| Orginal Article |
|
|
|
|
| The Role of Wnt/β-catenin Signaling Pathway in Carcinogenesis and Immunotherapy |
ZHANG Hui1,CHEN Hua-ning1,KUDELAIDI Kuerban1,WANG Song-na1,LIU Jia-yang1,ZHAO Zhen2,**( ),YE Li1,**() |
1 Biological Medicines and Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai 201203, China
2 Clinical Laboratory, Minhang Hospital, Fudan University, Shanghai 201199, China |
|
|
|
Abstract The classic Wnt/β-catenin signaling pathway is involved in regulating various biological functions including stem cell self-renewal, cell proliferation, differentiation, apoptosis, early embryonic development and tissue regeneration, and it is closely related to the occurrence and development of cancer. In addition, this signaling pathway plays an important role in the development and differentiation of thymic T cells, and affects many aspects of the anti-tumor immune effect. Abnormally activated Wnt/β-catenin signaling pathway can induce the formation of malignant tumors and mediate tumor immune escape. This review elaborated on the correlation of Wnt/β-catenin signaling pathway with cancer occurrence and development as well as anti-tumor immunotherapy, and discussed the research progress of drugs targeting Wnt/β-catenin signaling pathway, and the challenges and limitations of its clinical application.
|
|
Received: 08 August 2021
Published: 03 March 2022
|
|
|
|
Corresponding Authors:
Zhen ZHAO,Li YE
E-mail: fdmh_zz@fudan.edu.cn;yelil@fudan.edu.cn
|
|
|
| [1] |
Zhang X, Wang L, Qu Y. Targeting the β-catenin signaling for cancer therapy. Pharmacological Research, 2020, 160:104794.
doi: S1043-6618(20)31102-6
pmid: 32278038
|
|
|
| [2] |
Duchartre Y, Kim Y M, Kahn M. The Wnt signaling pathway in cancer. Critical Reviews in Oncology/ Hematology, 2016, 99:141-149.
|
|
|
| [3] |
Kim S, Jeong S. Mutation hotspots in the β-catenin gene: Lessons from the human cancer genome databases. Mol Cells, 2019, 42(1):8-16.
|
|
|
| [4] |
Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene, 2017, 36(11):1461-1473.
doi: 10.1038/onc.2016.304
pmid: 27617575
|
|
|
| [5] |
Li X, Xiang Y W, Li F L, et al. WNT/β-catenin signaling pathway regulating T cell-inflammation in the tumor microenvironment. Frontiers in Immunology, 2019, 10:2293.
doi: 10.3389/fimmu.2019.02293
|
|
|
| [6] |
Liu C L, Takada K, Zhu D. Targeting wnt/β-catenin pathway for drug therapy. Medicine in Drug Discovery, 2020, 8:100066.
doi: 10.1016/j.medidd.2020.100066
|
|
|
| [7] |
Monga S P. Β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology, 2015, 148(7):1294-1310.
doi: 10.1053/j.gastro.2015.02.056
|
|
|
| [8] |
Pramanik K C, Fofaria N M, Gupta P, et al. Inhibition of β-catenin signaling suppresses pancreatic tumor growth by disrupting nuclear β-Catenin/TCF-1 complex: Critical role of STAT-3. Oncotarget, 2015, 6(13):11561-11574.
pmid: 25869100
|
|
|
| [9] |
Vilchez V. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World Journal of Gastroenterology, 2016, 22(2):823.
doi: 10.3748/wjg.v22.i2.823
pmid: 26811628
|
|
|
| [10] |
Chen Z, Tang J, Cai X F, et al. HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway. Cancer Science, 2016, 107(10):1380-1389.
doi: 10.1111/cas.2016.107.issue-10
|
|
|
| [11] |
Stewart D J. Wnt signaling pathway in non-small cell lung cancer. Journal of the National Cancer Institute, 2014, 106(1):djt356.
doi: 10.1093/jnci/djt356
|
|
|
| [12] |
Wang Y, Lei L, Zheng Y W, et al. Odd-skipped related 1 inhibits lung cancer proliferation and invasion by reducing Wnt signaling through the suppression of SOX9 and β-catenin. Cancer Science, 2018, 109(6):1799-1810.
