Advertisement

Diversity of Wnt/β-Catenin Signaling in Head and Neck Cancer: Cancer Stem Cells, Epithelial-to-Mesenchymal Transition, and Tumor Microenvironment

  • Khalid Alamoud
  • Maria A. Kukuruzinska
Chapter
Part of the Current Cancer Research book series (CUCR)

Abstract

The Wnt/β-catenin signaling pathway is increasingly recognized for its roles in head and neck cancer, a devastating malignancy that presents primarily as head and neck squamous cell carcinoma (HNSCC). Wnt/β-catenin signaling impacts multiple cellular processes that endow cancer cells with the ability to maintain and expand immature stemlike phenotypes and proliferate, extend cancer cell survival, and promote aggressive characteristics resulting from loss of epithelial features and adoption of mesenchymal traits. A central component of the canonical Wnt signaling pathway is β-catenin, which balances a role as a structural component of cadherin junctions with function as a transcriptional coactivator of numerous target genes. While β-catenin is not frequently mutated in HNSCC, its activity is enhanced by some of the more common HNSCC mutations in NOTCH1, FAT1, and AJUBA. The impact of β-catenin on a wide range of epigenetic, transcriptional, and cellular processes is mediated by its interaction with numerous transcription factors, as well as with a multitude of transcriptional coactivators and corepressors, in a cell- and tissue-context-dependent manner. In addition, intrinsic β-catenin activity plays important roles in the tumor microenvironment and thus regulates extracellular matrix remodeling and immune response. Lastly, Wnt/β-catenin signaling collaborates with, and converges on, other signaling and metabolic pathways and cellular processes that modulate outputs of its activity. Unraveling the complex circuitries of Wnt/β-catenin signaling will facilitate its effective targeting for HNSCC therapy.

Keywords

β-catenin carcinoma epigenomics metabolism stroma threapeutics 

References

  1. 1.
    Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.CrossRefPubMedGoogle Scholar
  2. 2.
    MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    McNeill H, Woodgett JR. When pathways collide: collaboration and connivance among signalling proteins in development. Nat Rev Mol Cell Biol. 2010;11(6):404–13.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tsukamoto AS, et al. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell. 1988;55(4):619–25.CrossRefPubMedGoogle Scholar
  6. 6.
    Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006;281(32):22429–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Widelitz R. Wnt signaling through canonical and non-canonical pathways: recent progress. Growth Factors. 2005;23(2):111–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefGoogle Scholar
  9. 9.
    Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–92.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pectasides E, et al. Markers of epithelial to mesenchymal transition in association with survival in head and neck squamous cell carcinoma (HNSCC). PLoS One. 2014;9(4):e94273.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhou G. Wnt/beta-catenin signaling and oral cancer metastasis. In: Oral cancer metastasis. New York: Springer; 2010. p. 231–64.Google Scholar
  12. 12.
    Castilho R., Gutkind J. (2014) The Wnt/β-catenin Signaling Circuitry in Head and Neck Cancer. In: Burtness B., Golemis E. (eds) Molecular Determinants of Head and Neck Cancer. Current Cancer Research. Springer, New York, NYGoogle Scholar
  13. 13.
    Liu G, et al. N-glycosylation induces the CTHRC1 protein and drives oral cancer cell migration. J Biol Chem. 2013;288(28):20217–27.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Adamska M, et al. Structure and expression of conserved Wnt pathway components in the demosponge Amphimedon queenslandica. Evol Dev. 2010;12(5):494–518.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lapebie P, et al. WNT/beta-catenin signalling and epithelial patterning in the homoscleromorph sponge Oscarella. PLoS One. 2009;4(6):e5823.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kusserow A, et al. Unexpected complexity of the Wnt gene family in a sea anemone. Nature. 2005;433(7022):156–60.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gonzalez-Sancho JM, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24(6):1098–103.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Katoh M. Comparative genomics on SFRP2 orthologs. Oncol Rep. 2005;14(3):783–7.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Carmon KS, et al. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A. 2011;108(28):11452–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Carmon KS, et al. RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling. Proc Natl Acad Sci U S A. 2014;111(13):E1221–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hao HX, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012;485(7397):195–200.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Koo BK, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012;488(7413):665–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gonzalez-Sancho JM, et al. Functional consequences of Wnt-induced dishevelled 2 phosphorylation in canonical and noncanonical Wnt signaling. J Biol Chem. 2013;288(13):9428–37.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Grumolato L, et al. Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev. 2010;24(22):2517–30.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Korinek V, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science. 1997;275(5307):1784–7.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Morin PJ, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275(5307):1787–90.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yang F, et al. Wnt/beta-catenin signaling inhibits death receptor-mediated apoptosis and promotes invasive growth of HNSCC. Cell Signal. 2006;18(5):679–87.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Beck TN, Golemis EA. Genomic insights into head and neck cancer. Cancers Head Neck. 2016;1(1):1.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  32. 32.
