Volume 22, Issue 3 (Aug - Sep 2018)                   2018, 22(3): 77-92 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Forouzesh F, Agharezaee N. Review on the molecular signaling pathways involved in controlling cancer stem cells and treatment. Journal of Inflammatory Diseases. 2018; 22 (3) :77-92
URL: http://journal.qums.ac.ir/article-1-2588-en.html
1- Department of Genetics,Tehran Medical Sciences Branch ,Islamic Azad University, Tehran, Iran , f8forouzesh@gmail.com
2- Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
Abstract:   (6236 Views)
In recent years, knowledge of the biology of stem cell has been very effective and the precise and proper regulation of stem cell function are important for their bio-activity. Several main signaling pathways have roles in regulating them including Wnt/β-catenin, and Hedgehog which mediate different stem cell properties including self-renewal, survival, proliferation, and differentiation. Also, molecular structures such as microRNAs act as tumor inhibitors or oncogenes and will change the direction of the messenger. The purpose of this review is to find and introduce different signaling pathways involved in controlling cancer stem cells with cancer treatment goals. The search was conducted using several databases including Google Scholar, PubMed, Scopus, Science Direct and totally 93 papers were selected.
It seems that very important signaling pathways have been disturbed in cancers and excessive or abnormal signaling through these pathways can contribute to the survival of stem cells. Many of these pathways are not direct, but as an interconnected network of signaling could feed each other. Better therapeutic goals can be achieved with understanding signaling pathways involved in cancer stem cells and drug resistance.
Full-Text [PDF 232 kb]   (8566 Downloads)    
Type of Study: Review article | Subject: Biotechnology

1. Moghbeli M, Moghbeli F, Forghanifard MM, Abbaszadegan MR. Cancer stem cell detection and isolation. Med Oncol 2014; 31(9):69. [DOI] [PubMed]
2. Lau EY, Ho NP, Lee TK. Cancer stem cells and their microenvironment: biology and therapeutic implications. Stem Cells Int 2017; 2017: 3714190. [DOI] [PubMed]
3. Agharezaee N, Forouzesh F. The role of cancer stem cells in malignancies: properties, function and origin. J Jiroft Univ Med Sci 2017; 3(2): 95-106. [In Persian]
4. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med 2006; 355(12): 1253-61. [DOI] [PubMed]
5. Forouzesh F, Agharezaee N. The properties of cancer stem cells in tumor recurrence and metastasis in colorectal cancer. The 3rd International Gastrointestinal Cancer Congress 2016; Tehran, Iran: Shahid Beheshti University of Medical Sciences; Rasane Takhassosi Publishing; 2016: 149-50.
6. Jiang W, Peng J, Zhang Y, Cho WC, Jin K. The implications of cancer stem cells for cancer therapy. Int J Mol Sci 2012; 13(12): 16636-57. [DOI] [PubMed]
7. Koury J, Zhong L, Hao J. Targeting signaling pathways in cancer stem cells for cancer treatment. Stem Cells Int 2017; 2017: 2925869. [DOI] [PubMed]
8. Moheb-Alian A, Forouzesh F, Rostami-Nejad M, Rostami K. Mesenchymal stem cells as potential therapeutic approaches in celiac disease. Gastroenterol Hepatol Bed Bench 2016; 9(Suppl1): S1-7. [PubMed]
9. Sun X, Jiao X, Pestell TG, Fan C, Qin S, Mirabelli E, et al. MicroRNAs and cancer stem cells: the sword and the shield. Oncogene 2014; 33(42): 4967-77. doi: 10. 1038/onc. 2013.492. [PubMed]
10. Huelsken J, Behrens J. The Wnt signalling pathway. J Cell Sci 2002; 115(Pt 21): 3977-8. [DOI] [PubMed]
11. Ghahhari NM, Babashah S. Interplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer. Eur J Cancer 2015; 51(12): 1638-49. [DOI] [PubMed]
12. Bogaerts E, Heindryckx F, Vandewynckel YP, Van Grunsven LA, Van Vlierberghe H. The roles of transforming growth factor-beta, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours (Review). Int J Oncol 2014; 44(4): 1015-22. [DOI] [PubMed]
