TGF‑β signaling: A complex role in tumorigenesis (Review)

  • Authors:
    • Shuang Liu
    • Shuang Chen
    • Jun Zeng
  • View Affiliations

  • Published online on: November 6, 2017     https://doi.org/10.3892/mmr.2017.7970
  • Pages: 699-704
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Tumor progression can be affected by various cellular components of tumor cells and/or by tumor microenvironmental factors. The tumor microenvironment comprises a variety of nonmalignant stromal cells and inflammatory cytokines, which are pivotal in tumor promotion and progression. The transforming growth factor‑β (TGF‑β) ligands (TGF‑β1, 2 and 3) are secreted inflammatory cytokines, which are known to be involved in various aspects of tumor development through two transmembrane serine‑threonine kinase receptors, TGFβR1 and TGFβR2. TGF‑β promotes or inhibits tumorigenesis depending on the concurrent gene mutations and tissue microenvironment present through the small mothers against decapentaplegic (Smad) and non‑Smad pathways. This review aims to provide a comprehensive overview of the role of the TGF‑β pathway in tumor initiation and progression.

Introduction

Transforming growth factor-β (TGF-β) signaling forms a complex web in the progression of cancer. There is substantial evidence indicating that downregulated TGF-β signaling in tumor initiation. However, in certain tumors, TGF-β appears to have the ability to exert a tumor-promoting effect depending on cellular context (13). Accordingly, TGF-β signaling has been considered as a tumor suppressor and a promoter of tumor progression (4,5). It acts as a tumor suppressor by inhibiting cell proliferation through repressing the expression of c-Myc and certain cyclin-depenent kinase inhibitors (CDKIs) and through the secretion of anti-angiogenic factors (6,7). It functions as a tumor promoter through the stimulation of matrix deposition, perturbation of immune function and induction of epithelial-mesenchymal transition (EMT) (8). The TGF-β super-family is a large group of structurally associated proteins including TGF-β, nodal, activin, lefty, bone morphogenetic proteins and growth and differentiation factor. There are numerous cellular context-dependent factors tightly implicated in the balance of TGF-β signaling, thus TGF-β signaling forms a complicated network in cancer cells (5).

TGF-β signaling pathways

TGF-β signaling is transduced through Smad and non-Smad pathways. These pathways are mediated by TGF-β ligands, type1 and type2 receptors and Smad or non-Smad proteins, including Akt, extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK; Fig. 1). In mammals, there are three types of TGF-β (TGF-β1, 2 and 3), which are encoded by different genes and which function through the same receptor signaling systems (9). Of these, TGF-β1 is most frequently upregulated in tumor cells (10,11). However, the fate of cells following TGF-β1 treatment is often determined by cellular context and experimental conditions (1214).

The TGF-β protein is produced as an inactive ‘latent’ high weight complex (14) and can be activated through the activity of plasminogen, which preferentially degrades the TGF-β prosegments (15,16) and through its conformational change by the metalloproteinases, matrix metalloproteinase (MMP)-9 and MMP-2 (17). There are other activation mechanisms. For example, the extracellular matrix protein, thrombospondin (18,19) and αvβ6 integrin can regulate the activity of TGF-β through a conformational change (20). Taken together, tumor cells are well equipped to activate TGF-β locally.

The effects of TGF-β signaling are mediated by three TGF-β ligands (TGF-β1-3) through TGF-β type1 (TGFβR1) and type2 receptors TGFβR2 (2123). TGFβR1 recruits and phosphorylates receptor-regulated Smads (R-Smads) when phosphorylated. TGF-β ligands can bind to TGFβR2 with high affinity once activated by metalloproteinases. Binding of the ligands causes the formation of a heterotetrameric active receptor complex, which results in the phosphorylation of TGFβR1 by TGFβR2. The phosphorylation of R-Smads by TGFβR1 form heteromeric complexes with the common partner Smad (co-Smad; Smad4 in mammals) (17) and these R-Smads-co-Smad complexes translocate into the nucleus to regulate the expression of target genes with other DNA-binding transcription factors.