    Puram SV, et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017;171(7):1611–24. e24.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Jamal B, et al. Aberrant amplification of the crosstalk between canonical Wnt signaling and N-glycosylation gene DPAGT1 promotes oral cancer. Oral Oncol. 2012;48:523–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wend P, et al. Wnt/beta-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. EMBO J. 2013;32(14):1977–89.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chang HW, et al. Knockdown of beta-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines. Cell Signal. 2013;25(4):839–47.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Duan L, et al. Growth suppression induced by Notch1 activation involves Wnt-beta-catenin down-regulation in human tongue carcinoma cells. Biol Cell. 2006;98(8):479–90.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fu L, et al. Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/beta-catenin signalling pathway. Gut. 2011;60(12):1635–43.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ge C, et al. miR-942 promotes cancer stem cell-like traits in esophageal squamous cell carcinoma through activation of Wnt/beta-catenin signalling pathway. Oncotarget. 2015;6(13):10964–77.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gonzalez-Moles MA, et al. Beta-catenin in oral cancer: an update on current knowledge. Oral Oncol. 2014;50(9):818–24.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Goto M, et al. Rap1 stabilizes beta-catenin and enhances beta-catenin-dependent transcription and invasion in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2010;16(1):65–76.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Iwai S, et al. Involvement of the Wnt-beta-catenin pathway in invasion and migration of oral squamous carcinoma cells. Int J Oncol. 2010;37(5):1095–103.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lee SH, et al. Wnt/beta-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4. J Pathol. 2014;234(1):99–107.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Li L, et al. Overexpression of beta-catenin induces cisplatin resistance in oral squamous cell carcinoma. Biomed Res Int. 2016;2016:5378567.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Li M, et al. Aberrant expression of CDK8 regulates the malignant phenotype and associated with poor prognosis in human laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2017;274:2205–13.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Liang S, et al. LncRNA, TUG1 regulates the oral squamous cell carcinoma progression possibly via interacting with Wnt/beta-catenin signaling. Gene. 2017;608:49–57.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lo Muzio L, et al. WNT-1 expression in basal cell carcinoma of head and neck. An immunohistochemical and confocal study with regard to the intracellular distribution of beta-catenin. Anticancer Res. 2002;22(2A):565–76.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Takei S, et al. Roles of beta-catenin overexpression and adenomatous polyposis coli mutation in head and neck cancer. Nihon Jibiinkoka Gakkai Kaiho. 2003;106(6):692–9.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pannone G, et al. WNT pathway in oral cancer: epigenetic inactivation of WNT-inhibitors. Oncol Rep. 2010;24(4):1035–41.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Shiratsuchi H, et al. beta-Catenin nuclear accumulation in head and neck mucoepidermoid carcinoma: its role in cyclin D1 overexpression and tumor progression. Head Neck. 2007;29(6):577–84.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Padhi S, et al. Clinico-pathological correlation of beta-catenin and telomere dysfunction in head and neck squamous cell carcinoma patients. J Cancer. 2015;6(2):192–202.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13(12):767–79.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mikels AJ, Nusse R. Wnts as ligands: processing, secretion and reception. Oncogene. 2006;25(57):7461–8.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31(12):2714–36.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Gottardi CJ, Peifer M. Terminal regions of beta-catenin come into view. Structure. 2008;16(3):336–8.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Xing Y, et al. Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex. Genes Dev. 2003;17(22):2753–64.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Xing Y, et al. Crystal structure of a full-length beta-catenin. Structure. 2008;16(3):478–87.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Lee E, et al. The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. 2003;1(1):E10.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Maeda O, et al. Plakoglobin (gamma-catenin) has TCF/LEF family-dependent transcriptional activity in beta-catenin-deficient cell line. Oncogene. 2004;23(4):964–72.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ben-Ze’ev A, Geiger B. Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signalling and cancer. Curr Opin Cell Biol. 1998;10:629–39.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Simcha I, et al. Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. J Cell Biol. 1996;133(1):199–209.CrossRefPubMedGoogle Scholar
  61. 61.