13. DiMeo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S, et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res 2009; 69(13): 5364-73. [DOI] [PubMed]
14. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006; 127[47]: 469-80. [DOI] [PubMed]
15. Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol 2012; 4(5). pii: a008052. [DOI] [PubMed]
16. Rich JN. Cancer stem cells in radiation resistance. Cancer Res 2007; 67(19): 8980-4. [DOI] [PubMed]
17. Duchartre Y, Kim YM, Kahn M. The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol 2016; 99: 141-9. [DOI] [PubMed]
18. Shiras A, Chettiar ST, Shepal V, Rajendran G, Prasad GR, Shastry P. Spontaneous transformation of human adult nontumorigenic stem cells to cancer stem cells is driven by genomic instability in a human model of glioblastoma. Stem Cells 2007; 25(6): 1478-89. [DOI] [PubMed]
19. Ayyanan A, Civenni G, Ciarloni L, Morel C, Mueller N, Lefort K, et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci U S A 2006; 103(10): 3799-804. doi:10.1073/ pnas.0600065103. [PubMed]
20. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol 2011; 23(6): 744-55. [DOI] [PubMed]
21. Zhang T, Otevrel T, Gao Z, Gao Z, Ehrlich SM, Fields JZ, et al. Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res 2001; 61(24): 8664-7. [PubMed]
22. Kim PJ, Plescia J, Clevers H, Fearon ER, Altieri DC. Survivin and molecular pathogenesis of colorectal cancer. Lancet 2003; 362(9379): 205-9. [DOI] [PubMed]
23. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103(2): 311-20. [DOI] [PubMed]
24. Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14(15): 1837-51. doi: 10. 1101/gad.14.15.1837. [PubMed]
25. Vaz AP, Ponnusamy MP, Seshacharyulu P, Batra SK. A concise review on the current understanding of pancreatic cancer stem cells. J Cancer Stem Cell Res 2014; 2. pii: e1004. [DOI] [PubMed]
26. Eisenmann DM. Wnt signaling. WormBook 2005; 1-17. doi: 10.1895/ wormbook.1. 7.1.
27. Lamming DW. Diminished mTOR signaling: a common mode of action for endocrine longevity factors. Springerplus 2014; 3: 735. [DOI] [PubMed]
28. Sinha S. Reproducibility of parameter learning with missing observations in naive Wnt Bayesian network trained on colorectal cancer samples and doxycycline-treated cell lines. Mol BioSyst 2015; 11(7): 1802-19. [DOI] [PubMed]
29. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006; 107(6): 2223-33. [DOI] [PubMed]
30. Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, et al. Targeting Notch to target cancer stem cells. Clin Cancer Res 2010; 16(12): 3141-52. [DOI] [PubMed]
31. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, et al. Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 2007; 13(1): 70-7. [DOI] [PubMed]
32. McCleary-Wheeler AL, McWilliams R, Fernandez-Zapico ME. Aberrant signaling pathways in pancreatic cancer: a two compartment view. Mol Carcinog 2012; 51(1): 25-39. [DOI] [PubMed]
33. Hu YY, Zheng MH, Zhang R, Liang YM, Han H. Notch signaling pathway and cancer metastasis. Adv Exp Med Biol 2012; 727: 186-98. [DOI] [PubMed]
34. Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H, et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 2010; 28(6): 1019-29. [DOI] [PubMed]
35. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442(7104): 823-6. [DOI] [PubMed]
36. Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR, et al. Notch promotes radioresistance of glioma stem cells. Stem Cells 2010; 28(1): 17-28. [DOI] [PubMed]
37. Stockhausen MT, Kristoffersen K, Poulsen HS. The functional role of Notch signaling in human gliomas. Neuro Oncol 2010; 12(2): 199-211. [DOI] [PubMed]
38. Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2010; 28(1): 5-16. doi: 10.1002/stem. 254. [PubMed]