TGF-β can also activate non-canonical signaling pathways, also termed non-Smad pathways. For example, TGF-β1 is known to activate the Erk/MAPK (24,25) pathway and the phosphoinositide 3-kinase (PI3K)/Akt (2628) pathway. These non-Smad pathways work independently or together with Smad complexes to regulate the functions of TGF-β. For example, the activation of Akt signaling by TGF-β1 has been shown to promote cell proliferation (28). TGF-β receptors activate MMPs, p38MAPK and Zinc finger E-box-binding homeobox 1 (ZEB1), ZEB2, Snail and Slug, leading to EMT, which is required for cancer cell invasion and metastasis. TGF-β can also regulate target gene expression through the MAPK signaling pathway (29,30).

TGF-β and cell proliferation

TGF-β can regulate cell growth, apoptosis, differentiation and fibrosis (1). There is substantial evidence suggesting that TGF-β can inhibit the proliferation of normal epithelial cells (31,32). TGF-β signaling has been reported to mediate cell-cycle progression inpancreatic β-cells by regulating the nuclear localization of CDKI, p27 (31). TGF-β signaling has also been reported to inhibit the proliferation of tumor cells in certain cases. The findings of a study by Senturk et al suggested that TGF-β induced p53-independent and p16 (Ink4a)-independent and reactive oxygen species (ROS)-dependent, senescence in hepatocellular carcinoma (HCC) cells and inhibited tumor growth (32). TGF-β was also reported to mediate galangin-induced autophagy. The induction of autophagy reflected the anti-proliferation effect of TGF-β signaling on HCC cells (33). Certain drugs, including Akbu-LAAO, an L-amino acid oxidase with apparent antibacterial activities, inhibits the growth and induces the apoptosis of HepG2 cells via the TGF-β signaling pathway (34). By contrast, TGF-β signaling may have a completely different role in cell growth. A previous study demonstrated that TGF-β1 induced the activation of Akt to promote β-catenin nuclear accumulation, which then regulated cyclin D1/c-myc gene transcription to eventually promote mouse precartilaginous stem cell proliferation (35).

TGF-β signaling is involved in the regulation of epithelial-mesenchymal transition

EMT is a key step in the progression of cancer invasion and metastasis, characterized by reduced epithelial marker and elevated mesenchymal marker expression (36,37). The EMT process is often associated with upregulation of TGF-β signaling and TGF-β drives EMT through the Smad-mediated or non-Smad-mediated reprogramming of gene expression (Fig. 2) (38). TGF-β receptors can induce the expression of ZEB1, ZEB2, Snail and Slug through the Smad pathway and mediate MMPs and p38MAPK through non-Smad pathways, which both lead to EMT (39). ROS are also important in TGF-β-induced EMT, primarily through the activation of MAPK and through subsequent ERK-directed activation of the Smad pathway in proximal tubular epithelial cells (40). TGF-β signaling not only mediates EMT, but it is also required for distant metastases. A previous study demonstrated that TGF-β in the breast cancer microenvironment promoted pulmonary metastases of breast cancer cells (41).

TGF-β and cancer stem cells

Advances in cancer stem cell (CSC) research have indicated that the TGF-β signaling pathway is essential for the maintenance of CSCs. CSCs have been reported to be responsible for the recurrence of disease following anticancer therapy (42). Certain extracellular and intracellular signals allow cancer progenitors to dynamically revert to a stem cell state. Evidence has shown that TGF-β induced the expression of CD133, a CSC marker, in liver cancer cell lines and increased tumor initiating ability in mice, compared with the milder and transient effect of interleukin-6 (43). Chanmee et al found that the over production of hyaluronan allowed cancer progenitors to revert to stem cell states via Twist and the TGF-β-Snail signaling axis (44). Furthermore, tumor-associated macrophages (TAMs) in the tumor microenvironment promoted CSC-like properties via TGF-β1-induced EMT in HCC (45). MicroRNA (miR)-106b is significantly upregulated in CD44(+) cells and the inhibition of miR-106b shows suppression of the TGF-β/Smad signaling pathway and decreases self-renewal capacity and cell invasiveness (46). These findings suggest that TGF-β signaling is associated with cancer cell stemness.