    Zhurinsky J, Shtutman M, Ben-Ze’ev A. Plakoglobin and beta-catenin: protein interactions, regulation and biological roles. J Cell Sci. 2000;113(Pt 18):3127–39.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Williams BO, Barish GD, Klymkowsky MW, Varmus HE. A comparative evaluation of beta-catenin and plakoglobin signaling activity. Oncogene. 2000;19:5720–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Narkio-Makela M, et al. Reduced gamma-catenin expression and poor survival in oral squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2009;135(10):1035–40.CrossRefPubMedGoogle Scholar
  64. 64.
    Mosimann C, Hausmann G, Basler K. Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol. 2009;10(4):276–86.CrossRefPubMedGoogle Scholar
  65. 65.
    Mulholland DJ, et al. Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis. Oncogene. 2003;22(36):5602–13.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Pawlowski JE, et al. Liganded androgen receptor interaction with beta-catenin: nuclear co-localization and modulation of transcriptional activity in neuronal cells. J Biol Chem. 2002;277(23):20702–10.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Beildeck ME, Gelmann EP, Byers SW. Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway. Exp Cell Res. 2010;316(11):1763–72.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol. 2007;9(2):210–7.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Essers MA, et al. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005;308(5725):1181–4.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Brembeck FH, et al. BCL9-2 promotes early stages of intestinal tumor progression. Gastroenterology. 2011;141(4):1359–70, 1370 e1–3.Google Scholar
  71. 71.
    Hikasa H, et al. Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification. Dev Cell. 2010;19(4):521–32.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Yu Y, et al. Kindlin 2 forms a transcriptional complex with beta-catenin and TCF4 to enhance Wnt signalling. EMBO Rep. 2012;13(8):750–8.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Hoffmeyer K, et al. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549–54.CrossRefPubMedGoogle Scholar
  74. 74.
    Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19(11):1438–49.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Aguilera O, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene. 2006;25(29):4116–21.CrossRefPubMedGoogle Scholar
  76. 76.
    Chen J, et al. Pygo2 associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion. Mol Cell Biol. 2010;30(24):5621–35.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Li Z, et al. Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. Proc Natl Acad Sci U S A. 2011;108(8):3116–23.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Mohan M, et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 2010;24(6):574–89.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Ma H, et al. Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene. 2005;24(22):3619–31.CrossRefPubMedGoogle Scholar
  80. 80.
    Varelas X, et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell. 2010;18(4):579–91.CrossRefPubMedGoogle Scholar
  81. 81.
    Azzolin L, et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158(1):157–70.CrossRefPubMedGoogle Scholar
  82. 82.
    Azzolin L, et al. Role of TAZ as mediator of Wnt signaling. Cell. 2012;151(7):1443–56.CrossRefPubMedGoogle Scholar
  83. 83.
    Rosenbluh J, et al. Beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell. 2012;151(7):1457–73.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Qu Y, et al. Axitinib blocks Wnt/beta-catenin signaling and directs asymmetric cell division in cancer. Proc Natl Acad Sci U S A. 2016;113(33):9339–44.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Stamos JL, Weis WI. The beta-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5(1):a007898.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Hart M, et al. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol. 1999;9(4):207–10.CrossRefPubMedGoogle Scholar
  87. 87.
    Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev. 2006;16(1):51–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010;2(2):a002915.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Holland JD, et al. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol. 2013;25(2):254–64.CrossRefPubMedGoogle Scholar
  90. 90.
    Asahina M, et al. Crosstalk between a nuclear receptor and beta-catenin signaling decides cell fates in the C. elegans somatic gonad. Dev Cell. 2006;11(2):203–11.CrossRefPubMedGoogle Scholar
  91. 91.
