Wnt Signaling and Plasticity of Lung Cancer Cells
Cancer cell plasticity includes their interconversion into various subtypes or entirely different cells through transdifferentiation. This allows the cells to survive in difficult microenvironments while remaining unresponsive to treatment. Plastic characteristics of cancer cells include increased metastasis, tumorigenesis, and chemoresistance. Though many pathways regulate these activities, this paper focuses on the Wnt signaling pathway. When Wnt is activated, the Axin is dephosphorylated, allowing the phosphorylation of β-catenin (β-Cat) and the degradation of antigen-presenting cell (APC). This degradation is important because APC is classified as a tumor suppressor; therefore, when Wnt is on, tumorigenesis is more likely to occur. Lung cancer contains a subpopulation of cancer stem-like cells (CS-LCs), which are highly resistant to anticancer drugs and are a major catalyst for tumor recurrence. The Wnt signaling pathway, in conjunction with other pathways, is a key player in the development and maintenance of cancer stem cells, catalyzing increased chemoresistance and metastasis. The Wnt signaling pathway can sustain these CS-LCs with β-Cat present in the pathway. In this review, we summarize the current knowledge surrounding the Wnt signaling pathway as well as its crosstalk with other pathways and their implications for cancer cell plasticity.
1. Roy PS, Saikia BJ. Cancer and cure: A critical analysis. Indian J Cancer 2016;53:441–2.
2. Murphy SL, Xu J, Kochanek KD, Arias E. Mortality in the United States, 2017. NCHS Data Brief 2018:1–8.
3. Wullkopf L, West AV, Leijnse N, Cox TR, Madsen CD, Oddershede LB, et al. Cancer cells' ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential. Mol Biol Cell 2018;29:2378–85.
4. Zeeshan R, Mutahir Z. Cancer metastasis - tricks of the trade. Bosn J Basic Med Sci 2017;17:172–82.
5. Stone JB, DeAngelis LM. Cancer-treatment-induced neurotoxicity--focus on newer treatments. Nat Rev Clin Oncol 2016;13:92–105.
6. Kaushik V, Kulkarni Y, Felix K, Azad N, Iyer AKV, Yakisich JS. Alternative models of cancer stem cells: The stemness phenotype model, 10 years later. World J Stem Cells 2021;13:934–43.
7. Zheng X, Yu C, Xu M. Linking tumor microenvironment to plasticity of cancer stem cells: mechanisms and application in cancer therapy. Front Oncol 2021;11:678333.
8. Dubey AK, Gupta U, Jain S. Epidemiology of lung cancer and approaches for its prediction: a systematic review and analysis. Chin J Cancer 2016;35:71.
9. Romaszko AM, Doboszyńska A. Multiple primary lung cancer: A literature review. Adv Clin Exp Med 2018;27:725–30.
10. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584–94.
11. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013;501:328–37.
12. Blandin Knight S, Crosbie PA, Balata H, Chudziak J, Hussell T, Dive C. Progress and prospects of early detection in lung cancer. Open Biol 2017;7:170070.
13. Shaurova T, Zhang L, Goodrich DW, Hershberger PA. Understanding lineage plasticity as a path to targeted therapy failure in EGFR-mutant non-small cell lung cancer. Front Genet 2020;11:281.
14. Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Fam Physician 2007;75:56–63.
15. Wadowska K, Bil-Lula I, Trembecki Ł, Śliwińska-Mossoń M. Genetic markers in lung cancer diagnosis: a review. Int J Mol Sci 2020;21:4569.
16. Filip S, Mokrý J, English D, Vojácek J. Stem cell plasticity and issues of stem cell therapy. Folia Biol (Praha) 2005;51:180–7.
17. Quesenberry PJ, Abedi M, Aliotta J, Colvin G, Demers D, Dooner M, et al. Stem cell plasticity: an overview. Blood Cells Mol Dis 2004;32:1–4.