doi: 10.1111/cas.2018.109.issue-6
|
|
|
| [13] |
Pearson H B, Phesse T J, Clarke A R. K-ras and Wnt signaling synergize to accelerate prostate tumorigenesis in the mouse. Cancer Research, 2009, 69(1):94-101.
doi: 10.1158/0008-5472.CAN-08-2895
pmid: 19117991
|
|
|
| [14] |
Yu X, Wang Y, DeGraff D J, et al. Wnt/β-catenin activation promotes prostate tumor progression in a mouse model. Oncogene, 2011, 30(16):1868-1879.
doi: 10.1038/onc.2010.560
pmid: 21151173
|
|
|
| [15] |
Shen T S, Zhang K, Siegal G P, et al. Prognostic value of E-cadherin and β-catenin in triple-negative breast cancer. American Journal of Clinical Pathology, 2016, 146(5):603-610.
doi: 10.1093/ajcp/aqw183
|
|
|
| [16] |
Merino V F, Cho S, Liang X H, et al. Inhibitors of STAT3, β-catenin, and IGF-1R sensitize mouse PIK3CA-mutant breast cancer to PI3K inhibitors. Molecular Oncology, 2017, 11(5):552-566.
doi: 10.1002/1878-0261.12053
|
|
|
| [17] |
G?tze S, Wolter M, Reifenberger G, et al. Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas. International Journal of Cancer, 2010, 126(11):2584-2593.
|
|
|
| [18] |
Kornblum H I. A multipronged approach to the identification and study of an important oncogene in GBM. Cancer Cell, 2010, 17(5):417-418.
doi: 10.1016/j.ccr.2010.04.019
pmid: 20478522
|
|
|
| [19] |
Yin H S, Que R S, Liu C Y, et al. Survivin-targeted drug screening platform identifies a matrine derivative WM-127 as a potential therapeutics against hepatocellular carcinoma. Cancer Letters, 2018, 425:54-64.
doi: 10.1016/j.canlet.2018.03.044
|
|
|
| [20] |
Bisso A, Filipuzzi M, Gamarra Figueroa G P, et al. Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/taz. Hepatology, 2020, 72(4):1430-1443.
doi: 10.1002/hep.v72.4
|
|
|
| [21] |
Wang J K, Li M, Chen D D, et al. Expression of C-myc and β-catenin and their correlation in triple negative breast cancer. Minerva Medica, 2017, 108(6):513-517. DOI: 10.23736/s0026-4806.17.05213-2.
doi: 10.23736/s0026-4806.17.05213-2
|
|
|
| [22] |
Basu S, Cheriyamundath S, Ben-Ze’ev A. Cell-cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis. F1000Research, 2018, 7:1488.
doi: 10.12688/f1000research
|
|
|
| [23] |
Aiello N M, Maddipati R, Norgard R J, et al. EMT subtype influences epithelial plasticity and mode of cell migration. Developmental Cell, 2018, 45(16):681-695.e4.
doi: 10.1016/j.devcel.2018.05.027
|
|
|
| [24] |
Yook J I, Li X Y, Ota I, et al. Wnt-dependent regulation of the E-cadherin repressor snail. The Journal of Biological Chemistry, 2005, 280(12):11740-11748.
doi: 10.1074/jbc.M413878200
|
|
|
| [25] |
Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Reviews, 2009, 28(1-2):151-166.
doi: 10.1007/s10555-008-9179-y
pmid: 19153669
|
|
|
| [26] |
Song B, Lin H X, Dong L L, et al. MicroRNA-338 inhibits proliferation, migration, and invasion of gastric cancer cells by the Wnt/β-catenin signaling pathway. European Review for Medical and Pharmacological Sciences, 2018, 22(5):1290-1296.
doi: 14470
pmid: 29565486
|
|
|
| [27] |
Yang J T, Han F, Liu W B, et al. ALX4, an epigenetically down regulated tumor suppressor, inhibits breast cancer progression by interfering Wnt/β-catenin pathway. Journal of Experimental & Clinical Cancer Research, 2017, 36(1):170.