    Lien WH, Fuchs E. Wnt some lose some: transcriptional governance of stem cells by Wnt/beta-catenin signaling. Genes Dev. 2014;28(14):1517–32.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Yang H, et al. Epithelial-Mesenchymal micro-niches govern stem cell lineage choices. Cell. 2017;169(3):483–96. e13.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Oskarsson T, Batlle E, Massague J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14(3):306–21.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Scheel C, Weinberg RA. Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int J Cancer. 2011;129(10):2310–4.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Prince ME, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104(3):973–8.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Monroe MM, et al. Cancer stem cells in head and neck squamous cell carcinoma. J Oncol. 2011;2011:762780.CrossRefPubMedGoogle Scholar
  97. 97.
    Krishnamurthy S, et al. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res. 2010;70(23):9969–78.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Clay MR, et al. Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 2010;32(9):1195–201.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Song J, et al. Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling. PLoS One. 2010;5(7):e11456.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Chen C, et al. Epithelial-to-mesenchymal transition and cancer stem(-like) cells in head and neck squamous cell carcinoma. Cancer Lett. 2013;338(1):47–56.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Nor C, et al. Cisplatin induces Bmi-1 and enhances the stem cell fraction in head and neck cancer. Neoplasia. 2014;16(2):137–46.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Chen D, et al. Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Cell Stem Cell. 2017;20(5):621–34. e6.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Chen YW, et al. Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma--derived CD44(+)ALDH1(+) cells. Mol Cancer Ther. 2010;9(11):2879–92.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Schepers AG, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337(6095):730–5.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Myant KB, et al. ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell. 2013;12(6):761–73.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Malanchi I, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature. 2008;452(7187):650–3.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Peng Y, et al. The crosstalk between microRNAs and the Wnt/beta-catenin signaling pathway in cancer. Oncotarget. 2017;8(8):14089–106.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Huang K, et al. MicroRNA roles in beta-catenin pathway. Mol Cancer. 2010;9:252.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Behrens J, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996;382(6592):638–42.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Albert M, Peters AH. Genetic and epigenetic control of early mouse development. Curr Opin Genet Dev. 2009;19(2):113–21.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Parker DS, et al. Wingless signaling induces widespread chromatin remodeling of target loci. Mol Cell Biol. 2008;28(5):1815–28.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Sierra J, et al. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev. 2006;20(5):586–600.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Zhou B, et al. Interactions between beta-catenin and transforming growth factor-beta signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 2012;287(10):7026–38.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 2014;105(9):1087–92.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Chan KC, et al. Therapeutic targeting of CBP/beta-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin. Sci Rep. 2015;5:9979.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Li J, et al. CBP/p300 are bimodal regulators of Wnt signaling. EMBO J. 2007;26(9):2284–94.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Wend P, et al. Wnt signaling in stem and cancer stem cells. Semin Cell Dev Biol. 2010;21(8):855–63.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    de Sousa EM, et al. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17(4):647–53.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    de Sousa EMF, et al. Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell. 2011;9(5):476–85.CrossRefGoogle Scholar
  121. 121.
    Wilhelm F, et al. Novel insights into gastric cancer: methylation of R-spondins and regulation of LGR5 by SP1. Mol Cancer Res. 2017;15(6):776–85.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Chinn SB, Myers JN. Oral cavity carcinoma: current management, controversies, and future directions. J Clin Oncol. 2015;33(29):3269–76.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Hedberg ML, et al. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. J Clin Invest. 2016;126(4):1606.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Baum B, Settleman J, Quinlan MP. Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol. 2008;19(3):294–308.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Thiery JP, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol. 2012;22(5–6):396–403.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Ye X, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525(7568):256–60.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Katoh M. Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs. Oncol Rep. 2005;14(4):1083–6.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Sanchez-Tillo E, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010;29(24):3490–500.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Wang Y, et al. ASPP2 controls epithelial plasticity and inhibits metastasis through beta-catenin-dependent regulation of ZEB1. Nat Cell Biol. 2014;16(11):1092–104.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Tenbaum SP, et al. Beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012;18(6):892–901.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Nijkamp MM, et al. Expression of E-cadherin and vimentin correlates with metastasis formation in head and neck squamous cell carcinoma patients. Radiother Oncol. 2011;99(3):344–8.CrossRefPubMedGoogle Scholar
  134. 134.