18. Chacón-Martínez CA, Koester J, Wickström SA. Signaling in the stem cell niche: regulating cell fate, function and plasticity. Development 2018;145:dev165399.
19. Saijo H, Hirohashi Y, Torigoe T, Horibe R, Takaya A, Murai A, et al. Plasticity of lung cancer stem-like cells is regulated by the transcription factor HOXA5 that is induced by oxidative stress. Oncotarget 2016;7:50043–56.
20. Yuan S, Norgard RJ, Stanger BZ. Cellular plasticity in cancer. Cancer Discov 2019;9:837–51.
21. Jong ED, Chan ICW, Nedelcu AM. A model-system to address the impact of phenotypic heterogeneity and plasticity on the development of cancer therapies. Front Oncol 2019;9:842.
22. Shen S, Clairambault J. Cell plasticity in cancer cell populations. F1000Res 2020;9:F1000 Faculty Rev-635.
23. Agalioti T, Villablanca EJ, Huber S, Gagliani N. TH17 cell plasticity: The role of dendritic cells and molecular mechanisms. J Autoimmun 2018;87:50–60.
24. Boerboom A, Dion V, Chariot A, Franzen R. Molecular mechanisms involved in Schwann cell plasticity. Front Mol Neurosci 2017;10:38
25. Katoh M. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review). Int J Oncol 2017;51:1357–69.
26. Königshoff M, Eickelberg O. WNT signaling in lung disease: a failure or a regeneration signal? Am J Respir Cell Mol Biol 2010;42:21–31.
27. Mao X, Jin F. The exosome and breast cancer cell plasticity. Onco Targets Ther 2019;12:9817–25.
28. Poltavets V, Kochetkova M, Pitson SM, Samuel MS. The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front Oncol 2018;8:431.
29. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009;19:156–72.
30. Nelson WJ. Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol 2009;1:a000513.
31. Jung HY, Fattet L, Tsai JH, Kajimoto T, Chang Q, Newton AC, et al. Apical-basal polarity inhibits epithelial-mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation. Nat Cell Biol 2019;21:359–71.
32. Kowalczyk AP, Green KJ. Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 2013;116:95–118.
33. Macara IG, McCaffrey L. Cell polarity in morphogenesis and metastasis. Philos Trans R Soc Lond B Biol Sci 2013;368:20130012.
34. Luo J, Zhou X, Yakisich JS. Stemness and plasticity of lung cancer cells: paving the road for better therapy. Onco Targets Ther 2014;7:1129–34.
35. Yakisich JS, Azad N, Kaushik V, Iyer AKV. Cancer cell plasticity: rapid reversal of chemosensitivity and expression of stemness markers in lung and breast cancer tumorspheres. J Cell Physiol 2017;232:2280–6.
36. Tata PR, Rajagopal J. Plasticity in the lung: making and breaking cell identity. Development 2017;144:755–66.
37. Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev 2018;62:50–60.
38. Wiese KE, Nusse R, van Amerongen R. Wnt signalling: conquering complexity. Development. 2018 Jun 26;145:dev165902.
39. Li N, Lu N, Xie C. The Hippo and Wnt signalling pathways: crosstalk during neoplastic progression in gastrointestinal tissue. FEBS J 2019;286:3745–56.
40. Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O'Flaherty JD, et al. Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLos One 2013;8:e54193.
41. Vert G, Chory J. Crosstalk in cellular signaling: background noise or the real thing? Dev Cell 2011;21:985–91.
42. Katoh M, Katoh M. Precision medicine for human cancers with Notch signaling dysregulation (Review). Int J Mol Med 2020;45:279–97.
43. Tang J, Chen L, Wang Z, Huang G, Hu X. SOX2 mediates crosstalk between Sonic Hedgehog and the Wnt/β-catenin signaling pathway to promote proliferation of pituitary adenoma cells. Oncol Lett 2019;18:81–6.
