Signaling Pathways Associated with Cancer Stem Cells Play a Significant Role in Immunotherapy Resistance

Authors

  • Yajuan Zhu Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Yuwen Zhou Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • Yao Xie Department of Dermatovenerology, West China Hospital, Sichuan University, Chengdu 610041, China
  • Pan Song Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
  • Xuelei Ma Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

DOI:

https://doi.org/10.30564/jor.v1i2.1409

Abstract

Cancer stem cells (CSCs) are a subpopulation of tumor cells with properties of self-renewal, pluripotency, plasticity, and differentiation, and are associated with various aberrantly stimulated signaling pathways. They are responsible for tumor recurrence, distant metastasis, and drug resistance, thus inducing poor prognosis. Immunotherapy has achieved encouraging results. However, the resistance associated with its clinical application is a persistent problem in clinical and scientific researches. Increasing evidence shows that signaling pathways associated with CSCs mediate immunotherapy resistance. This review highlights the link between them, and focuses on the underlying mechanism so as to provide potential strategies and approaches for the development of new targets against the immune resistance challenge.

Keywords:

Checkpoint inhibitors; Cancer stem cells; Signaling transduction; Tumor relapse; Recurrence; Immunosuppression

References

[1] Shackleton M, Quintana E, Fearon ER, and Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution [J]. Cell, 2009, 138(5): 822-9. DOI: 10.1016/j.cell.2009.08.017

[2] Marquardt S, Solanki M, Spitschak A, Vera J, and Putzer BM. Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis [J]. Semin Cancer Biol. 2018, 53: 90-109. DOI: 10.1016/j.semcancer.2018.06.006

[3] Takebe N, Harris PJ, Warren RQ, and Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways [J]. Nat Rev Clin Oncol. 2011, 8(2): 97-106. DOI: 10.1038/nrclinonc.2010.196

[4] Tang DG. Understanding cancer stem cell heterogeneity and plasticity [J]. Cell Res. 2012, 22(3): 457-72. DOI: 10.1038/cr.2012.13

[5] Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice [J]. Nature, 1994, 367(6464): 645-8. DOI: 10.1038/367645a0

[6] Bonnet D, and Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell [J]. Nat Med. 1997, 3(7): 730-7.

[7] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, and Clarke MF. Prospective identification of tumorigenic breast cancer cells [J]. Proc Natl Acad Sci U S A. 2003, 100(7): 3983-8. DOI: 10.1073/pnas.0530291100

[8] Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, et al. Cancerous stem cells can arise from pediatric brain tumors [J]. Proc Natl Acad Sci U S A. 2003, 100(25): 15178-83. DOI: 10.1073/pnas.2036535100

[9] Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells [J]. Nature, 2004, 432(7015): 396-401. DOI: 10.1038/nature03128

[10] Todaro M, Iovino F, Eterno V, Cammareri P, Gambara G, Espina V, et al. Tumorigenic and metastatic activity of human thyroid cancer stem cells [J]. Cancer Res. 2010, 70(21): 8874-85. DOI: 10.1158/0008-5472.Can-10-1994

[11] Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271 [J]. Nature, 2010, 466(7302): 133-7. DOI: 10.1038/nature09161

[12] Fukuda K, Saikawa Y, Ohashi M, Kumagai K, Kitajima M, Okano H, et al. Tumor initiating potential of side population cells in human gastric cancer [J]. Int J Oncol. 2009, 34(5): 1201-7.