There are epigenetic differences in TGF-β signaling-related genes between cancer stem-like cells and differentiated cancer cells. It was previously reported that the methylation levels of genes coding TGF-β signaling-related proteins can regulate breast cancer stem cell differentiation (47). Evidence suggests that several members of the TGF-β pathway are targeted by long non-coding RNAs, key epigenetic mediators and this may, at least in part, explain the association between cancer cell stemness and TGF-β signaling (48). These findings may assist in the development of novel agents, which can specifically control increases and decreases in the TGF-β signaling pathway in CSCs and thereby provide a novel avenue for the prevention and treatment of malignant cancer (48).

Crosstalk between TGF-β signaling and inflammation

Acute inflammation is an essential component of the wound-healing response to stimuli. However, chronic inflammation favors the accumulation of mutations and epigenetic aberrations in normal cells, thereby promoting malignant transformation (49,50). This process is mediated by chemokines, cytokines and growth factors secreted by stromal components of the tumor microenvironment. Among those secreted factors, the TGF-β subfamily has been shown to generate a favorable immune microenvironment for tumor growth. TGF-β can impair anticancer immune responses in several ways, including immune cell inhibition and the elimination of major histocompatibility complex class I and II (51). It can also induce TAMs and generate ROS with genotoxic activity (5254). TAMs are primarily a macrophage subpopulation with an M2 phenotype. TAM-derived factors may enhance the invasiveness of tumor cells by enhancing their adhesion to extracellular matrix in the tumor stroma (55,56). Evidence from clinical and epidemiological studies has shown that TAM density is positively associated with poor survival rates in several types of cancer (56,57). The involvement of ROS signaling in tumor progression has also been recognized (58,59). Previous studies have suggested that the increased generation of ROS in tumor cells may affect certain redox-sensitive molecules, leading to mutations and genetic instability, cellular proliferation and metastasis (60,61).

TGF-β signaling in the regulation of tumor angiogenesis

The ability of tumor cells to induce the formation of blood vessels is crucial for tumor growth, invasion and metastasis. TGF-β is a key mediator of angiogenesis in the tumor microenvironment, contributing to angiogenesis by inducing proangiogenic factors (62).

TGF-β can induce a proangiogenic environment and stimulate tumor-associated angiogenesis. Elevated expression levels of TGF-β have been linked to increased microvessel density in certain tumor types (63). The mechanism of angiogenesis stimulated by TGF-β signaling includes the induction of key angiogenic factors, including connective tissue growth factor, vascular endothelial growth factor and insulin-like growth factor-binding protein 7, in epithelial cells and fibroblasts (64,65). In addition, TGF-β can induce the expression, secretion and activation of matrix metalloproteinase 2 (MMP2) and MMP9 and down regulate the expression of tissue inhibitor of metalloproteinase in tumor and endothelial cells (6668).

However, TGF-β also has angiostatic functions. For example, in pancreatic cancer and diffuse-type gastric cancer, TGF-β induces the production of thrombospondin1, a potent angiogenic inhibitor, whereas perturbations of TGF-β signaling resulted in accelerated angiogenesis and growth of tumors (69). Whether TGF-β is angiogenic or angiostaticis is dependent on the cellular context of tumor cells, epithelial cells and the tumor microenvironment.

Conclusion

Several lines of evidence suggest that the TGF-β family is involved in tumor initiation and progression, including cell proliferation, angiogenesis, cancer cell stemness, EMT, invasion and inflammation. TGF-β signaling is complex and mediates pro- and anti-tumoral activities in cancer cells depending on their context in space and time and their microenvironment (52). It is generally accepted that TGF-β is primarily a tumor suppressor in premalignant cells but functions as a promoter of metastasis in cancer cells (70,71). However, the mechanisms underlying the contextual changes in the role of TGF-β remain to be elucidated. Xu et al provided molecular insight into how TGF-β converts from a tumor suppressor to a tumor promoter. It was found that 14-3-3ζ turned off the tumor suppression function of TGF-β by destabilizing p53, a Smad partner in premalignant cells. By contrast, 14-3-3ζ promoted TGF-β-induced distant metastasis by stabilizing Gli family zinc finger 2 (Gli2) and inducing the partnering of Gli2 with Smads in malignant cells (70). Therefore, the 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may provide therapeutic targets in TGF-β-mediated cancer progression.