|
|
|
| [28] |
Qu B, Liu B R, Du Y J, et al. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncology Letters, 2014, 7(4):1175-1178.
doi: 10.3892/ol.2014.1828
|
|
|
| [29] |
Wang B M, Li N. Retracted: Effect of the Wnt/β-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma cells after transcatheter arterial chemoembolization in rats. Journal of Cellular Biochemistry, 2018, 119(5):4050-4060.
doi: 10.1002/jcb.v119.5
|
|
|
| [30] |
Gallagher S J, Rambow F, Kumasaka M, et al. Beta-catenin inhibits melanocyte migration but induces melanoma metastasis. Oncogene, 2013, 32(17):2230-2238.
doi: 10.1038/onc.2012.229
pmid: 22665063
|
|
|
| [31] |
Damsky W E, Curley D P, Santhanakrishnan M, et al. Β-catenin signaling controls metastasis in braf-activated pten-deficient melanomas. Cancer Cell, 2011, 20(6):741-754.
doi: 10.1016/j.ccr.2011.10.030
|
|
|
| [32] |
Yi G Z, Liu Y W, Xiang W, et al. Akt and β-catenin contribute to TMZ resistance and EMT of MGMT negative malignant glioma cell line. Journal of the Neurological Sciences, 2016, 367:101-106.
doi: 10.1016/j.jns.2016.05.054
|
|
|
| [33] |
Martin-Orozco E, Sanchez-Fernandez A, Ortiz-Parra I, et al. WNT signaling in tumors: the way to evade drugs and immunity. Frontiers in Immunology, 2019, 10:2854.
doi: 10.3389/fimmu.2019.02854
pmid: 31921125
|
|
|
| [34] |
Li B, Lee C, Cadete M, et al. Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis. Cell Death & Disease, 2019, 10(10):1-11.
|
|
|
| [35] |
El-Sahli S, Xie Y, Wang L S, et al. Wnt signaling in cancer metabolism and immunity. Cancers, 2019, 11(7):904.
doi: 10.3390/cancers11070904
|
|
|
| [36] |
Jang G B, Kim J Y, Cho S D, et al. Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Scientific Reports, 2015, 5(1):1-15.
|
|
|
| [37] |
Fan Z Y, Duan J J, Wang L X, et al. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling. Cancer Letters, 2019, 450:132-143.
doi: 10.1016/j.canlet.2019.02.040
|
|
|
| [38] |
Valkenburg K C, Graveel C R, Zylstra-Diegel C R, et al. Wnt/β-catenin signaling in normal and cancer stem cells. Cancers, 2011, 3(2):2050-2079.
doi: 10.3390/cancers3022050
pmid: 24212796
|
|
|
| [39] |
Moon B S, Jeong W J, Park J, et al. Role of oncogenic K-ras in cancer stem cell activation by aberrant Wnt/β-catenin signaling. Journal of the National Cancer Institute, 2014, 106(2):djt373.
|
|
|
| [40] |
Kumaradevan S, Lee S Y, Richards S, et al. C-cbl expression correlates with human colorectal cancer survival and its Wnt/β-catenin suppressor function is regulated by Tyr371 phosphorylation. The American Journal of Pathology, 2018, 188(8):1921-1933.
doi: 10.1016/j.ajpath.2018.05.007
|
|
|
| [41] |
Verbeek S, Izon D, Hofhuis F, et al. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature, 1995, 374(6517):70-74.
doi: 10.1038/374070a0
|
|
|
| [42] |
van Beest M, Dooijes D, van de Wetering M, et al. Sequence-specific high mobility group box factors recognize 10-12-base pair minor groove motifs. The Journal of Biological Chemistry, 2000, 275(35):27266-27273.
doi: 10.1016/S0021-9258(19)61506-1
|
|
|
| [43] |
Gattinoni L, Zhong X S, Palmer D C, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Medicine, 2009, 15(7):808-813.