[13] Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells [J]. Gastroenterology, 2007, 132(7): 2542-56. DOI: 10.1053/j.gastro.2007.04.025

[14] Paraiso KH, and Smalley KS. Fibroblast-mediated drug resistance in cancer [J]. Biochem Pharmacol, 2013, 85(8): 1033-41. DOI: 10.1016/j.bcp.2013.01.018

[15] Collins AT, Berry PA, Hyde C, Stower MJ, and Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells [J]. Cancer Res. 2005, 65(23): 10946-51. DOI: 10.1158/0008-5472.Can-05-2018

[16] Batlle E, and Clevers H. Cancer stem cells revisited [J]. Nat Med. 2017, 23(10): 1124-34. DOI: 10.1038/nm.4409

[17] Lytle NK, Barber AG, and Reya T. Stem cell fate in cancer growth, progression and therapy resistance [J]. Nat Rev Cancer, 2018, 18(11): 669-80. DOI: 10.1038/s41568-018-0056-x

[18] Vlashi E, and Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy [J]. Semin Cancer Biol. 2015, 31: 28-35. DOI: 10.1016/j.semcancer.2014.07.001

[19] Allen KE, and Weiss GJ. Resistance may not be futile: microRNA biomarkers for chemoresistance and potential therapeutics [J]. Mol Cancer Ther. 2010, 9(12): 3126-36. DOI: 10.1158/1535-7163.Mct-10-0397

[20] Visvader JE, and Lindeman GJ. Cancer stem cells: current status and evolving complexities [J]. Cell Stem Cell, 2012, 10(6): 717-28. DOI: 10.1016/j.stem.2012.05.007

[21] Moore N, and Lyle S. Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance [J]. J Oncol. 2011, 2011. DOI: 10.1155/2011/396076

[22] Plaks V, Kong N, and Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? [J]. Cell Stem Cell, 2015, 16(3): 225-38. DOI: 10.1016/j.stem.2015.02.015

[23] Ramos EK, Hoffmann AD, Gerson SL, and Liu H. New Opportunities and Challenges to Defeat Cancer Stem Cells [J]. Trends Cancer, 2017, 3(11): 780-96. DOI: 10.1016/j.trecan.2017.08.007

[24] Sun Y. Tumor microenvironment and cancer therapy resistance [J]. Cancer Lett. 2016, 380(1): 205-15. DOI: 10.1016/j.canlet.2015.07.044

[25] Fakhrejahani F, Tomita Y, Maj-Hes A, Trepel JB, De Santis M, and Apolo AB. Immunotherapies for bladder cancer: a new hope [J]. Curr Opin Urol. 2015, 25(6): 586-96. DOI: 10.1097/mou.0000000000000213

[26] Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates [J]. J Clin Oncol. 2010, 28(19): 3167-75.

[27] DOI: 10.1200/jco.2009.26.7609

[28] Vanpouille-Box C, Lhuillier C, Bezu L, Aranda F, Yamazaki T, Kepp O, et al. Trial watch: Immune checkpoint blockers for cancer therapy [J]. Oncoimmunology. 2017, 6(11): e1373237. DOI: 10.1080/2162402x.2017.1373237

[29] Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance [J]. J Exp Med. 2006, 203(4): 883-95. DOI: 10.1084/jem.20051776

[30] Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, and Rosen HR. Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction [J]. J Virol. 2007, 81(17): 9249-58. DOI: 10.1128/jvi.00409-07

[31] Nishimura H, Nose M, Hiai H, Minato N, and Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor [J]. Immunity, 1999, 11(2): 141-51.

[32] Kabacaoglu D, Ciecielski KJ, Ruess DA, and Algul H. Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options [J]. Front Immunol. 2018, 9: 1878. DOI: 10.3389/fimmu.2018.01878

[33] Pitt JM, Vetizou M, Daillere R, Roberti MP, Yamazaki T, Routy B, et al. Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors [J]. Immunity, 2016, 44(6): 1255-69. DOI: 10.1016/j.immuni.2016.06.001

[34] Sharma P, Hu-Lieskovan S, Wargo JA, and Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy [J]. Cell, 2017, 168(4): 707-23. DOI: 10.1016/j.cell.2017.01.017

[35] Tieche CC, Gao Y, Buhrer ED, Hobi N, Berezowska SA, Wyler K, et al. Tumor Initiation Capacity and Therapy Resistance Are Differential Features of EMT-Related Subpopulations in the NSCLC Cell Line A549 [J]. Neoplasia. 2019, 21(2): 185-96. DOI: 10.1016/j.neo.2018.09.008