Acknowledgements

This review was supported by grants from the National Natural Science Foundation of China (grant no. 81502131), The Natural Science Foundation of Chongqing (grant no. cstc2016jcyjA0405) and the Science and Technology Project of Chongqing Municipal Education Commission (grant no. KJ1500332).

Glossary

Abbreviations

Abbreviations:

TGF-β

transforming growth factor-β

EMT

epithelial-mesenchymal transition

CDKIs

cyclin-dependent kinase inhibitors

PI3K

phosphoinositide 3-kinase

MAPK

mitogen-activated protein kinase

CSCs

cancer stem cells

TAMs

tumor-associated macrophages

ROS

reactive oxygen species

MMP

matrix metalloproteinase

References

1 

Morris SM, Carter KT, Baek JY, Koszarek A, Yeh MM, Knoblaugh SE and Grady WM: TGF-β signaling alters the pattern of liver tumorigenesis induced by Pten inactivation. Oncogene. 34:3273–3282. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, et al: Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 113:1774–1783. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Attisano L and Wrana JL: Signal integration in TGF-β, WNT, and Hippo pathways. F1000Prime Rep. 5:172013. View Article : Google Scholar : PubMed/NCBI

4 

Ikushima H and Miyazono K: TGFbeta signalling: A complex web in cancer progression. Nat Rev Cancer. 10:415–424. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Derynck R, Akhurst RJ and Balmain A: TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 29:117–129. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Kiyono K, Suzuki HI, Morishita Y, Komuro A, Iwata C, Yashiro M, Hirakawa K, Kano MR and Miyazono K: c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma. Cancer Sci. 100:1809–1816. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Komuro A, Yashiro M, Iwata C, Morishita Y, Johansson E, Matsumoto Y, Watanabe A, Aburatani H, Miyoshi H, Kiyono K, et al: Diffuse-type gastric carcinoma: Progression, angiogenesis, and transforming growth factor beta signaling. J Natl Cancer Inst. 101:592–604. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Roberts AB and Wakefield LM: The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA. 100:8621–8623. 2003. View Article : Google Scholar : PubMed/NCBI

9 

Massagué J: TGF-beta signal transduction. Annu Rev Biochem. 67:753–791. 1998. View Article : Google Scholar : PubMed/NCBI

10 

Massagué J, Blain SW and Lo RS: TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 103:295–309. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Wang Y, Liu T, Tang W, Deng B, Chen Y, Zhu J and Shen X: Hepatocellular carcinoma cells induce regulatory T cells and lead to poor prognosis via production of transforming growth factor-β1. Cell Physiol Biochem. 38:306–318. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Shen H, Guan D, Shen J, Wang M, Chen X, Xu T, Liu L and Shu Y: TGF-β1 induces erlotinib resistance in non-small cell lung cancer by down-regulating PTEN. Biomed Pharmacother. 77:1–6. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Yoshimoto T, Fujita T, Kajiya M, Matsuda S, Ouhara K, Shiba H and Kurihara H: Involvement of smad2 and Erk/Akt cascade in TGF-β1-induced apoptosis in human gingival epithelial cells. Cytokine. 75:165–173. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Dai C, Yang J and Liu Y: Transforming growth factor-beta1 potentiates renal tubular epithelial cell death by a mechanism independent of Smad signaling. J Biol Chem. 278:12537–12545. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Lyons RM, Gentry LE, Purchio AF and Moses HL: Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol. 110:1361–1367. 1990. View Article : Google Scholar : PubMed/NCBI

16 

Andreasen PA, Kjøller L, Christensen L and Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: A review. Int J Cancer. 72:1–22. 1997. View Article : Google Scholar : PubMed/NCBI

17 

Yu Q and Stamenkovic I: Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14:163–176. 2000.PubMed/NCBI

18 

Mir FA, Contreras-Ruiz L and Masli S: Thrombospondin-1-dependent immune regulation by transforming growth factor-β2-exposed antigen-presenting cells. Immunology. 146:547–556. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Murphy-Ullrich JE and Poczatek M: Activation of latent TGF-beta by thrombospondin-1: Mechanisms and physiology. Cytokine Growth Factor Rev. 11:59–69. 2000. View Article : Google Scholar : PubMed/NCBI

