A Mini Review on the Multifaceted Role of TGF-β in Metastasis Progression: Molecular Mechanisms and Novel Therapeutic Strategies
Abstract
TGF-β acts as a cytokine with a dual role in tumor control and metastasis. In the early stages, TGF-β functions as a tumor suppressor, helping to maintain cellular homeostasis. However, as cancer progresses, this cytokine can promote tumor invasion and metastasis by regulating the tumor microenvironment and the immune system. TGF-β controls multiple functions, including growth regulation, differentiation, apoptosis, and cell signaling, through SMAD and non-SMAD signaling pathways. In cancer, the signaling pathway of this cytokine activates the epithelial-mesenchymal transition (EMT) process, leading to reduced cell adhesion, increased motility, and ultimately, tumor invasion. These changes are also associated with resistance to chemotherapy. Additionally, TGF-β stimulates angiogenesis by inducing pro-angiogenic factors such as VEGF and PDGF, which are crucial for the spread of metastatic tumors. Furthermore, this cytokine plays a significant role in tumor immune evasion by suppressing the activity of T cells and NK cells while promoting regulatory T cells (Tregs). Targeted therapies against TGF-β, including ligand receptors, monoclonal antibodies, kinase inhibitors, and antisense oligonucleotides (ASO), have shown promising results in preclinical and clinical studies. However, challenges such as tumor resistance to therapy and side effects due to the broad inhibition of TGF-β isoforms remain. Therefore, efforts to improve TGF-β-based therapies and combine them with other treatments, including immunotherapy, are ongoing.
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3. Wang A, Huang Y, Yang X. TGF-β promotes proliferation and inhibits apoptosis of liver cancer Huh-7 cells by regulating MiR-182/CADM1. Tropical Journal of Pharmaceutical Research. 2023;22(9):1785-95.
4. Golán-Cancela I, Caja L. The TGF-β Family in Glioblastoma. International journal of molecular sciences. 2024;25(2).
5. David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, et al. TGF-β Tumor Suppression through a Lethal EMT. Cell. 2016;164(5):1015-30.
6. Zhang M, Zhang YY, Chen Y, Wang J, Wang Q, Lu H. TGF-β Signaling and Resistance to Cancer Therapy. Frontiers in cell and developmental biology. 2021;9:786728.
7. Li L, Yu R, Cai T, Chen Z, Lan M, Zou T, et al. Effects of immune cells and cytokines on inflammation and immunosuppression in the tumor microenvironment. International immunopharmacology. 2020;88:106939.
8. Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, et al. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC cancer. 2015;15:97.
9. Zhu Y, Wu J, Ma W, Zhang H, Wang D. Expression of TGF-β1, Snail, E-cadherin and N-cadherin in gastric cancer and its significance. Chinese Journal of Clinical Oncology. 2007;4:384-9.
10. Minto AW, Wilson HM, Rees AJ, Quigg RJ, Brown PA. Selective expression of TGF-beta2 and TGF-beta3 isoforms in early mesangioproliferative glomerulonephritis. Nephron Experimental nephrology. 2004;96(4):e111-8.
11. Li Y, Fan W, Link F, Wang S, Dooley S. Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease. JHEP reports : innovation in hepatology. 2022;4(2):100397.
12. Wu M-Z, Yuan Y-c, Huang B-Y, Chen J-X, Li B-K, Fang J-H, et al. Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis. Signal Transduction and Targeted Therapy. 2021;6(1):395.
13. Afshari H, Noori S, Nourbakhsh M, Daraei A, Azami Movahed M, Zarghi A. A novel imidazo[1,2-a]pyridine derivative and its co-administration with curcumin exert anti-inflammatory effects by modulating the STAT3/NF-κB/iNOS/COX-2 signaling pathway in breast and ovarian cancer cell lines. BioImpacts : BI. 2024;14(2):27618.