[36] Maccalli C, Parmiani G, and Ferrone S. Immunomodulating and Immunoresistance Properties of Cancer-Initiating Cells: Implications for the Clinical Success of Immunotherapy [J]. Immunol Invest. 2017, 46(3): 221-38. DOI: 10.1080/08820139.2017.1280051

[37] Reim F, Dombrowski Y, Ritter C, Buttmann M, Hausler S, Ossadnik M, et al. Immunoselection of breast and ovarian cancer cells with trastuzumab and natural killer cells: selective escape of CD44high/CD24low/HER2low breast cancer stem cells [J]. Cancer Res. 2009, 69(20): 8058-66. DOI: 10.1158/0008-5472.Can-09-0834

[38] Okamoto OK. Cancer stem cell genomics: the quest for early markers of malignant progression [J]. Expert Rev Mol Diagn, 2009, 9(6): 545-54. DOI: 10.1586/erm.09.40

[39] Regenbrecht CR, Lehrach H, and Adjaye J. Stemming cancer: functional genomics of cancer stem cells in solid tumors [J]. Stem Cell Rev. 2008, 4(4): 319-28. DOI: 10.1007/s12015-008-9034-0

[40] Curtin JC, and Lorenzi MV. Drug discovery approaches to target Wnt signaling in cancer stem cells [J]. Oncotarget. 2010, 1(7): 563-77. DOI: 10.18632/oncotarget.191

[41] Bierie B, and Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer [J]. Nat Rev Cancer, 2006, 6(7): 506-20. DOI: 10.1038/nrc1926

[42] Nawshad A, Lagamba D, Polad A, and Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis [J]. Cells Tissues Organs, 2005, 179(1-2): 11-23. DOI: 10.1159/000084505

[43] Labelle M, Begum S, and Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis [J]. Cancer Cell. 2011, 20(5): 576-90. DOI: 10.1016/j.ccr.2011.09.009

[44] Gomes LR, Terra LF, Sogayar MC, and Labriola L. Epithelial-mesenchymal transition: implications in cancer progression and metastasis [J]. Curr Pharm Biotechnol, 2011, 12(11): 1881-90.

[45] Blank U, and Karlsson S. TGF-beta signaling in the control of hematopoietic stem cells [J]. Blood. 2015, 125(23): 3542-50. DOI: 10.1182/blood-2014-12-618090

[46] Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer [J]. Nat Genet. 2015, 47(4): 320-9. DOI: 10.1038/ng.3225

[47] Pickup M, Novitskiy S, and Moses HL. The roles of TGFbeta in the tumour microenvironment [J]. Nat Rev Cancer, 2013, 13(11): 788-99. DOI: 10.1038/nrc3603

[48] Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis [J]. Nature, 2018, 554(7693): 538-43. DOI: 10.1038/nature25492

[49] Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells [J]. Nature, 2018, 554(7693): 544-8. DOI: 10.1038/nature25501

[50] Miao Y, Yang H, Levorse J, Yuan S, Polak L, Sribour M, et al. Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells [J]. Cell, 2019, 177(5): 1172-86 e14. DOI: 10.1016/j.cell.2019.03.025

[51] Ganesh K, and Massague J. TGF-beta Inhibition and Immunotherapy: Checkmate [J]. Immunity, 2018, 48(4): 626-8. DOI: 10.1016/j.immuni.2018.03.037

[52] Jaeckel S, Kaller M, Jackstadt R, Gotz U, Muller S, Boos S, et al. Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells [J]. Nat Commun, 2018, 9(1): 3573. DOI: 10.1038/s41467-018-06001-x

[53] Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling [J]. Nature, 2008, 452(7187): 650-3. DOI: 10.1038/nature06835

[54] Wu CX, Wang XQ, Chok SH, Man K, Tsang SHY, Chan ACY, et al. Blocking CDK1/PDK1/beta-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma [J]. Theranostics, 2018, 8(14): 3737-50. DOI: 10.7150/thno.25487

