The Multifaceted Role of TGF-β in Gastrointestinal Tumors

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Aug 27

PMID 34439114

Citations 17

Authors

Fabio Sabbadini

Monica Bertolini

Serena De Matteis

Domenico Mangiameli

Serena Contarelli

Silvia Pietrobono

Davide Melisi

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors.

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References

Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K . NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 2004; 386(Pt 3):461-70. PMC: 1134864. DOI: 10.1042/BJ20040738. View

Hyytiainen M, Penttinen C, Keski-Oja J . Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci. 2004; 41(3):233-64. DOI: 10.1080/10408360490460933. View

Burch M, Zheng W, Little P . Smad linker region phosphorylation in the regulation of extracellular matrix synthesis. Cell Mol Life Sci. 2010; 68(1):97-107. PMC: 11115152. DOI: 10.1007/s00018-010-0514-4. View

Wang H, Li J, He J, Liu Y, Feng W, Zhou H . Methyl-CpG-binding protein 2 drives the Furin/TGF-β1/Smad axis to promote epithelial-mesenchymal transition in pancreatic cancer cells. Oncogenesis. 2020; 9(8):76. PMC: 7450052. DOI: 10.1038/s41389-020-00258-y. View

Karimi P, Islami F, Anandasabapathy S, Freedman N, Kamangar F . Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014; 23(5):700-13. PMC: 4019373. DOI: 10.1158/1055-9965.EPI-13-1057. View

Rifkin D . Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem. 2004; 280(9):7409-12. DOI: 10.1074/jbc.R400029200. View

David C, Massague J . Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018; 19(7):419-435. PMC: 7457231. DOI: 10.1038/s41580-018-0007-0. View

Gambardella V, Castillo J, Tarazona N, Gimeno-Valiente F, Martinez-Ciarpaglini C, Cabeza-Segura M . The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target. Cancer Treat Rev. 2020; 86:102015. DOI: 10.1016/j.ctrv.2020.102015. View

Oft M, Akhurst R, Balmain A . Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol. 2002; 4(7):487-94. DOI: 10.1038/ncb807. View

10.

Wherry E . T cell exhaustion. Nat Immunol. 2011; 12(6):492-9. DOI: 10.1038/ni.2035. View

11.

Perlman R, Schiemann W, Brooks M, Lodish H, Weinberg R . TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol. 2001; 3(8):708-14. DOI: 10.1038/35087019. View

12.

Wang X, Wang L, Mo Q, Dong Y, Wang G, Ji A . Changes of Th17/Treg cell and related cytokines in pancreatic cancer patients. Int J Clin Exp Pathol. 2015; 8(5):5702-8. PMC: 4503155. View

13.

Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E . In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer. 2019; 146(4):895-905. PMC: 6972582. DOI: 10.1002/ijc.32193. View

14.

Attisano L, Carcamo J, Ventura F, Weis F, Massague J, Wrana J . Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993; 75(4):671-80. DOI: 10.1016/0092-8674(93)90488-c. View

15.

Hao Y, Baker D, Ten Dijke P . TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int J Mol Sci. 2019; 20(11). PMC: 6600375. DOI: 10.3390/ijms20112767. View

16.

Ai X, Wu Y, Zhang W, Zhang Z, Jin G, Zhao J . Targeting the ERK pathway reduces liver metastasis of Smad4-inactivated colorectal cancer. Cancer Biol Ther. 2013; 14(11):1059-67. PMC: 3925661. DOI: 10.4161/cbt.26427. View

17.

Dong C . TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008; 8(5):337-48. DOI: 10.1038/nri2295. View

18.

Tolcher A, Berlin J, Cosaert J, Kauh J, Chan E, Piha-Paul S . A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2017; 79(4):673-680. PMC: 5893148. DOI: 10.1007/s00280-017-3245-5. View

19.

Massague J, Seoane J, Wotton D . Smad transcription factors. Genes Dev. 2005; 19(23):2783-810. DOI: 10.1101/gad.1350705. View

20.

Schrader J, Gordon-Walker T, Aucott R, van Deemter M, Quaas A, Walsh S . Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology. 2011; 53(4):1192-205. PMC: 3076070. DOI: 10.1002/hep.24108. View