14. Wrana JL. Signaling by the TGFβ superfamily. Cold Spring Harbor perspectives in biology. 2013;5(10):a011197.
15. Budi EH, Duan D, Derynck R. Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility. Trends in cell biology. 2017;27(9):658-72.
16. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. The EMBO journal. 1997;16(17):5353-62.
17. Li J, Zou L, Zhou Y, Li L, Zhu Y, Yang Y, et al. A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population. Molecular carcinogenesis. 2017;56(7):1798-807.
18. Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. Journal of cellular physiology. 2022;237(1):59-85.
19. Baek SH, Ko JH, Lee JH, Kim C, Lee H, Nam D, et al. Ginkgolic Acid Inhibits Invasion and Migration and TGF-β-Induced EMT of Lung Cancer Cells Through PI3K/Akt/mTOR Inactivation. Journal of cellular physiology. 2017;232(2):346-54.
20. Manickam N, Patel M, Griendling KK, Gorin Y, Barnes JL. RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. American journal of physiology Renal physiology. 2014;307(2):F159-71.
21. Li J, Zhao Z, Liu J, Huang N, Long D, Wang J, et al. MEK/ERK and p38 MAPK regulate chondrogenesis of rat bone marrow mesenchymal stem cells through delicate interaction with TGF-beta1/Smads pathway. Cell proliferation. 2010;43(4):333-43.
22. Papageorgis P. TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis. Journal of oncology. 2015;2015:587193.
23. Loh C-Y, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, et al. The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells [Internet]. 2019; 8(10).
24. Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer cell. 2011;20(3):370-83.
25. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472-6.
26. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525-30.
27. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nature reviews Molecular cell biology. 2014;15(3):178-96.
28. Shirakihara T, Saitoh M, Miyazono K. Differential regulation of epithelial and mesenchymal markers by deltaEF1 proteins in epithelial mesenchymal transition induced by TGF-beta. Molecular biology of the cell. 2007;18(9):3533-44.
29. Boye A. A cytokine in turmoil: Transforming growth factor beta in cancer. Biomedicine & Pharmacotherapy. 2021;139:111657.
30. Majidpoor J, Mortezaee K. Steps in metastasis: an updated review. Medical oncology (Northwood, London, England). 2021;38(1):3.
31. Chen Q, Yang D, Zong H, Zhu L, Wang L, Wang X, et al. Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway. Oncogenesis. 2017;6(8):e375.
32. Jung HY, Fattet L, Yang J. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(5):962-8.
33. Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization. Nature reviews Cancer. 2009;9(4):274-84.
34. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. The Journal of clinical investigation. 1999;103(2):197-206.
35. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer cell. 2003;3(6):537-49.
36. Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis. Frontiers in immunology. 2022;13:824117.
37. Guo J, Hu Z, Yan F, Lei S, Li T, Li X, et al. Angelica dahurica promoted angiogenesis and accelerated wound healing in db/db mice via the HIF-1α/PDGF-β signaling pathway. Free Radical Biology and Medicine. 2020;160:447-57.
38. Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, et al. The role of microenvironment in tumor angiogenesis. Journal of experimental & clinical cancer research : CR. 2020;39(1):204.
39. Zong J, Jiang J, Shi P, Liu J, Wang W, Li B, et al. Fatty acid extracts facilitate cutaneous wound healing through activating AKT, ERK, and TGF-β/Smad3 signaling and promoting angiogenesis. American journal of translational research. 2020;12(2):478-92.
40. Tsuda T. Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions. International journal of molecular sciences [Internet]. 2018; 19(9).
41. Davis GE, Senger DR. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circulation research. 2005;97(11):1093-107.
42. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, et al. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation. 2014;129(15):1586-97.
43. Rossi E, Bernabeu C, Smadja DM. Endoglin as an Adhesion Molecule in Mature and Progenitor Endothelial Cells: A Function Beyond TGF-β. Frontiers in medicine. 2019;6:10.
44. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12(2):171-81.
