Transforming growth factor-β signaling: Tumorigenesis and targeting for cancer therapy

Abstract

Transforming growth factor (TGF)-β is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF-β is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF-β is a main inducer of epithelial-mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF-β exerts most of its functions by acting on TβRI and TβRII receptors in canonical (Smad-dependent) or noncanonical (Smad-independent) pathways. Members of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and nuclear factor κβ are involved in the non-Smad TGF-β pathway. TGF-β acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF-β are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF-β signaling in cancer, among them the special focus is on TβRII suppression.

Keywords: Smad4; TβRII; cancer cell; cancer stem cell (CSC); cancer therapy; epithelial-mesenchymal transition (EMT); metastasis; transforming growth factor (TGF)-β; tumor microenvironment (TME).