The paradoxical role of transforming growth factor-β in controlling oral squamous cell carcinoma development
Abstract
Transforming growth factor-
1.Introduction
Oral cancer is the most common malignant tumor in the head and neck region, and its incidence has been on the rise. According to the latest data from the International Agency for Research on Cancer, there were approximately 377,713 new cases and 177,757 deaths worldwide [1]. Oral squamous cell carcinoma (OSCC) accounts for 90% of all oral cancer cases. Despite the effectiveness of surgical treatment combined with postoperative radiotherapy and chemotherapy, the 5-year survival rate of oral cancer patients is still around 50
The transforming growth factor-
TGF-
2.TGF-𝜷 inhibits OSCC development
Figure 1.
The double role of TGF-
![The double role of TGF-β signaling in OSCC development. Figure note: TGF-β signaling pathway can be activated through typical and non-typical TGF-β signaling pathway. TGF-β plays a double role on the development of oral squamous cell carcinoma. TGF-β can inhibit the proliferation of OSCC cells and inhibit tumor occurrence by interfering with cell cycle, mediating cell apoptosis and cellular senescence effects, etc. TGF-β also can promote the development of OSCC by promoting cell survival and proliferation, promoting cell migration and invasion, and participating in immune escape, etc. The figure is created by Adobe AI software.](https://content.iospress.com:443/media/cbm/2024/40-3-4/cbm-40-3-4-cbm230354/cbm-40-cbm230354-g001.jpg)
TGF-
2.1TGF-β can mediate cell cycle arrest in multiple ways
Firstly, TGF-
TGF-
In summary, the inhibition of oral squamous cell carcinoma cell proliferation by TGF-
2.2TGF-β can induce cell apoptosis and senescence
Apoptosis is a genetically controlled autonomous and orderly death process that eliminates excessive or damaged cells during embryonic organogenesis and adult organ homeostasis, maintaining stable internal environment [35]. TGF-
Cellular senescence is a stress response program that limits cell proliferation by inducing persistent and irreversible cell cycle arrest [39]. Cellular senescence can be triggered by telomere shortening (referred to as replicative senescence) or various cell stresses, such as activation of oncogenes, mitochondrial dysfunction, inactivation of tumor suppressor genes, endoplasmic reticulum stress, DNA damage, etc [40]. The cell cycle arrest associated with cellular senescence is one of the key mechanisms that limit the proliferation of epithelial tumor cells. Loss of genes such as p53 and p16Ink4a in late-stage malignant tumors leads to the occurrence of genetically unstable OSCC (GU-OSCC) [41]. Hassona et al. found that fibroblasts extracted from GU-OSCC showed high levels of cellular senescence, with an increased activity of senescence-associated
3.TGF-𝜷 promotes OSCC development
TGF-
3.1TGF-β can promote cell survival and proliferation
TGF-
TGF-
In summary, researchers have found that TGF-
3.2TGF-β can promote cell migration
Epithelial to mesenchymal transition (EMT) plays a key driving role in tumor cell migration and invasion. When epithelial-mesenchymal-like cells lose adhesion to the extracellular matrix, they undergo mesenchymal-to-amoeboid transition (MAT), which enhances the contractile ability of actin and forms cell membrane protrusions, thereby enhancing the movement of deformed cells [54]. During the process of EMT, the expression of epithelial cell-cell adhesion proteins such as E-cadherin and zonula occludens-1(ZO-1) is downregulated, while the expression of mesenchymal markers such as N-cadherin, vimentin, and
Increasing evidence suggests that EMT is not a single, rigid process, but a multi-step process that passes through a partial EMT state (P-EMT), and the TGF-
Angiogenesis provides the necessary nutrients and oxygen for tumors, and TGF-
In summary, recent studies pointed out that TGF-
3.3TGF-β can promote cell immune escape
The tumor microenvironment (TME) is a complex system composed of various cell components, such as fibroblasts, endothelial cells, and various immune cells, including T cells and natural killer (NK) cells, which have natural cytotoxic effects on tumor cells [68]. Dendritic cells present tumor antigens to T cells, while macrophages and neutrophils clear cell debris through phagocytosis. TGF-
TGF-
TGF-
In summary, recent studies have found that TGF-
4.Conclusions and outlooks
Indeed, the dual role of TGF-
The dual role of TGF-
Funding
This study was supported by Science Foundation of Sichuan (2023NSFSC0558).
Author contributions
PENG Ruiting: Contributed to conception, interpretation of data, preparation of the manuscript.
HUANG Yun & HUANG Ping & LIU Linyi: Contributed to conception, preparation of the manuscript.
CHENG Lei: Contributed to conception, revision for important intellectual content.
PENG Xian: Contributed to revision for important intellectual content, supervision.
All authors gave their final approval and agree to be accountable for all aspects of the work.
Conflict of interest
The authors declare no conflict of interest.
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