45. Ma X, Gao Y, Chen Y, Liu J, Yang C, Bao C, et al. M2-Type Macrophages Induce Tregs Generation by Activating the TGF-β/Smad Signalling Pathway to Promote Colorectal Cancer Development. OncoTargets and therapy. 2021;14:5391-402.
46. Fucikova J, Palova-Jelinkova L, Bartunkova J, Spisek R. Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications. Frontiers in immunology. 2019;10:2393.
47. Ge Z, Ding S. The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy. Frontiers in oncology. 2020;10:590941.
48. Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25(3):455-71.
49. Danielpour D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals [Internet]. 2024; 17(4).
50. Teixeira AF, Ten Dijke P, Zhu HJ. On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges? Frontiers in cell and developmental biology. 2020;8:605.
51. Edwards JR, Nyman JS, Lwin ST, Moore MM, Esparza J, O'Quinn EC, et al. Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;25(11):2419-26.
52. Cordeiro MF, Gay JA, Khaw PT. Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent. Investigative ophthalmology & visual science. 1999;40(10):2225-34.
53. Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, et al. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer chemotherapy and pharmacology. 2015;76(6):1143-52.
54. Nadal E, Saleh M, Aix SP, Ochoa-de-Olza M, Patel SP, Antonia S, et al. A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer. BMC cancer. 2023;23(1):708.
55. Garrison K, Hahn T, Lee WC, Ling LE, Weinberg AD, Akporiaye ET. The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer immunology, immunotherapy : CII. 2012;61(4):511-21.
56. Mohammad KS, Javelaud D, Fournier PG, Niewolna M, McKenna CR, Peng XH, et al. TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer research. 2011;71(1):175-84.
57. Xie F, Ling L, van Dam H, Zhou F, Zhang L. TGF-β signaling in cancer metastasis. Acta biochimica et biophysica Sinica. 2018;50(1):121-32.
58. Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, et al. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer science. 2011;102(6):1193-200.
59. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Translational lung cancer research. 2016;5(3):288-300.
60. Ramsey JD, Flynn NH. Cell-penetrating peptides transport therapeutics into cells. Pharmacology & therapeutics. 2015;154:78-86.
61. Kang JH, Jung MY, Yin X, Andrianifahanana M, Hernandez DM, Leof EB. Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling. The Journal of clinical investigation. 2017;127(7):2541-54.
62. Zhao BM, Hoffmann FM. Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Molecular biology of the cell. 2006;17(9):3819-31.
2. Gholinejad Z, Kheiripour N, Nourbakhsh M, Ilbeigi D, Behroozfar K, Hesari Z, et al. Extracellular NAMPT/Visfatin induces proliferation through ERK1/2 and AKT and inhibits apoptosis in breast cancer cells. Peptides. 2017;92:9-15.
3. Wang A, Huang Y, Yang X. TGF-β promotes proliferation and inhibits apoptosis of liver cancer Huh-7 cells by regulating MiR-182/CADM1. Tropical Journal of Pharmaceutical Research. 2023;22(9):1785-95.
4. Golán-Cancela I, Caja L. The TGF-β Family in Glioblastoma. International journal of molecular sciences. 2024;25(2).
5. David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, et al. TGF-β Tumor Suppression through a Lethal EMT. Cell. 2016;164(5):1015-30.
6. Zhang M, Zhang YY, Chen Y, Wang J, Wang Q, Lu H. TGF-β Signaling and Resistance to Cancer Therapy. Frontiers in cell and developmental biology. 2021;9:786728.
7. Li L, Yu R, Cai T, Chen Z, Lan M, Zou T, et al. Effects of immune cells and cytokines on inflammation and immunosuppression in the tumor microenvironment. International immunopharmacology. 2020;88:106939.
8. Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, et al. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC cancer. 2015;15:97.
9. Zhu Y, Wu J, Ma W, Zhang H, Wang D. Expression of TGF-β1, Snail, E-cadherin and N-cadherin in gastric cancer and its significance. Chinese Journal of Clinical Oncology. 2007;4:384-9.