39. Merchant AA, Matsui W. Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res 2010; 16(12): 3130-40. doi: 10. 1158/1078-0432.CCR-09-2846. [PubMed]
40. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003; 3(12): 903-11. [DOI] [PubMed]
41. Nicolis SK. Cancer stem cells and "stemness" genes in neuro-oncology. Neurobiol Dis 2007; 25(2): 217-29. [DOI] [PubMed]
42. Xu Q, Yuan X, Liu G, Black KL, Yu JS. Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 2008; 26(12): 3018-26. [DOI] [PubMed]
43. Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007; 17(2): 165-72. [DOI] [PubMed]
44. Peukert S, Miller-Moslin K. Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics. Chem Med Chem 2010; 5(4): 500-12. [DOI] [PubMed]
45. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12(1): 9-22. [DOI] [PubMed]
46. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27(41): 5497-510. [DOI] [PubMed]
47. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A 2007; 104(41): 16158-63. [DOI] [PubMed]
48. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 2008; 22(4): 436-48. [PubMed]
49. Fruman DA. mTOR signaling: new networks for ALL. Blood 2016; 127(22): 2658-9. [DOI] [PubMed]
50. Dvorak P, Dvorakova D, Hampl A. Fibroblast growth factor signaling in embryonic and cancer stem cells. FEBS Lett 2006; 580(12): 2869-74. [DOI] [PubMed]
51. Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol 2008; 26(17): 2916-24. doi: 10. 1200/JCO.2008.17.6792. [PubMed]
52. Song Z, Yue W, Wei B, Wang N, Li T, Guan L, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One 2011; 6(47): e17687. [DOI] [PubMed]
53. Gotoh N. Control of stemness by fibroblast growth factor signaling in stem cells and cancer stem cells. Curr Stem Cell Res Ther 2009; 4(1): 9-15. [DOI] [PubMed]
54. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 2011; 7(2): 292-306. [DOI] [PubMed]
55. Douville J, Beaulieu R, Balicki D. ALDH1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev 2009; 18(1): 17-25. [DOI] [PubMed]
56. Opdenaker LM, Modarai SR, and Boman BM. The Proportion of ALDEFLUOR-Positive Cancer Stem Cells Changes with Cell Culture Density Due to the Expression of Different ALDH Isoforms. Cancer Stud Mol Med 2015; 2(2): 87-95. [DOI] [PubMed]
57. Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008; 27(47): 6120-30. [DOI] [PubMed]
58. Nami B, Wang Z. HER2 in breast cancer stemness: a negative feedback loop towards Trastuzumab resistance. Cancers (Basel) 2017; 9(5): pii: E40. [DOI] [PubMed]
59. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006; 9(5): 391-403. [DOI] [PubMed]
60. Soeda A, Inagaki A, Oka N, Ikegame Y, Aoki H, Yoshimura S, et al. Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem 2008; 283(16): 10958-66. [DOI] [PubMed]
61. Sasaki T, Hiroki K, Yamashita Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Biomed Res Int 2013; 2013: 546318. [DOI] [PubMed]
62. Dreesen O, Brivanlou AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 2007; 3(1): 7-17. doi: 10. 1007/s12015-007-0004-8. [PubMed]
63. Chen DL, Zeng ZL, Yang J, Ren C, Wang DS, Wu WJ, et al. L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer. J Hematol Oncol 2013; 6: 43. [DOI] [PubMed]
64. Sherry MM, Reeves A, Wu JK, Cochran BH. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 2009; 27(10): 2383-92. [DOI] [PubMed]
65. Cao Y, Lathia JD, Eyler CE, Wu Q, Li Z, Wang H, et al. Erythropoietin receptor signaling through STAT3 is required for glioma stem cell maintenance. Genes Cancer 2010; 1(1): 50-61. [DOI] [PubMed]
66. Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007; 282(28): 20059-63. [DOI] [PubMed]
67. Forouzesh F, Agharezaei N. Therapeutic approaches to target the breast cancer stem cells using nanomedicines. The First Congress on Stem Cells, Cell Therapy & Regenerative Medicine 2017; Tehran, Iran: Rasane Takhassosi Publishing; 2017: 88.