20 

Dutta A, Li J, Fedele C, Sayeed A, Singh A, Violette SM, Manes TD and Languino LR: αvβ6 integrin is required for TGFβ1-mediated matrix metalloproteinase2 expression. Biochem J. 466:525–536. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Feng XH and Derynck R: Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 21:659–693. 2005. View Article : Google Scholar : PubMed/NCBI

22 

Shi Y and Massagué J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 113:685–700. 2003. View Article : Google Scholar : PubMed/NCBI

23 

Heldin CH, Miyazono K and ten Dijke P: TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 390:465–471. 1997. View Article : Google Scholar : PubMed/NCBI

24 

Park S, Jung HH, Park YH, Ahn JS and Im YH: ERK/MAPK pathways play critical roles in EGFR ligands-induced MMP1 expression. Biochem Biophys Res Commun. 407:680–686. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Cheng X, Gao W, Dang Y, Liu X, Li Y, Peng X and Ye X: Both ERK/MAPK and TGF-Beta/Smad signaling pathways play a role in the kidney fibrosis of diabetic mice accelerated by blood glucose fluctuation. J Diabetes Res. 2013:4637402013. View Article : Google Scholar : PubMed/NCBI

26 

Yu JS, Ramasamy TS, Murphy N, Holt MK, Czapiewski R, Wei SK and Cui W: PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation. Nat Commun. 6:72122015. View Article : Google Scholar : PubMed/NCBI

27 

Vo BT, Morton D Jr, Komaragiri S, Millena AC, Leath C and Khan SA: TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology. 154:1768–1779. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Singha PK, Pandeswara S, Geng H, Lan R, Venkatachalam MA and Saikumar P: TGF-β induced TMEPAI/PMEPA1 inhibits canonical Smad signaling through R-Smad sequestration and promotes non-canonical PI3K/Akt signaling by reducing PTEN in triple negative breast cancer. Genes Cancer. 5:320–336. 2014.PubMed/NCBI

29 

Reduced beta 2 glycoprotein I improve diabetic nephropathy via inhibiting TGF-β1-p38 MAPK pathway [Retraction]. Int J Clin Exp Med. 8:197922015.PubMed/NCBI

30 

Chen IT, Hsu PH, Hsu WC, Chen NJ and Tseng PH: Polyubiquitination of transforming growth factor β-activated Kinase 1 (TAK1) at lysine 562 residue regulates TLR4-mediated JNK and p38 MAPK activation. Sci Rep. 5:123002015. View Article : Google Scholar : PubMed/NCBI

31 

Suzuki T, Dai P, Hatakeyama T, Harada Y, Tanaka H, Yoshimura N and Takamatsu T: TGF-β signaling regulates pancreatic β-Cell proliferation through control of cell cycle regulator p27 expression. Acta Histochem Cytochem. 46:51–58. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC and Ozturk M: Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology. 52:966–974. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Wang Y, Wu J, Lin B, Li X, Zhang H, Ding H, Chen X, Lan L and Luo H: Galangin suppresses HepG2 cell proliferation by activating the TGF-β receptor/Smad pathway. Toxicology. 326:9–17. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Guo C, Liu S, Dong P, Zhao D, Wang C, Tao Z and Sun MZ: Akbu-LAAO exhibits potent anti-tumor activity to HepG2 cells partially through produced H2O2 via TGF-β signal pathway. Sci Rep. 5:182152015. View Article : Google Scholar : PubMed/NCBI

35 

Cheng L, Zhang C, Li D, Zou J and Wang J: Transforming growth factor-β1 (TGF-β1) induces mouse precartilaginous stem cell proliferation through TGF-β receptor II (TGFRII)-Akt-β-catenin signaling. Int J Mol Sci. 15:12665–12676. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Kudo-Saito C, Shirako H, Takeuchi T and Kawakami Y: Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 15:195–206. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Hay ED: An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 154:8–20. 1995. View Article : Google Scholar : PubMed/NCBI