10. Minto AW, Wilson HM, Rees AJ, Quigg RJ, Brown PA. Selective expression of TGF-beta2 and TGF-beta3 isoforms in early mesangioproliferative glomerulonephritis. Nephron Experimental nephrology. 2004;96(4):e111-8.
11. Li Y, Fan W, Link F, Wang S, Dooley S. Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease. JHEP reports : innovation in hepatology. 2022;4(2):100397.
12. Wu M-Z, Yuan Y-c, Huang B-Y, Chen J-X, Li B-K, Fang J-H, et al. Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis. Signal Transduction and Targeted Therapy. 2021;6(1):395.
13. Afshari H, Noori S, Nourbakhsh M, Daraei A, Azami Movahed M, Zarghi A. A novel imidazo[1,2-a]pyridine derivative and its co-administration with curcumin exert anti-inflammatory effects by modulating the STAT3/NF-κB/iNOS/COX-2 signaling pathway in breast and ovarian cancer cell lines. BioImpacts : BI. 2024;14(2):27618.
14. Wrana JL. Signaling by the TGFβ superfamily. Cold Spring Harbor perspectives in biology. 2013;5(10):a011197.
15. Budi EH, Duan D, Derynck R. Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility. Trends in cell biology. 2017;27(9):658-72.
16. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. The EMBO journal. 1997;16(17):5353-62.
17. Li J, Zou L, Zhou Y, Li L, Zhu Y, Yang Y, et al. A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population. Molecular carcinogenesis. 2017;56(7):1798-807.
18. Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. Journal of cellular physiology. 2022;237(1):59-85.
19. Baek SH, Ko JH, Lee JH, Kim C, Lee H, Nam D, et al. Ginkgolic Acid Inhibits Invasion and Migration and TGF-β-Induced EMT of Lung Cancer Cells Through PI3K/Akt/mTOR Inactivation. Journal of cellular physiology. 2017;232(2):346-54.
20. Manickam N, Patel M, Griendling KK, Gorin Y, Barnes JL. RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. American journal of physiology Renal physiology. 2014;307(2):F159-71.
21. Li J, Zhao Z, Liu J, Huang N, Long D, Wang J, et al. MEK/ERK and p38 MAPK regulate chondrogenesis of rat bone marrow mesenchymal stem cells through delicate interaction with TGF-beta1/Smads pathway. Cell proliferation. 2010;43(4):333-43.
22. Papageorgis P. TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis. Journal of oncology. 2015;2015:587193.
23. Loh C-Y, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, et al. The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells [Internet]. 2019; 8(10).
24. Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer cell. 2011;20(3):370-83.
25. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472-6.
26. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525-30.
27. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nature reviews Molecular cell biology. 2014;15(3):178-96.
28. Shirakihara T, Saitoh M, Miyazono K. Differential regulation of epithelial and mesenchymal markers by deltaEF1 proteins in epithelial mesenchymal transition induced by TGF-beta. Molecular biology of the cell. 2007;18(9):3533-44.
29. Boye A. A cytokine in turmoil: Transforming growth factor beta in cancer. Biomedicine & Pharmacotherapy. 2021;139:111657.
30. Majidpoor J, Mortezaee K. Steps in metastasis: an updated review. Medical oncology (Northwood, London, England). 2021;38(1):3.
31. Chen Q, Yang D, Zong H, Zhu L, Wang L, Wang X, et al. Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway. Oncogenesis. 2017;6(8):e375.
32. Jung HY, Fattet L, Yang J. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(5):962-8.
33. Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization. Nature reviews Cancer. 2009;9(4):274-84.
34. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. The Journal of clinical investigation. 1999;103(2):197-206.
35. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer cell. 2003;3(6):537-49.
36. Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis. Frontiers in immunology. 2022;13:824117.