44. Guimaraes PPG, Tan M, Tammela T, Wu K, Chung A, Oberli M, et al. Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes. J Control Release 2018;290:75–87.
45. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A 2013;110:20224–9.
46. Zhang Q, Zhang B, Sun L, Yan Q, Zhang Y, Zhang Z, et al. MicroRNA-130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β-catenin pathway. Cell Biochem Funct 2018;36:194–202.
47. Zhan P, Zhang B, Xi GM, Wu Y, Liu HB, Liu YF, et al. PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/β-catenin signaling pathway. Mol Cancer 2017;16:108.
48. Cai J, Fang L, Huang Y, Li R, Xu X, Hu Z, et al. Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR128-3p confers chemoresistance-associated metastasis in NSCLC. Nat Commun 2017;8:15870.
49. Giroux-Leprieur E, Costantini A, Ding VW, He B. Hedgehog signaling in lung cancer: from oncogenesis to cancer treatment resistance. Int J Mol Sci 2018;19:2835.
50. Shi S, Deng YZ, Zhao JS, Ji XD, Shi J, Feng YX, et al. RACK1 promotes non-small-cell lung cancer tumorigenicity through activating sonic hedgehog signaling pathway. J Biol Chem 2012;287:7845–58.
51. Lim S, Lim SM, Kim MJ, Park SY, Kim JH. Sonic hedgehog pathway as the prognostic marker in patients with extensive stage small cell lung cancer. Yonsei Med J 2019;60:898–904.
52. Zhao M, Xu P, Liu Z, Zhen Y, Chen Y, Liu Y, et al. Dual roles of miR-374a by modulated c-Jun respectively targets CCND1- inducing PI3K/AKT signal and PTEN-suppressing Wnt/βcatenin signaling in non-small-cell lung cancer. Cell Death Dis 2018;9:78.
53. Shao W, Li S, Li L, Lin K, Liu X, Wang H, et al. Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun. Protein Cell 2019;10:161–77.
54. Bordonaro M. Crosstalk between Wnt Signaling and RNA processing in colorectal cancer. J Cancer 2013;4:96–103.
55. Hassan WA, Yoshida R, Kudoh S, Kameyama H, Hasegawa K, Niimori-Kita K, et al. Notch1 controls cell chemoresistance in small cell lung carcinoma cells. Thorac Cancer 2016;7:123–8.
56. Sun QS, Luo M, Zhao HM, Sun H. Overexpression of PKMYT1 indicates the poor prognosis and enhances proliferation and tumorigenesis in non-small cell lung cancer via activation of Notch signal pathway. Eur Rev Med Pharmacol Sci 2019;23:4210–9.
57. Wang Y, Yang R, Wang X, Ci H, Zhou L, Zhu B, et al. Evaluation of the correlation of vasculogenic mimicry, Notch4, DLL4, and KAI1/CD82 in the prediction of metastasis and prognosis in non-small cell lung cancer. Medicine (Baltimore) 2018;97:e13817.
58. Yao Y, Ni Y, Zhang J, Wang H, Shao S. The role of Notch signaling in gastric carcinoma: molecular pathogenesis and novel therapeutic targets. Oncotarget 2017;8:53839–53.
59. Chou YT, Lee CC, Hsiao SH, Lin SE, Lin SC, Chung CH, et al. The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. Stem Cells 2013;31:2607–19.
60. Kaufhold S, Garbán H, Bonavida B. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res 2016;35:84.
61. Feng YH, Su YC, Lin SF, Lin PR, Wu CL, Tung CL, et al. Oct4 upregulates osteopontin via Egr1 and is associated with poor outcome in human lung cancer. BMC Cancer 2019;19:791.
62. Wu K, Xie D, Zou Y, Zhang T, Pong RC, Xiao G, et al. The mechanism of DAB2IP in chemoresistance of prostate cancer cells. Clin Cancer Res 2013;19:4740–9.