    Smith A, Teknos TN, Pan Q. Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol. 2013;49(4):287–92.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Zheng L, et al. Twist-related protein 1 enhances oral tongue squamous cell carcinoma cell invasion through beta-catenin signaling. Mol Med Rep. 2015;11(3):2255–61.CrossRefPubMedGoogle Scholar
  136. 136.
    Ma MZ, et al. CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling. Neoplasia. 2014;16(3):265–78, 278 e1–13.Google Scholar
  137. 137.
    Park EH, et al. Collagen triple helix repeat containing-1 promotes pancreatic cancer progression by regulating migration and adhesion of tumor cells. Carcinogenesis. 2013;34:694–702.CrossRefPubMedGoogle Scholar
  138. 138.
    Zhang J, Ma L. MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev. 2012;31(3–4):653–62.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Park SM, et al. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22(7):894–907.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Yan J, et al. Regulation of mesenchymal phenotype by MicroRNAs in cancer. Curr Cancer Drug Targets. 2013;13(9):930–4.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    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.CrossRefPubMedGoogle Scholar
  142. 142.
    Sun L, et al. MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene. 2012;31(4):432–45.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Jung AC, et al. A poor prognosis subtype of HNSCC is consistently observed across methylome, transcriptome, and miRNome analysis. Clin Cancer Res. 2013;19(15):4174–84.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Coordes A, et al. Cancer stem cell phenotypes and miRNA: therapeutic targets in head and neck squamous cell carcinoma. HNO. 2014;62(12):867–72.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Shibue T, Weinberg RA. Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin Cancer Biol. 2011;21(2):99–106.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Luga V, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542–56.CrossRefPubMedGoogle Scholar
  147. 147.
    Chairoungdua A, et al. Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol. 2010;190(6):1079–91.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Hinck L, Nelson WJ, Papkoff J. Wnt-1 modulates cell-cell adhesion in mammalian cells by stabilizing beta-catenin binding to the cell adhesion protein cadherin. J Cell Biol. 1994;124:729–41.CrossRefPubMedGoogle Scholar
  150. 150.
    Hoschuetzky H, Aberle H, Kemler R. Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol. 1994;127:1375–80.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993;9:317–21.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994;1198:11–26.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Chen Y-T, Stewart DB, Nelson WJ. Coupling assembly of the E-cadherin/β-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells. J Cell Biol. 1999;144:687–99.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Sengupta PK, et al. Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion. J Cell Sci. 2012;126:484–496.Google Scholar
  155. 155.
    Varelas X, Bouchie MP, Kukuruzinska MA. Protein N-glycosylation in oral cancer: dysregulated cellular networks among DPAGT1, E-cadherin adhesion and canonical Wnt signaling. Glycobiology. 2014;24(7):579–91.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Nita-Lazar M, et al. Overexpression of DPAGT1 leads to aberrant N-glycosylation of E-cadherin and cellular discohesion in oral cancer. Cancer Res. 2009;69(14):5673–80.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000;36:1607–20.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Morris LG, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45(3):253–61.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Xie J, et al. CDH4 suppresses the progression of salivary adenoid cystic carcinoma via E-cadherin co-expression. Oncotarget. 2016;7(50):82961–71.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Yamamoto S, et al. Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell. 2008;15(1):23–36.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Wang Q, et al. NFAT5 represses canonical Wnt signaling via inhibition of beta-catenin acetylation and participates in regulating intestinal cell differentiation. Cell Death Dis. 2013;4:e671.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Thrasivoulou C, Millar M, Ahmed A. Activation of intracellular calcium by multiple Wnt ligands and translocation of beta-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/beta-catenin pathways. J Biol Chem. 2013;288(50):35651–9.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Lecarpentier Y, et al. Thermodynamics in cancers: opposing interactions between PPAR gamma and the canonical WNT/beta-catenin pathway. Clin Transl Med. 2017;6(1):14.CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Whitman M. Smads and early developmental signaling by the TGFbeta superfamily. Genes Dev. 1998;12(16):2445–62.CrossRefPubMedGoogle Scholar
  165. 165.
