The Role of TGF-β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target

Yang, Yun; Ye, Wen-Long; Zhang, Ruonan; He, Xiaoshun; Wang, Jingru; Liu, Yuxuan; Wang, Yi; Yang, Xuemei; Zhang, Yujuan; Gan, Wen-Juan

doi:10.1155/2021/6675208

Cited by 34 publications

(34 citation statements)

References 195 publications

(189 reference statements)

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“…TGF-β1 can suppress early-stage tumors through its potent antiproliferative activity and the induction of cell differentiation and apoptosis 65 , 66 . In advanced cancer, however, TGF-β1 actually promotes tumor invasion and metastasis by inducing the epithelial-mesenchymal transition, facilitating tumor angiogenesis, and hampering tumor immune surveillance by the host 65 – 67 . TGF-β1 is also implicated in many fibrotic human diseases, including pulmonary fibrosis 68 .…”

Section: Discussionmentioning

confidence: 99%

Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation

et al. 2022

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Fortilin is a 172-amino acid multifunctional protein present in both intra- and extracellular spaces. Although fortilin binds and regulates various cellular proteins, the biological role of extracellular fortilin remains unknown. Here we report that fortilin specifically interacts with TGF-β1 and prevents it from activating the TGF-β1 signaling pathway. In a standard immunoprecipitation-western blot assay, fortilin co-immunoprecipitates TGF-β1 and its isoforms. The modified ELISA assay shows that TGF-β1 remains complexed with fortilin in human serum. Both bio-layer interferometry and surface plasmon resonance (SPR) reveal that fortilin directly bind TGF-β1. The SPR analysis also reveals that fortilin and the TGF-β receptor II (TGFβRII) compete for TGF-β1. Both luciferase and secreted alkaline phosphatase reporter assays show that fortilin prevents TGF-β1 from activating Smad3 binding to Smad-binding element. Fortilin inhibits the phosphorylation of Smad3 in both quantitative western blot assays and ELISA. Finally, fortilin inhibits TGFβ-1-induced differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells. A computer-assisted virtual docking reveals that fortilin occupies the pocket of TGF-β1 that is normally occupied by TGFβRII and that TGF-β1 can bind either fortilin or TGFβRII at any given time. These data support the role of extracellular fortilin as a negative regulator of the TGF-β1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation

et al. 2022

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“…Recent studies have shown that TGF-β and vimentin play a role in immune suppression in many human cancers and are associated with tumor dissemination, metastasis, and poor prognosis [29]. This immune suppression may be related to the tumor immune microenvironment regulated by TGF-β, indicating the importance of TGF-β as a tumor marker and possibly as a target for inhibiting the infiltration of immune cells and their toxicity to cancer cells [53]. Our results show that autocrine TGF-β1-and vimentin-mediated cytoskeleton remodeling affects the adhesion and detachment of human cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Cytoskeleton Remodeling Drives Invasive Leading Cells Detachment

Peng

Chen

Cheng

et al. 2021

Cancers

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Detachment of cancer cells is the first step in tumor metastasis and malignancy. However, studies on the balance of initial tumor anchoring and detachment are limited. Herein, we revealed that the regulation of cytoskeleton proteins potentiates tumor detachment. The blockage of TGF-β1 using neutralizing antibodies induced cancer cell detachment in the Boyden chamber and 3D in-gel spheroid models. Moreover, treatment with latrunculin B, an actin polymerization inhibitor, enhanced cell dissociation by abolishing actin fibers, indicating that TGF-β1 mediates the formation of actin stress fibers, and is likely responsible for the dynamics of anchoring and detachment. Indeed, latrunculin B disrupted the formation of external TGF-β1-induced actin fibers and translocation of intracellular vinculin, a focal adhesion protein, resulting in the suppression of cell adhesion. Moreover, the silencing of vimentin substantially reduced cell adhesion and enhanced cell detachment, revealing that cell adhesion and focal adhesion protein translocation stimulated by TGF-β1 require vimentin. Using the 3D in-gel spheroid model, we found that latrunculin B suppressed the cell adhesion promoted by external TGF-β1, increasing the number of cells that penetrated the Matrigel and detached from the tumor spheres. Thus, cytoskeleton remodeling maintained the balance of cell anchoring and detachment, and the TGF-β1/vimentin/focal adhesion protein assembly axis was involved in the control dynamics of initial tumor detachment.

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“…После фосфорилирования SMAD2 и SMAD3 связываются с шаперонным белком SMAD4 и котранспортируются в ядро, где они могут регулировать экспрессию генов-мишеней TGF-β (рис. 1) [16,39,43,47].…”

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“…1. Схема сигнального пути TGF-β [47]. TGF-β стабилизирует клеточный цикл эпителиальных клеток, регулируя множественные циклин-зависимые киназы: p15, p21 и p27 каноническим путем.…”

unclassified

“…Напротив, неканонические пути могут опосредовать апоптотический эффект TGF-β, индуцируя экспрессию каспазы-8. Различие в передаче сигналов апоптоза, опосредованного TGF-β, указывает на то, что клеточный контекст важен для контроля основного пути, подавляющего опухолевые эффекты TGF-β [12,40,47].…”

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Role of transforming growth factor beta in tumor process

Кукес¹,

Prokofiev²,

Parfenova³

et al. 2021

Humans and their Health

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The study and application of representatives of the transforming growth factor-beta (TGF-β) family in practical medicine remains an urgent task at the present time. A more detailed study of the properties and activity of proteins related to TGF-β opens up new possibilities in the treatment and diagnosis of diseases associated with skeletal muscles, female reproductive system, oncology and the cardiovascular system, as well as in the development of drugs based on them. This work examines the role of TGF-β in tumor development and the potential of this protein as a therapeutic target, as well as the signaling pathway, various marker proteins, and various types of receptors involved in this process. During tumor development, TGF-β uses two pathways: the classic SMAD-dependent pathway and the non-SMAD-dependent pathway. In the early stages of tumorigenesis, TGF-β acts as a tumor suppressor, causing a cytostatic effect and apoptosis in normal and pre-malignant cells. However, after tumor development, TGF-β functions as a tumor promoter, triggering the transition of the epithelium to the mesenchyme, which leads to increased invasiveness and the development of metastases. The role of TGF-β in oncogenesis in various organ systems has been studied, including in breast, colon, stomach, hepatocellular carcinoma, thyroid cancer, etc. Specifically, TGF-β1 causes a wide range of different physiological reactions, regulates development, differentiation, carcinogenesis and tumor progression of epithelial cells, has multiple effects on the entire process of hematopoiesis. Directions for the creation of drugs for the treatment of tumors targeting TGF-β are presented.

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The Role of TGF-β Signaling Pathways in Cancer and Its Potential as a Therapeutic Target

Cited by 34 publications

References 195 publications

Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation

Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation

Dysregulation of Cytoskeleton Remodeling Drives Invasive Leading Cells Detachment

Role of transforming growth factor beta in tumor process

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