63. Qiu Z, Zhu W, Meng H, Tong L, Li X, Luo P, et al. CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter. Theranostics 2019;9:4717–29.
64. Hsu HS, Lin JH, Huang WC, Hsu TW, Su K, Chiou SH, et al. Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27. Cancer 2011;117:1516–28.
65. Brichkina A, Bertero T, Loh HM, Nguyen NT, Emelyanov A, Rigade S, et al. p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis. Genes Dev 2016;30:2623–36.
66. Cai XD, Che L, Lin JX, Huang S, Li J, Liu XY, et al. Krüppel-like factor 17 inhibits urokinase plasminogen activator gene expression to suppress cell invasion through the Src/p38/ MAPK signaling pathway in human lung adenocarcionma. Oncotarget 2017;8:38743–54.
67. Lu T, Dang S, Zhu R, Wang Y, Nie Z, Hong T, et al. Adamts18 deficiency promotes colon carcinogenesis by enhancing β-catenin and p38MAPK/ERK1/2 signaling in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer. Oncotarget 2017;8:18979–90.
68. Sun H, Zhou X, Bao Y, Xiong G, Cui Y, Zhou H. Involvement of miR-4262 in paclitaxel resistance through the regulation of PTEN in non-small cell lung cancer. Open Biol 2019;9:180227.
69. Di X, Jin X, Ma H, Wang R, Cong S, Tian C, et al. The oncogene IARS2 promotes non-small cell lung cancer tumorigenesis by activating the AKT/MTOR pathway. Front Oncol 2019;9:393.
70. Yu T, Zhao Y, Hu Z, Li J, Chu D, Zhang J, et al. MetaLnc9 facilitates lung cancer metastasis via a PGK1-Activated AKT/mTOR pathway. Cancer Res 2017;77:5782–94.
71. Sales KU, Giudice FS, Castilho RM, Salles FT, Squarize CH, Abrahao AC, et al. Cyclin D1-induced proliferation is independent of beta-catenin in head and neck cancer. Oral Dis 2014;20:e42–8.
72. Whittall N, Moran DM, Wheeler AW, Cottam GP. Suppression of murine IgE responses with amino acid polymer/allergen conjugates. I. Preparation of poly-(N-methylglycine)/grass pollen extract conjugates using 4-(methylmercapto)phenylsuccinimidyl succinate as coupling reagent. Int Arch Allergy Appl Immunol 1985;76:354–60.
73. Best SA, De Souza DP, Kersbergen A, Policheni AN, Dayalan S, Tull D, et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab 2018;27:935–43.e4.
74. Wang H, Ma Z, Liu X, Zhang C, Hu Y, Ding L, et al. MiR-183-5p is required for non-small cell lung cancer progression by repressing PTEN. Biomed Pharmacother 2019;111:1103–11.
75. Wu T, Wang MC, Jing L, Liu ZY, Guo H, Liu Y, et al. Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway. Drug Des Devel Ther 2015;9:6421–31.
76. Li N, Wang Y, Neri S, Zhen Y, Fong LWR, Qiao Y, et al. Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling. Nat Commun 2019;10:4363.
77. Xu F, Cui WQ, Wei Y, Cui J, Qiu J, Hu LL, et al. Astragaloside IV inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling. J Exp Clin Cancer Res 2018;37:207.
78. Nam S, Chang HR, Kim KT, Kook MC, Hong D, Kwon CH, et al. PATHOME: an algorithm for accurately detecting differentially expressed subpathways. Oncogene 2014;33:4941–51.
79. Zhang Y, Han CY, Duan FG, Fan XX, Yao XJ, Parks RJ, et al. p53 sensitizes chemoresistant non-small cell lung cancer via elevation of reactive oxygen species and suppression of EGFR/ PI3K/AKT signaling. Cancer Cell Int 2019;19:188.
