We and others have previously shown that TGF-β signaling pathway is activated in endometrial cancer cells [22, 23, 38].…”

Id-1, a Protein Repressed by miR-29b, Facilitates the TGF�1-Induced Epithelial-Mesenchymal Transition in Human Ovarian Cancer Cells

“…Because increased motility occurs during this transition, EMT is currently recognized as an important event and the initiating step for tumor invasion and metastasis. A variety of cytokines and growth factors are induced during EMT, which further stimulates the EMT process and promotes cell migration and invasion; these factors include TGFβ (transforming growth factor β), Wnt, Notch ligands, ILEI (interleukin-like EMT-inducer), EGF (epidermal growth factor), PDGF (platelet-derived growth factor), and HGF (hepatocyte growth factor) [7,8,9,10]. …”