Canonical TGFβ Signaling and Its Contribution to Endometrial Cancer Development and Progression-Underestimated Target of Anticancer Strategies

Overview

Journal J Clin Med

Specialty General Medicine

Date 2021 Sep 10

PMID 34501347

Citations 10

Authors

Piotr K Zakrzewski

Affiliations

Soon will be listed here.

Abstract

Endometrial cancer is one of the leading gynecological cancers diagnosed among women in their menopausal and postmenopausal age. Despite the progress in molecular biology and medicine, no efficient and powerful diagnostic and prognostic marker is dedicated to endometrial carcinogenesis. The canonical TGFβ pathway is a pleiotropic signaling cascade orchestrating a variety of cellular and molecular processes, whose alterations are responsible for carcinogenesis that originates from different tissue types. This review covers the current knowledge concerning the canonical TGFβ pathway (Smad-dependent) induced by prototypical TGFβ isoforms and the involvement of pathway alterations in the development and progression of endometrial neoplastic lesions. Since Smad-dependent signalization governs opposed cellular processes, such as growth arrest, apoptosis, tumor cells growth and differentiation, as well as angiogenesis and metastasis, TGFβ cascade may act both as a tumor suppressor or tumor promoter. However, the final effect of TGFβ signaling on endometrial cancer cells depends on the cancer disease stage. The multifunctional role of the TGFβ pathway indicates the possible utilization of alterations in the TGFβ cascade as a potential target of novel anticancer strategies.

Citing Articles

Integral Roles of the TGFβ Signaling Pathway in Uterine Function and Disease.

Unser A, Monsivais D Endocrinology. 2025; 166(3).

PMID: 39950970 PMC: 11843549. DOI: 10.1210/endocr/bqaf032.

A novel TGFbeta/TGILR axis mediates crosstalk between cancer-associated fibroblasts and tumor cells to drive gastric cancer progression.

Qin S, Guo Q, Liu Y, Zhang X, Huang P, Yu H Cell Death Dis. 2024; 15(5):368.

PMID: 38806480 PMC: 11133402. DOI: 10.1038/s41419-024-06744-0.

Interplay between LncRNA/miRNA and TGF-β Signaling in the Tumorigenesis of Gynecological Cancer.

Safavi P, Moghadam K, Haghighi Z, Ferns G, Rahmani F Curr Pharm Des. 2024; 30(5):352-361.

PMID: 38303530 DOI: 10.2174/0113816128284380240123071409.

The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review.

Al-Kuraishy H, Al-Maiahy T, Al-Gareeb A, Alexiou A, Papadakis M, Saad H Cancer Rep (Hoboken). 2023; 7(1):e1920.

PMID: 38018319 PMC: 10809206. DOI: 10.1002/cnr2.1920.

MicroRNA Landscape in Endometrial Carcinomas in an Asian population: Unraveling Subtype-Specific Signatures.

Tan G, Leong S, Jin Y, Kuick C, Chee J, Low S Cancers (Basel). 2023; 15(21).

PMID: 37958433 PMC: 10648581. DOI: 10.3390/cancers15215260.

References

Teng F, Tian W, Wang Y, Zhang Y, Guo F, Zhao J . Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol. 2016; 9:8. PMC: 4744391. DOI: 10.1186/s13045-015-0231-4. 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

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

Penheiter S, Singh R, Repellin C, Wilkes M, Edens M, Howe P . Type II transforming growth factor-beta receptor recycling is dependent upon the clathrin adaptor protein Dab2. Mol Biol Cell. 2010; 21(22):4009-19. PMC: 2982134. DOI: 10.1091/mbc.E09-12-1019. View

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

Annes J, Munger J, Rifkin D . Making sense of latent TGFbeta activation. J Cell Sci. 2002; 116(Pt 2):217-24. DOI: 10.1242/jcs.00229. View

Shi Y, Hata A, Lo R, Massague J, Pavletich N . A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997; 388(6637):87-93. DOI: 10.1038/40431. View

Zakrzewski P, Forma E, Cygankiewicz A, Brys M, Wojcik-Krowiranda K, Bienkiewicz A . Betaglycan Gene () Polymorphism Is Associated with Increased Risk of Endometrial Cancer. J Clin Med. 2020; 9(10). PMC: 7650668. DOI: 10.3390/jcm9103082. View

10.

Erdem O, Taskiran C, Onan M, Erdem M, Guner H, Ataoglu O . CD105 expression is an independent predictor of survival in patients with endometrial cancer. Gynecol Oncol. 2006; 103(3):1007-11. DOI: 10.1016/j.ygyno.2006.06.010. View

11.

Massague J . Complementation between kinase-defective and activation-defective TGF-beta receptors reveals a novel form of receptor cooperativity essential for signaling. EMBO J. 1996; 15(2):276-89. PMC: 449943. View

12.

Li Q, Zhang D, Wang Y, Sun P, Hou X, Larner J . MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation. Sci Rep. 2013; 3:2038. PMC: 3687228. DOI: 10.1038/srep02038. View

13.

Xu P, Lin X, Feng X . Posttranslational Regulation of Smads. Cold Spring Harb Perspect Biol. 2016; 8(12). PMC: 5131773. DOI: 10.1101/cshperspect.a022087. View

14.

Yu Y, Feng X . TGF-β signaling in cell fate control and cancer. Curr Opin Cell Biol. 2019; 61:56-63. DOI: 10.1016/j.ceb.2019.07.007. View

15.

Souchelnytskyi S, Tamaki K, Engstrom U, Wernstedt C, Ten Dijke P, Heldin C . Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem. 1997; 272(44):28107-15. DOI: 10.1074/jbc.272.44.28107. View

16.

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu Y, Grinnell B . The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997; 89(7):1165-73. DOI: 10.1016/s0092-8674(00)80303-7. View

17.

Kim Y, Park J, Lee H, Lee S, Kim S . TGF-β sensitivity is determined by N-linked glycosylation of the type II TGF-β receptor. Biochem J. 2012; 445(3):403-11. PMC: 3462611. DOI: 10.1042/BJ20111923. View

18.

Bokhman J . Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983; 15(1):10-7. DOI: 10.1016/0090-8258(83)90111-7. View

19.

Jones R, Stoikos C, Findlay J, Salamonsen L . TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction. 2006; 132(2):217-32. DOI: 10.1530/rep.1.01076. View

20.

Zawel L, Dai J, Buckhaults P, Zhou S, Kinzler K, Vogelstein B . Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell. 1998; 1(4):611-7. DOI: 10.1016/s1097-2765(00)80061-1. View