doi: 10.1038/nm.1982
pmid: 19525962
|
|
|
| [44] |
Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines, 2016, 4(3):28.
doi: 10.3390/vaccines4030028
|
|
|
| [45] |
van Loosdregt J, Fleskens V, Tiemessen M M, et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity, 2013, 39(2):298-310.
doi: 10.1016/j.immuni.2013.07.019
pmid: 23954131
|
|
|
| [46] |
Dai W J, Liu F W, Li C, et al. Blockade of Wnt/β-catenin pathway aggravated silica-induced lung inflammation through tregs regulation on Th immune responses. Mediators of Inflammation, 2016, 2016:1-14.
|
|
|
| [47] |
Wang B J, Tian T, Kalland K H, et al. Targeting Wnt/β-catenin signaling for cancer immunotherapy. Trends in Pharmacological Sciences, 2018, 39(7):648-658.
doi: 10.1016/j.tips.2018.03.008
|
|
|
| [48] |
Cohen S B, Smith N L, McDougal C, et al. Β-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells. The Journal of Immunology, 2015, 194(1):210-222.
doi: 10.4049/jimmunol.1402453
|
|
|
| [49] |
Hong Y, Manoharan I, Suryawanshi A, et al. Β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Research, 2015, 75(4):656-665.
doi: 10.1158/0008-5472.CAN-14-2377
|
|
|
| [50] |
Zhu J F. T helper cell differentiation, heterogeneity, and plasticity. Cold Spring Harbor Perspectives in Biology, 2018, 10(10):a030338.
doi: 10.1101/cshperspect.a030338
|
|
|
| [51] |
Giuntoli R L, Lu J, Kobayashi H, et al. Direct costimulation of tumor-reactive CTL by helper T cells potentiate their proliferation, survival, and effector function. Clinical Cancer Research, 2002, 8(3):922-931.
pmid: 11895927
|
|
|
| [52] |
Sorcini D, Bruscoli S, Frammartino T, et al. Wnt/β-catenin signaling induces integrin α4β1 in T cells and promotes a progressive neuroinflammatory disease in mice. The Journal of Immunology, 2017, 199(9):3031-3041.
doi: 10.4049/jimmunol.1700247
|
|
|
| [53] |
Lee Y S, Lee K A, Yoon H B, et al. The Wnt inhibitor secreted Frizzled-Related Protein 1 (sFRP1) promotes human Th17 differentiation. European Journal of Immunology, 2012, 42(10):2564-2573.
doi: 10.1002/eji.201242445
pmid: 22740051
|
|
|
| [54] |
Kaler P, Augenlicht L, Klampfer L. Activating mutations in β-catenin in colon cancer cells alter their interaction with macrophages; the role of snail. PLoS One, 2012, 7(9):e45462. DOI: 10.1371/journal.pone.0045462.
doi: 10.1371/journal.pone.0045462
|
|
|
| [55] |
Kaler P, Augenlicht L, Klampfer L. Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene, 2009, 28(44):3892-3902.
doi: 10.1038/onc.2009.247
pmid: 19701245
|
|
|
| [56] |
Ramos R N, Piaggio E, Romano E. Mechanisms of resistance to immune checkpoint antibodies//Mechanisms of Drug Resistance in Cancer Therapy. Cham: Springer International Publishing, 2017: 109-128.
|
|
|
| [57] |
Zheng C H, Zheng L T, Yoo J K, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell, 2017, 169(7):1342-1356.e16.
doi: 10.1016/j.cell.2017.05.035
|
|
|
| [58] |
Spranger S, Bao R Y, Gajewski T F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature, 2015, 523(7559):231-235.
doi: 10.1038/nature14404
|
|
|
| [59] |
Grasso C S, Giannakis M, Wells D K, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discovery, 2018, 8(6):730-749.
doi: 10.1158/2159-8290.CD-17-1327
|
|
|
| [60] |
Chovanec M, Cierna Z, Miskovska V, et al. Βcatenin is a marker of poor clinical characteristics and suppressed immune infiltration in testicular germ cell tumors. BMC Cancer, 2018, 18(1):1062.