38 

Muthusamy BP, Budi EH, Katsuno Y, Lee MK, Smith SM, Mirza AM, Akhurst RJ and Derynck R: ShcA protects against epithelial-mesenchymal transition through compartmentalized inhibition of TGF-β-Induced Smad activation. PLoS Biol. 13:e10023252015. View Article : Google Scholar : PubMed/NCBI

39 

Xu J, Lamouille S and Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19:156–172. 2009. View Article : Google Scholar : PubMed/NCBI

40 

Lee JY, Chang JW, Yang WS, Kim SB, Park SK, Park JS and Lee SK: Albumin-induced epithelial-mesenchymal transition and ER stress are regulated through a common ROS-c-Src kinase-mTOR pathway: Effect of imatinib mesylate. Am J Physiol Renal Physiol. 300:F1214–1222. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR and Massagué J: TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 133:66–77. 2008. View Article : Google Scholar : PubMed/NCBI

42 

Naka K: TGF-β signaling in cancer stem cells. Nihon Rinsho. 73:784–789. 2015.(In Japanese). PubMed/NCBI

43 

You H, Ding W and Rountree CB: Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology. 51:1635–1644. 2010. View Article : Google Scholar : PubMed/NCBI

44 

Chanmee T, Ontong P, Mochizuki N, Kongtawelert P, Konno K and Itano N: Excessive hyaluronan production promotes acquisition of cancer stem cell signatures through the coordinated regulation of Twist and the transforming growth factor β (TGF-β)-Snail signaling axis. J Biol Chem. 289:26038–26056. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Fan QM, Jing YY, Yu GF, Kou XR, Ye F, Gao L, Li R, Zhao QD, Yang Y, Lu ZH and Wei LX: Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 352:160–168. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Yu D, Shin HS, Lee YS and Lee YC: miR-106b modulates cancer stem cell characteristics through TGF-β/Smad signaling in CD44-positive gastric cancer cells. Lab Invest. 94:1370–1381. 2014. View Article : Google Scholar : PubMed/NCBI

47 

El Helou R, Wicinski J, Guille A, Adélaïde J, Finetti P, Bertucci F, Chaffanet M, Birnbaum D, Charafe-Jauffret E and Ginestier C: Brief reports: A distinct DNA methylation signature defines breast cancer stem cells and predicts cancer outcome. Stem Cells. 32:3031–3036. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Wang J, Shao N, Ding X, Tan B, Song Q, Wang N, Jia Y, Ling H and Cheng Y: Crosstalk between transforming growth factor-β signaling pathway and long non-coding RNAs in cancer. Cancer Lett. 370:296–301. 2016. View Article : Google Scholar : PubMed/NCBI

49 

Martin M and Herceg Z: From hepatitis to hepatocellular carcinoma: A proposed model for cross-talk between inflammation and epigenetic mechanisms. Genome Med. 4:82012. View Article : Google Scholar : PubMed/NCBI

50 

Hernandez-Gea V, Toffanin S, Friedman SL and Llovet JM: Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 144:512–527. 2013. View Article : Google Scholar : PubMed/NCBI

51 

Nana AW, Yang PM and Lin HY: Overview of transforming growth factor β superfamily involvement in glioblastoma initiation and progression. Asian Pac J Cancer Prev. 16:6813–6823. 2015. View Article : Google Scholar : PubMed/NCBI

52 

Neuzillet C, de Gramont A, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S and Raymond E: Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas. Oncotarget. 5:78–94. 2014. View Article : Google Scholar : PubMed/NCBI

53 

Yang L, Pang Y and Moses HL: TGF-beta and immune cells: An important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31:220–227. 2010. View Article : Google Scholar : PubMed/NCBI

54 

Yang L: TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy. Curr Mol Med. 10:374–380. 2010. View Article : Google Scholar : PubMed/NCBI

55 

Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L, et al: CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 19:541–555. 2011. View Article : Google Scholar : PubMed/NCBI

56 

Pittet MJ: Behavior of immune players in the tumor microenvironment. Curr Opin Oncol. 21:53–59. 2009. View Article : Google Scholar : PubMed/NCBI