37. Guo J, Hu Z, Yan F, Lei S, Li T, Li X, et al. Angelica dahurica promoted angiogenesis and accelerated wound healing in db/db mice via the HIF-1α/PDGF-β signaling pathway. Free Radical Biology and Medicine. 2020;160:447-57.
38. Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, et al. The role of microenvironment in tumor angiogenesis. Journal of experimental & clinical cancer research : CR. 2020;39(1):204.
39. Zong J, Jiang J, Shi P, Liu J, Wang W, Li B, et al. Fatty acid extracts facilitate cutaneous wound healing through activating AKT, ERK, and TGF-β/Smad3 signaling and promoting angiogenesis. American journal of translational research. 2020;12(2):478-92.
40. Tsuda T. Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions. International journal of molecular sciences [Internet]. 2018; 19(9).
41. Davis GE, Senger DR. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circulation research. 2005;97(11):1093-107.
42. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, et al. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation. 2014;129(15):1586-97.
43. Rossi E, Bernabeu C, Smadja DM. Endoglin as an Adhesion Molecule in Mature and Progenitor Endothelial Cells: A Function Beyond TGF-β. Frontiers in medicine. 2019;6:10.
44. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12(2):171-81.
45. Ma X, Gao Y, Chen Y, Liu J, Yang C, Bao C, et al. M2-Type Macrophages Induce Tregs Generation by Activating the TGF-β/Smad Signalling Pathway to Promote Colorectal Cancer Development. OncoTargets and therapy. 2021;14:5391-402.
46. Fucikova J, Palova-Jelinkova L, Bartunkova J, Spisek R. Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications. Frontiers in immunology. 2019;10:2393.
47. Ge Z, Ding S. The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy. Frontiers in oncology. 2020;10:590941.
48. Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25(3):455-71.
49. Danielpour D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals [Internet]. 2024; 17(4).
50. Teixeira AF, Ten Dijke P, Zhu HJ. On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges? Frontiers in cell and developmental biology. 2020;8:605.
51. Edwards JR, Nyman JS, Lwin ST, Moore MM, Esparza J, O'Quinn EC, et al. Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;25(11):2419-26.
52. Cordeiro MF, Gay JA, Khaw PT. Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent. Investigative ophthalmology & visual science. 1999;40(10):2225-34.
53. Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, et al. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer chemotherapy and pharmacology. 2015;76(6):1143-52.
54. Nadal E, Saleh M, Aix SP, Ochoa-de-Olza M, Patel SP, Antonia S, et al. A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer. BMC cancer. 2023;23(1):708.
55. Garrison K, Hahn T, Lee WC, Ling LE, Weinberg AD, Akporiaye ET. The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer immunology, immunotherapy : CII. 2012;61(4):511-21.
56. Mohammad KS, Javelaud D, Fournier PG, Niewolna M, McKenna CR, Peng XH, et al. TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer research. 2011;71(1):175-84.
57. Xie F, Ling L, van Dam H, Zhou F, Zhang L. TGF-β signaling in cancer metastasis. Acta biochimica et biophysica Sinica. 2018;50(1):121-32.
58. Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, et al. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer science. 2011;102(6):1193-200.
59. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Translational lung cancer research. 2016;5(3):288-300.
60. Ramsey JD, Flynn NH. Cell-penetrating peptides transport therapeutics into cells. Pharmacology & therapeutics. 2015;154:78-86.
61. Kang JH, Jung MY, Yin X, Andrianifahanana M, Hernandez DM, Leof EB. Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling. The Journal of clinical investigation. 2017;127(7):2541-54.
62. Zhao BM, Hoffmann FM. Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Molecular biology of the cell. 2006;17(9):3819-31.
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| Section | Review Article(s) | |
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How to Cite
1.
Mohammadi Y, Nourbakhsh M. A Mini Review on the Multifaceted Role of TGF-β in Metastasis Progression: Molecular Mechanisms and Novel Therapeutic Strategies. ABI. 2024;2(3):125-131.