[55] Comoglio PM, Trusolino L, and Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy [J]. Nat Rev Cancer, 2018, 18(6): 341-58. DOI: 10.1038/s41568-018-0002-y

[56] Medema JP, and Vermeulen L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer [J]. Nature, 2011, 474(7351): 318-26. DOI: 10.1038/nature10212

[57] Khuu CH, Barrozo RM, Hai T, and Weinstein SL. Activating transcription factor 3 (ATF3) represses the expression of CCL4 in murine macrophages [J]. Mol Immunol, 2007, 44(7): 1598-605. DOI: 10.1016/j.molimm.2006.08.006

[58] Driessens G, Zheng Y, Locke F, Cannon JL, Gounari F, and Gajewski TF. Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-gamma1 phosphorylation [J]. J Immunol. 2011, 186(2): 784-90. DOI: 10.4049/jimmunol.1001562

[59] Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines [J]. Cancer Res. 2012, 72(20): 5209-18.

[60] DOI: 10.1158/0008-5472.Can-12-1187

[61] Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment [J]. Cancer Res. 2009, 69(7): 3077-85. DOI: 10.1158/0008-5472.Can-08-2281

[62] Yaguchi T, Goto Y, Kido K, Mochimaru H, Sakurai T, Tsukamoto N, et al. Immune suppression and resistance mediated by constitutive activation of Wnt/beta-catenin signaling in human melanoma cells [J]. J Immunol, 2012, 189(5): 2110-7. DOI: 10.4049/jimmunol.1102282

[63] Spranger S, Bao R, and Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity [J]. Nature. 2015, 523(7559): 231-5. DOI: 10.1038/nature14404

[64] Xue J, Yu X, Xue L, Ge X, Zhao W, and Peng W. Intrinsic beta-catenin signaling suppresses CD8(+) T-cell infiltration in colorectal cancer [J]. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2019, 115: 108921. DOI: 10.1016/j.biopha.2019.108921

[65] Turkson J, and Jove R. STAT proteins: novel molecular targets for cancer drug discovery [J]. Oncogene. 2000, 19(56): 6613-26. DOI: 10.1038/sj.onc.1204086

[66] Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity [J]. Proc Natl Acad Sci U S A. 2007, 104(18): 7391-6. DOI: 10.1073/pnas.0609757104

[67] Schindler C, Levy DE, and Decker T. JAK-STAT signaling: from interferons to cytokines [J]. J Biol Chem. 2007, 282(28): 20059-63. DOI: 10.1074/jbc.R700016200

[68] Yu H, Lee H, Herrmann A, Buettner R, and Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions [J]. Nat Rev Cancer, 2014, 14(11): 736-46. DOI: 10.1038/nrc3818

[69] Yu H, Pardoll D, and Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3 [J]. Nat Rev Cancer, 2009, 9(11): 798-809. DOI: 10.1038/nrc2734

[70] Avalle L, Camporeale A, Camperi A, and Poli V. STAT3 in cancer: A double edged sword [J]. Cytokine, 2017, 98: 42-50. DOI: 10.1016/j.cyto.2017.03.018

[71] Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells [J]. Nat Commun. 2017, 8(1): 1751. DOI: 10.1038/s41467-017-01883-9

[72] Zhang N, Zeng Y, Du W, Zhu J, Shen D, Liu Z, et al. The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer [J]. Int J Oncol. 2016, 49(4): 1360-8. DOI: 10.3892/ijo.2016.3632

[73] Sun L, Wang Q, Chen B, Zhao Y, Shen B, Wang H, et al. Gastric cancer mesenchymal stem cells derived IL-8 induces PD-L1 expression in gastric cancer cells via STAT3/mTOR-c-Myc signal axis [J]. Cell Death Dis. 2018, 9(9): 928. DOI: 10.1038/s41419-018-0988-9

[74] Lee Y, Shin JH, Longmire M, Wang H, Kohrt HE, Chang HY, et al. CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1 [J]. Clin Cancer Res. 2016, 22(14): 3571-81.