57 

Condeelis J and Pollard JW: Macrophages: obligate partners for tumor cell migration, invasion and metastasis. Cell. 124:263–266. 2006. View Article : Google Scholar : PubMed/NCBI

58 

Storz P: Reactive oxygen species in tumor progression. Front Biosci. 10:1881–1896. 2005. View Article : Google Scholar : PubMed/NCBI

59 

Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, et al: Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 436:123–127. 2005. View Article : Google Scholar : PubMed/NCBI

60 

Pelicano H, Carney D and Huang P: ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 7:97–110. 2004. View Article : Google Scholar : PubMed/NCBI

61 

Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK and Lambeth JD: Cell transformation by the superoxide-generating oxidase Mox1. Nature. 401:79–82. 1999. View Article : Google Scholar : PubMed/NCBI

62 

Kalluri R: Basement membranes: Structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 3:422–433. 2003. View Article : Google Scholar : PubMed/NCBI

63 

Hasegawa Y, Takanashi S, Kanehira Y, Tsushima T, Imai T and Okumura K: Transforming growth factor-beta1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer. 91:964–971. 2001. View Article : Google Scholar : PubMed/NCBI

64 

Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, Guise TA and Massagué J: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 3:537–549. 2003. View Article : Google Scholar : PubMed/NCBI

65 

Sánchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L and Bernabéu C: Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem. 276:38527–38535. 2001. View Article : Google Scholar : PubMed/NCBI

66 

Zhao J, Cheng Q, Ye P, Yang G, Liu S, Ao Q, Liu Y and Hu Y: Atorvastatin improves pathological changes in the aged kidney by upregulating peroxisome proliferator-activated receptor expression and reducing matrix metalloproteinase-9 and transforming growth factor-β1 levels. Exp Gerontol. 74:37–42. 2016. View Article : Google Scholar : PubMed/NCBI

67 

Hua Y, Zhang W, Xie Z, Xu N and Lu Y: MMP-2 is mainly expressed in arterioles and contributes to cerebral vascular remodeling associated with TGF-β1 signaling. J Mol Neurosci. 59:317–325. 2016. View Article : Google Scholar : PubMed/NCBI

68 

Şekerci ÇA, Işbilen B, Işman F, Akbal C, Şimşek F and Tarcan T: Urinary NGF, TGF-β1, TIMP-2 and bladder wall thickness predict neurourological findings in children with myelodysplasia. J Urol. 191:199–205. 2014. View Article : Google Scholar : PubMed/NCBI

69 

Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Lüttges J, Klöppel G, Graeven U, Eilert-Micus C, et al: Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA. 97:9624–9629. 2000. View Article : Google Scholar : PubMed/NCBI

70 

Xu J, Acharya S, Sahin O, Zhang Q, Saito Y, Yao J, Wang H, Li P, Zhang L, Lowery FJ, et al: 14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. Cancer Cell. 27:177–192. 2015. View Article : Google Scholar : PubMed/NCBI

71 

Akahira J, Sugihashi Y, Suzuki T, Ito K, Niikura H, Moriya T, Nitta M, Okamura H, Inoue S, Sasano H, et al: Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: Its correlation with aberrant DNA methylation. Clin Cancer Res. 10:2687–2693. 2004. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

January-2018
Volume 17 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

The Cancer Story
Copy and paste a formatted citation
x
Spandidos Publications style
Liu S, Chen S and Zeng J: TGF‑β signaling: A complex role in tumorigenesis (Review). Mol Med Rep 17: 699-704, 2018
APA
Liu, S., Chen, S., & Zeng, J. (2018). TGF‑β signaling: A complex role in tumorigenesis (Review). Molecular Medicine Reports, 17, 699-704. https://doi.org/10.3892/mmr.2017.7970
MLA
Liu, S., Chen, S., Zeng, J."TGF‑β signaling: A complex role in tumorigenesis (Review)". Molecular Medicine Reports 17.1 (2018): 699-704.
Chicago
Liu, S., Chen, S., Zeng, J."TGF‑β signaling: A complex role in tumorigenesis (Review)". Molecular Medicine Reports 17, no. 1 (2018): 699-704. https://doi.org/10.3892/mmr.2017.7970