68. Wei W, Tweardy DJ, Zhang M, Zhang X, Landua J, Petrovic I, et al. STAT3 signaling is activated preferentially in tumor initiating cells in claudin low models of human breast cancer. Stem Cells 2014; 32(10): 2571-82. [DOI] [PubMed]
69. Nair RR, Tolentino JH, Hazlehurst LA. Role of STAT3 in transformation and drug resistance in CML. Front Oncol 2012; 2: 30. [DOI] [PubMed]
70. Gou Q, Gong X, Jin J, Shi J, Hou Y. Peroxisome proliferator-activated receptors (PPARs) are potential drug targets for cancer therapy. Oncotarget 2017; 8(36): 60704-9. [DOI] [PubMed]
71. Tachibana K, Yamasaki D, Ishimoto K, Doi T. The role of PPARs in cancer. PPAR Res 2008; 2008: 102737. [DOI] [PubMed]
72. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007; 11(1): 69-82. [DOI] [PubMed]
73. Azzi S, Bruno S, Giron-Michel J, Clay D, Devocelle A, Croce M, et al. Differentiation therapy: targeting human renal cancer stem cells with interleukin 15. J Natl Cancer Inst 2011; 103(24): 1884-98. [DOI] [PubMed]
74. Wei G, Ku S, Ma GK, Saito S, Tang AA, Zhang J, et al. HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proc Natl Acad Sci U S A 2007; 104(32): 13040-5. [DOI] [PubMed]
75. Alison MR, Lim SM, Nicholson LJ. Cancer stem cells: problems for therapy? J Pathol 2011; 223(2): 147-61. [DOI] [PubMed]
76. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A 2011; 108(4): 1397-402. [DOI] [PubMed]
77. Riccioni R, Dupuis ML, Bernabei M, Petrucci E, Pasquini L, Mariani G, et al. The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol Dis 2010; 45(1): 86-92. [DOI] [PubMed]
78. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006; 444(7120): 761-5. [DOI] [PubMed]
79. Chen ZH, Yu YP, Zuo ZH, Nelson JB, Michalopoulos GK, Monga S, et al. Targeting genomic rearrangements in tumor cells through Cas9-mediated insertion of a suicide gene. Nat Biotechnol 2017; 35(6): 543-50. [DOI] [PubMed]
80. Chitkara D, Singh S, Mittal A. Nanocarrier-based co-delivery of small molecules and siRNA/miRNA for treatment of cancer. Ther Deliv 2016; 7(4): 245-55. [DOI] [PubMed]
81. Guo W, Chen W, Yu W, Huang W, Deng W. Small interfering RNA-based molecular therapy of cancers. Chin J Cancer 2013; 32(9): 488-93. doi: 10.5732/ cjc.012.10280. [PubMed]
82. Kaya T, Kahraman B, Bazarov N, Toker AS, Celik A, Cigdem S, et al. Suppression of bromodomain-containing protein 4 by shRNA: A new approach for cancer treatment. Clin Invest Med 2016; 39(6): 27493. [DOI] [PubMed]
83. Suh JS, Lee HJ, Nam H, Jo BS, Lee DW, Kim JH, et al. Control of cancer stem cell like population by intracellular target identification followed by the treatment with peptide-siRNA complex. Biochem Biophys Res Commun 2017; 491(3): 827-33. doi: 10. 1016/j.bbrc.2017.05.148. [PubMed]
84. Wang L, Dong P, Wang W, Huang M, Tian B. Gemcitabine treatment causes resistance and malignancy of pancreatic cancer stem-like cells via induction of lncRNA HOTAIR. Exp Ther Med 2017; 14(5): 4773-80. [DOI] [PubMed]
85. Wang T, Shigdar S, Shamaileh HA, Gantier MP, Yin W, Xiang D, et al. Challenges and opportunities for siRNA-based cancer treatment. Cancer Lett 2017; 387: 77-83. [DOI] [PubMed]
86. Zhu H, Liu W, Cheng Z, Yao K, Yang Y, Xu B, et al. Targeted delivery of siRNA with pH-responsive hybrid gold nanostars for cancer treatment. Int J Mol Sci 2017; 18(10). Pii: E2029. [DOI] [PubMed]
87. Zinovieva OL, Grineva EN, Prokofjeva MM, Karpov DS, Krasnov GS, Prassolov VS, et al. Treatment with anti-cancer agents results in profound changes in lncRNA expression in colon cancer cells. Mol Biol (Mosk) 2017; 51(5): 841-8. doi: 10.7868/ S0026898417050123.
88. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med 2017; 23: 1124-34. doi: 10. 1038/nm.4409. [PubMed]
89. Arvelo F, Cotte C, Sojo F. Stem cells and cancer. Invest Clin 2014; 55(4): 371-91.
90. Grotenhuis BA, Wijnhoven BP, van Lanschot JJ. Cancer stem cells and their potential implications for the treatment of solid tumors. J Surg Oncol 2012; 106(2): 209-15. [DOI] [PubMed]
91. Cheng L, Alexander R, Zhang S, Pan CX, MacLennan GT, Lopez-Beltran A, et al. The clinical and therapeutic implications of cancer stem cell biology. Expert Rev Anticancer Ther 2011; 11(7): 1131-43. doi: 10.1586/era. 11.82. [PubMed]
92. Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med 2015; 5(4). pii: a006098. doi: 10.1101/ cshperspect.a006098 . [PubMed]
93. Noori-Daloii MR, Ebadi N. Pharmacogenomics and cancer stem cells. Med Sci J Islamic Azad Univ Tehran Med Branch 2015; 25(1): 1-15. [In Persian]

Add your comments about this article : Your username or Email:

Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2023 CC BY-NC 4.0 | Journal of Inflammatory Diseases

Designed & Developed by : Yektaweb