[75] DOI: 10.1158/1078-0432.CCR-15-2665

[76] Hsu JM, Xia W, Hsu YH, Chan LC, Yu WH, Cha JH, et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion [J]. Nat Commun. 2018, 9(1): 1908.

[77] DOI: 10.1038/s41467-018-04313-6

[78] Vaupel P, and Mayer A. Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications [J]. Adv Exp Med Biol. 2014, 812: 19-24.

[79] DOI: 10.1007/978-1-4939-0620-8_3

[80] Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology [J]. Annu Rev Pathol. 2014, 9: 47-71.

[81] DOI: 10.1146/annurev-pathol-012513-104720

[82] Kang S, Bader AG, and Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic [J]. Proc Natl Acad Sci U S A. 2005;102(3):802-7. DOI: 10.1073/pnas.0408864102

[83] Ziello JE, Jovin IS, and Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia [J]. Yale J Biol Med. 2007, 80(2): 51-60.

[84] Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha [J]. Oncogene, 2009, 28(45): 3949-59. DOI: 10.1038/onc.2009.252

[85] Wang Y, Liu Y, Malek SN, Zheng P, and Liu Y. Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies [J]. Cell Stem Cell. 2011, 8(4): 399-411. DOI: 10.1016/j.stem.2011.02.006

[86] Samanta D, Gilkes DM, Chaturvedi P, Xiang L, and Semenza GL. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells [J]. Proc Natl Acad Sci U S A. 2014, 111(50): E5429-38. DOI: 10.1073/pnas.1421438111

[87] Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells [J]. Cell. 2008, 133(4): 704-15. DOI: 10.1016/j.cell.2008.03.027

[88] Philip B, Ito K, Moreno-Sanchez R, and Ralph SJ. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression [J]. Carcinogenesis. 2013, 34(8): 1699-707. DOI: 10.1093/carcin/bgt209

[89] Lan L, Luo Y, Cui D, Shi BY, Deng W, Huo LL, et al. Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells [J]. Int J Oncol. 2013, 43(1): 113-20.

[90] DOI: 10.3892/ijo.2013.1913

[91] Luo Y, Cui X, Zhao J, Han Y, Li M, Lin Y, et al. Cells susceptible to epithelial-mesenchymal transition are enriched in stem-like side population cells from prostate cancer [J]. Oncol Rep. 2014, 31(2): 874-84. DOI: 10.3892/or.2013.2905

[92] Zhu H, Wang D, Zhang L, Xie X, Wu Y, Liu Y, et al. Upregulation of autophagy by hypoxia-inducible factor-1alpha promotes EMT and metastatic ability of CD133+ pancreatic cancer stem-like cells during intermittent hypoxia [J]. Oncol Rep. 2014, 32(3): 935-42. DOI: 10.3892/or.2014.3298

[93] Miao ZF, Zhao TT, Wang ZN, Xu YY, Mao XY, Wu JH, et al. Influence of different hypoxia models on metastatic potential of SGC-7901 gastric cancer cells [J]. Tumour Biol. 2014, 35(7): 6801-8. DOI: 10.1007/s13277-014-1928-7

[94] Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, et al. Hypoxia-inducible factor 1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer [J]. Breast Cancer Res. 2012, 14(1): R6. DOI: 10.1186/bcr3087

[95] Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation [J]. J Exp Med. 2014, 211(5): 781-90. DOI: 10.1084/jem.20131916

[96] Voron T, Marcheteau E, Pernot S, Colussi O, Tartour E, Taieb J, et al. Control of the immune response by pro-angiogenic factors [J]. Front Oncol. 2014, 4: 70. DOI: 10.3389/fonc.2014.00070

[97] Barsoum IB, Hamilton TK, Li X, Cotechini T, Miles EA, Siemens DR, et al. Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide [J]. Cancer Res. 2011, 71(24): 7433-41. DOI: 10.1158/0008-5472.Can-11-2104