    Labbe E, et al. Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis. Cancer Res. 2007;67(1):75–84.CrossRefPubMedGoogle Scholar
  166. 166.
    Masszi A, et al. Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol. 2004;165(6):1955–67.CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Akhmetshina A, et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun. 2012;3:735.CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Nowell CS, Radtke F. Notch as a tumour suppressor. Nat Rev Cancer. 2017;17(3):145–59.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Dotto GP. Notch tumor suppressor function. Oncogene. 2008;27(38):5115–23.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Croagh D, et al. Esophageal stem cells and genetics/epigenetics in esophageal cancer. Ann N Y Acad Sci. 2014;1325:8–14.CrossRefPubMedGoogle Scholar
  172. 172.
    Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Lawrence MS, et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  175. 175.
    van Es JH, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435(7044):959–63.CrossRefPubMedGoogle Scholar
  176. 176.
    Munoz-Chapuli R, Perez-Pomares JM. Cardiogenesis: an embryological perspective. J Cardiovasc Transl Res. 2010;3(1):37–48.CrossRefPubMedGoogle Scholar
  177. 177.
    Kwon C, et al. Notch post-translationally regulates beta-catenin protein in stem and progenitor cells. Nat Cell Biol. 2011;13(10):1244–51.CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57.CrossRefPubMedGoogle Scholar
  179. 179.
    Lamar JM, et al. The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proc Natl Acad Sci U S A. 2012;109(37):E2441–50.CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Camargo FD, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Current biology : CB. 2007;17(23):2054–60.CrossRefPubMedGoogle Scholar
  181. 181.
    Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15(2):73–9.CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Chan SW, et al. A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res. 2008;68(8):2592–8.CrossRefPubMedGoogle Scholar
  183. 183.
    Hiemer SE, et al. A YAP/TAZ-regulated molecular signature is associated with oral squamous cell carcinoma. Mol Cancer Res. 2015;13(6):957–68.CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Low BC, et al. YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth. FEBS Lett. 2014;588(16):2663–70.CrossRefPubMedGoogle Scholar
  185. 185.
    Hiemer SE, Varelas X. Stem cell regulation by the Hippo pathway. Biochim Biophys Acta. 2012;18:2323–2334.Google Scholar
  186. 186.
    Mauviel A, Nallet-Staub F, Varelas X. Integrating developmental signals: a Hippo in the (path)way. Oncogene. 2012;31(14):1743–56.CrossRefPubMedGoogle Scholar
  187. 187.
    Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642–56.PubMedPubMedCentralGoogle Scholar
  188. 188.
    Attisano L, Wrana JL. Signal integration in TGF-beta, WNT, and Hippo pathways. F1000Prime Rep. 2013;5:17.CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Li J, et al. LATS2 suppresses oncogenic Wnt signaling by disrupting beta-catenin/BCL9 interaction. Cell Rep. 2013;5(6):1650–63.CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Heallen T, et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332(6028):458–61.CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Park HW, et al. Alternative Wnt signaling activates YAP/TAZ. Cell. 2015;162(4):780–94.CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Boldrup L, et al. Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers. Int J Oncol. 2005;27(6):1661–7.PubMedGoogle Scholar
  193. 193.
    Hu T, Li C. Convergence between Wnt-beta-catenin and EGFR signaling in cancer. Mol Cancer. 2010;9:236.CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Kim SE, Choi KY. EGF receptor is involved in WNT3a-mediated proliferation and motility of NIH3T3 cells via ERK pathway activation. Cell Signal. 2007;19(7):1554–64.CrossRefPubMedGoogle Scholar
  195. 195.
    Lee CH, et al. Epidermal growth factor receptor regulates beta-catenin location, stability, and transcriptional activity in oral cancer. Mol Cancer. 2010;9:64.CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Veracini L, et al. Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck squamous cell carcinomas. Oncotarget. 2015;6(10):7570–83.CrossRefPubMedGoogle Scholar
  197. 197.
    Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol. 2009;10(7):445–57.CrossRefPubMedGoogle Scholar
  198. 198.