80. Li W, Yu X, Tan S, Liu W, Zhou L, Liu H. Oxymatrine inhibits nonsmall cell lung cancer via suppression of EGFR signaling pathway. Cancer Med 2018;7:208–18.
81. Gong WJ, Liu JY, Yin JY, Cui JJ, Xiao D, Zhuo W, et al. Resistin facilitates metastasis of lung adenocarcinoma through the TLR4/
Src/EGFR/PI3K/NF-κB pathway. Cancer Sci 2018;109:2391– 400.
82. Suzuki M, Shigematsu H, Nakajima T, Kubo R, Motohashi S, Sekine Y, et al. Synchronous alterations of Wnt and epidermal growth factor receptor signaling pathways through aberrant methylation and mutation in non small cell lung cancer. Clin Cancer Res 2007;13:6087–92.
83. Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 2010;120:1285–97.
84. Gu J, Liu Y, Xie B, Ye P, Huang J, Lu Z. Roles of toll-like receptors: From inflammation to lung cancer progression. Biomed Rep 2018;8:126–32.
85. Chow SC, Gowing SD, Cools-Lartigue JJ, Chen CB, Berube J, Yoon HW, et al. Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation. Int J Cancer 2015;136:1341–50.
86. Chung LY, Tang SJ, Sun GH, Chou TY, Yeh TS, Yu SL, et al. Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK, and cyclooxygenase-2. Clin Cancer Res 2012;18:4037–47.
87. Schmidt ML, Hobbing KR, Donninger H, Clark GJ. RASSF1A deficiency enhances RAS-driven lung tumorigenesis. Cancer Res 2018;78:2614–23.
88. Zheng G, Shen Z, Chen H, Liu J, Jiang K, Fan L, et al. Metapristone suppresses non-small cell lung cancer proliferation and metastasis via modulating RAS/RAF/MEK/MAPK signaling pathway. Biomed Pharmacother 2017;90:437–45.
89. Lin SR, Mokgautsi N, Liu YN. Ras and Wnt interaction contribute in prostate cancer bone metastasis. Molecules 2020;25:2380.
90. Iv Santaliz-Ruiz LE, Xie X, Old M, Teknos TN, Pan Q. Emerging role of nanog in tumorigenesis and cancer stem cells. Int J Cancer 2014;135:2741–8.
91. Ye T, Li J, Sun Z, Liu Y, Kong L, Zhou S, et al. Nr5a2 promotes cancer stem cell properties and tumorigenesis in nonsmall cell lung cancer by regulating Nanog. Cancer Med 2019;8:1232– 45.
92. Guo T, Kong J, Liu Y, Li Z, Xia J, Zhang Y, et al. Transcriptional activation of NANOG by YBX1 promotes lung cancer stem-like properties and metastasis. Biochem Biophys Res Commun 2017;487:153–9.
93. Li J, Zhu Y. Recent advances in liver cancer stem cells: Noncoding RNAs, oncogenes and oncoproteins. Front Cell Dev Biol 2020;8:548335.
94. Tripathi SC, Fahrmann JF, Celiktas M, Aguilar M, Marini KD, Jolly MK, et al. MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway. Cancer Res 2017;77:4414–25.
95. Zhu L, Chen Y, Liu J, Nie K, Xiao Y, Yu H. MicroRNA-629 promotes the tumorigenesis of non-small-cell lung cancer by targeting FOXO1 and activating PI3K/AKT pathway. Cancer Biomark 2020;29:347–57.
96. Wei C, Dong X, Lu H, Tong F, Chen L, Zhang R, et al. LPCAT1 promotes brain metastasis of lung adenocarcinoma by upregulating PI3K/AKT/MYC pathway. J Exp Clin Cancer Res 2019;38:95.
97. Walter DM, Yates TJ, Ruiz-Torres M, Kim-Kiselak C, Gudiel AA, Deshpande C, et al. RB constrains lineage fidelity and multiple stages of tumour progression and metastasis. Nature 2019;569:423–7.