[98] Wigerup C, Pahlman S, and Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer [J]. Pharmacol Ther. 2016, 164: 152-69. DOI: 10.1016/j.pharmthera.2016.04.009

[99] Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, and Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway [J]. J Biol Chem. 2002, 277(33): 29936-44. DOI: 10.1074/jbc.M204733200

[100] Lee K, Qian DZ, Rey S, Wei H, Liu JO, and Semenza GL. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells [J]. Proc Natl Acad Sci U S A. 2009, 106(7): 2353-8. DOI: 10.1073/pnas.0812801106

[101] Cortes JE, Gutzmer R, Kieran MW, and Solomon JA. Hedgehog signaling inhibitors in solid and hematological cancers [J]. Cancer Treat Rev. 2019, 76: 41-50. DOI: 10.1016/j.ctrv.2019.04.005

[102] Pak E, and Segal RA. Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy [J]. Dev Cell. 2016, 38(4): 333-44. DOI: 10.1016/j.devcel.2016.07.026

[103] Peer E, Tesanovic S, and Aberger F. Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy [J]. Cancers (Basel), 2019, 11(4). DOI: 10.3390/cancers11040538

[104] Corrales JD, Rocco GL, Blaess S, Guo Q, and Joyner AL. Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development [J]. Development, 2004, 131(22): 5581-90. DOI: 10.1242/dev.01438

[105] Ercan G, Karlitepe A, and Ozpolat B. Pancreatic Cancer Stem Cells and Therapeutic Approaches [J]. Anticancer Res. 2017, 37(6): 2761-75. DOI: 10.21873/anticanres.11628

[106] Onishi H, Kai M, Odate S, Iwasaki H, Morifuji Y, Ogino T, et al. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer [J]. Cancer Sci. 2011, 102(6): 1144-50. DOI: 10.1111/j.1349-7006.2011.01912.x

[107] Onishi H, Morifuji Y, Kai M, Suyama K, Iwasaki H, and Katano M. Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer [J]. Cancer Sci. 2012, 103(7): 1272-9. DOI: 10.1111/j.1349-7006.2012.02297.x

[108] Onishi H, Fujimura A, Oyama Y, Yamasaki A, Imaizumi A, Kawamoto M, et al. Hedgehog signaling regulates PDL-1 expression in cancer cells to induce anti-tumor activity by activated lymphocytes [J]. Cell Immunol. 2016, 310: 199-204. DOI: 10.1016/j.cellimm.2016.08.003

Downloads

How to Cite

Zhu, Y., Zhou, Y., Xie, Y., Song, P., & Ma, X. (2019). Signaling Pathways Associated with Cancer Stem Cells Play a Significant Role in Immunotherapy Resistance. Journal of Oncology Research, 1(2), 1–10. https://doi.org/10.30564/jor.v1i2.1409

Issue

Vol. 1 , Iss. 2 (December 2019)

Article Type

Articles

License

Copyright and Licensing

The authors shall retain the copyright of their work but allow the Publisher to publish, copy, distribute, and convey the work.

Journal of Oncology Research publishes accepted manuscripts under Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). Authors who submit their papers for publication by Journal of Oncology Research agree to have the CC BY-NC 4.0 license applied to their work, and that anyone is allowed to reuse the article or part of it free of charge for non-commercial use. As long as you follow the license terms and original source is properly cited, anyone may copy, redistribute the material in any medium or format, remix, transform, and build upon the material.

License Policy for Reuse of Third-Party Materials

If a manuscript submitted to the journal contains the materials which are held in copyright by a third-party, authors are responsible for obtaining permissions from the copyright holder to reuse or republish any previously published figures, illustrations, charts, tables, photographs, and text excerpts, etc. When submitting a manuscript, official written proof of permission must be provided and clearly stated in the cover letter.
The editorial office of the journal has the right to reject/retract articles that reuse third-party materials without permission.

Journal Policies on Data Sharing

We encourage authors to share articles published in our journal to other data platforms, but only if it is noted that it has been published in this journal.