Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

Abstract

Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFβ, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFβ, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFβ and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFβ synthesis, to molecules that block the interaction between TGFβ and its signaling receptors, together with inhibitors of the TGFβ signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.

Keywords: SMAD; TGFβ; antisense oligonucleotides; cancer; drug target; epithelial to mesenchymal transition; metastasis; miRNA; siRNA; small molecule inhibitor.

Figure 1

Schematic representation of transforming growth factor β (TGFβ) synthesis and secretion.

Figure 2

Schematic representation of latent TGFβ activation and the canonical TGFβ signaling pathway.

Figure 3

Systematic review workflow.

Figure 4

Graphical overview of therapeutic strategies (in red) aimed at TGFβ modulation in cancer treatment. The level at which each strategy is targeted (synthesis, activation, or signaling processes) can be noted.