Transforming growth factor‐β signaling: Tumorigenesis and targeting for cancer therapy. Issue 8 (7th December 2018)

• Record Type: Journal Article
• Authors: Ahmadi, Amirhossein; Najafi, Masoud; Farhood, Bagher; Mortezaee, Keywan
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 8(2019:Aug.)
• Page Start: 12173
• Page End: 12187
• Publication Date: 2018-12-07
• Subjects: cancer cell -- cancer stem cell (CSC) -- cancer therapy -- epithelial–mesenchymal transition (EMT) -- metastasis -- Smad4 -- transforming growth factor (TGF)‐β -- tumor microenvironment (TME) -- TβRII; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.27955
• Languages: English
• ISSNs: 0021-9541

Abstract

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. Abstract : Transforming growth factor‐β (TGF‐β) is a multifunctioning cytokine acting on many types of cells diversely (in a specific way) depending on the type and stage of tumor. Low expression of TGF‐β at early stages of tumorigenesis is for tumor suppressive purposes, while high expression of this cytokine at late stages leads to progression of the tumor. TGF‐β takes canonical and noncanonical pathways for influencing cancer progression. In the canonical pathway, stimulation of TGF‐β results in downstream Smad activity, while in the noncanonical pathway other downstream signalings (rather than Smads) are activated in response to TGF‐β stimulation. Interaction between TGF‐β and Smads is key for progression of cancer because it has been attested that Smad activation independent on TGF‐β may have antitumor activity. Cues from the tumor microenvironment (TME) are considered as the most determinant factor for regulation of TGF‐β activity. TGF‐β‐mediated immune evasion is exerted by acting on various cells of both the innate and adaptive immune system. TGF‐β transduces differentiation of several tumor‐promoting cells within the TME as well as dedifferentiation toward attaining a cancer stem cell‐like phenotype. By creating a strong control over TME cellularity and signaling, TGF‐β would make the milieu compatible for immune evasion, EMT, and metastasis. A number of ways are available to target TGF‐β signaling including stimulation of I‐Smad/TβRI complex, targeting co‐Smad, retaining the activity of endogenous TGF‐β inhibitors, disruption of the redox system, targeting microRNAs and long noncoding RNAs associated with TGF‐β singaling, immune checkpoint blockade approaches and TGF receptor blockade, among them the preferred option would be the last option, especially when the focus is on the blockade of TβRII.