doi: 10.1186/s12885-018-4929-x
pmid: 30390643
|
|
|
| [61] |
Hsu J M, Xia W Y, Hsu Y H, et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nature Communications, 2018, 9:1908.
doi: 10.1038/s41467-018-04313-6
|
|
|
| [62] |
Casey S C, Tong L, Li Y L, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science, 2016, 352(6282):227-231.
doi: 10.1126/science.aac9935
|
|
|
| [63] |
Gotwals P, Cameron S, Cipolletta D, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nature Reviews Cancer, 2017, 17(5):286-301.
doi: 10.1038/nrc.2017.17
pmid: 28338065
|
|
|
| [64] |
Lu X, Horner J W, Paul E, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature, 2017, 543(7647):728-732.
doi: 10.1038/nature21676
|
|
|
| [65] |
He Y Q, Lu M Y, Che J, et al. Biomarkers and future perspectives for hepatocellular carcinoma immunotherapy. Frontiers in Oncology, 2021, 11:716844.
doi: 10.3389/fonc.2021.716844
|
|
|
| [66] |
Fu C M, Liang X J, Cui W G, et al. Β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. PNAS, 2015, 112(9):2823-2828.
doi: 10.1073/pnas.1414167112
|
|
|
| [67] |
Zhang H, Bi Y Y, Wei Y X, et al. Blocking wnt/β-catenin signal amplifies anti-PD-1 therapeutic efficacy by inhibiting tumor growth, migration, and promoting immune infiltration in glioblastomas. Molecular Cancer Therapeutics, 2021, 20(7):1305-1315.
doi: 10.1158/1535-7163.MCT-20-0825
pmid: 34001635
|
|
|
| [68] |
Sferrazza G, Corti M, Brusotti G, et al. Nature-derived compounds modulating Wnt/β-catenin pathway: a preventive and therapeutic opportunity in neoplastic diseases. Acta Pharmaceutica Sinica B, 2020, 10(10):1814-1834.
doi: 10.1016/j.apsb.2019.12.019
|
|
|
| [69] |
Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treatment Reviews, 2018, 62:50-60.
doi: S0305-7372(17)30187-1
pmid: 29169144
|
|
|
| [70] |
Sharma P, Hu-Lieskovan S, Wargo J A, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell, 2017, 168(4):707-723.
doi: 10.1016/j.cell.2017.01.017
|
|
|
| [71] |
de Miguel M, Calvo E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell, 2020, 38(3):326-333.
doi: S1535-6108(20)30365-2
pmid: 32750319
|
|
|
| [72] |
Huang A C, Postow M A, Orlowski R J, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature, 2017, 545(7652):60-65.
doi: 10.1038/nature22079
|
|
|
| [73] |
Seifert A M, Zeng S, Zhang J Q, et al. PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clinical Cancer Research, 2017, 23(2):454-465.
doi: 10.1158/1078-0432.CCR-16-1163
pmid: 27470968
|
|
|
| [74] |
Havel J J, Chowell D, Chan T A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nature Reviews Cancer, 2019, 19(3):133-150.
doi: 10.1038/s41568-019-0116-x
|
|
|
| [75] |
Wang B J, Tian T, Kalland K H, et al. Targeting Wnt/β-catenin signaling for cancer immunotherapy. Trends in Pharmacological Sciences, 2018, 39(7):648-658.
doi: 10.1016/j.tips.2018.03.008
|
|
|
| [76] |
Velcheti V, Schalper K. Basic overview of current immunotherapy approaches in cancer. American Society of Clinical Oncology Educational Book American Society of Clinical Oncology Annual Meeting, 2016, 35:298-308.
|
|
|
| [77] |
Ott P A, Hodi F S, Kaufman H L, et al. Combination immunotherapy: a road map. Journal for Immunotherapy of Cancer, 2017, 5:16.
doi: 10.1186/s40425-017-0218-5
|
|
|
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
| |
Shared |
|
|
|
|
| |
Discussed |
|
|
|
|