    Whitman M, et al. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332(6165):644–6.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Locasale JW, Cantley LC. Altered metabolism in cancer. BMC Biol. 2010;8:88.CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Klempner SJ, Myers AP, Cantley LC. What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. Cancer Discov. 2013;3(12):1345–54.CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Lui VW, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761–9.CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Dihlmann S, et al. Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells. Carcinogenesis. 2005;26(9):1503–12.CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Nita-Lazar M, et al. Hypoglycosylated E-cadherin promotes the assembly of tight junctions through the recruitment of PP2A to adherens junctions. Exp Cell Res. 2010;316(11):1871–84.CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Warburg O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269–70.PubMedGoogle Scholar
  205. 205.
    Jose C, Bellance N, Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochim Biophys Acta. 2011;1807(6):552–61.CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Mazumdar J, et al. O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol. 2010;12(10):1007–13.CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Varki A, Kannagi R, Toole BP. Glycosylation changes in cancer. In: Varki A, et al., editors. Essentials of glycobiology. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2009.Google Scholar
  209. 209.
    Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15(9):540–55.CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Gillies RJ, Gatenby RA. Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr. 2007;39(3):251–7.CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Itkonen HM, et al. UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. Oncogene. 2015;34(28):3744–50.CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Anagnostou SH, Shepherd PR. Glucose induces an autocrine activation of the Wnt/beta-catenin pathway in macrophage cell lines. Biochem J. 2008;416(2):211–8.CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Kurayoshi M, et al. Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochem J. 2007;402(3):515–23.CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Sengupta PK, Bouchie MP, Kukuruzinska MA. N-glycosylation gene DPAGT1 is a target of the Wnt/beta-catenin signaling pathway. J Biol Chem. 2010;285(41):31164–73.CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Lau KS, et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell. 2007;129(1):123–34.CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Contessa JN, et al. Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. Cancer Res. 2008;68(10):3803–9.CrossRefPubMedPubMedCentralGoogle Scholar
  217. 217.
    Miller MA, et al. Reduced proteolytic shedding of receptor tyrosine kinases is a post-translational mechanism of kinase inhibitor resistance. Cancer Discov. 2016;6(4):382–99.CrossRefPubMedPubMedCentralGoogle Scholar
  218. 218.
    Junk DJ, et al. Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene. 2017;36(28):4001–13.CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Koontongkaew S. The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas. J Cancer. 2013;4(1):66–83.CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Salo T, et al. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. Exp Cell Res. 2014;325(2):58–64.CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Erdogan B, Webb DJ. Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. 2017;45(1):229–36.CrossRefPubMedPubMedCentralGoogle Scholar
  222. 222.
    Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582–98.CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786–801.CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Gradl D, Kuhl M, Wedlich D. The Wnt/Wg signal transducer beta-catenin controls fibronectin expression. Mol Cell Biol. 1999;19(8):5576–87.CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Wielenga VJ, et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol. 1999;154(2):515–23.CrossRefPubMedPubMedCentralGoogle Scholar
  226. 226.
    Gopal S, et al. Fibronectin-guided migration of carcinoma collectives. Nat Commun. 2017;8:14105.CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Bais MV, Kukuruzinska M, Trackman PC. Orthotopic non-metastatic and metastatic oral cancer mouse models. Oral Oncol. 2015;51(5):476–82.CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Lu KW, et al. Gypenosides inhibited invasion and migration of human tongue cancer SCC4 cells through down-regulation of NFkappaB and matrix metalloproteinase-9. Anticancer Res. 2008;28(2A):1093–9.PubMedPubMedCentralGoogle Scholar
  229. 229.
    van Loosdregt J, et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity. 2013;39(2):298–310.CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Swafford D, Manicassamy S. Wnt signaling in dendritic cells: its role in regulation of immunity and tolerance. Discov Med. 2015;19(105):303–10.PubMedPubMedCentralGoogle Scholar
  231. 231.
    Spranger S, Gajewski TF. A new paradigm for tumor immune escape: beta-catenin-driven immune exclusion. J Immunother Cancer. 2015;3:43.CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Pai SG, et al. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017;10(1):101.CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Lyford-Pike S, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73(6):1733–41.CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.CrossRefGoogle Scholar
  235. 235.
    Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.PubMedPubMedCentralGoogle Scholar
  236. 236.
    Spranger S. Tumor heterogeneity and tumor immunity: a chicken-and-egg problem. Trends Immunol. 2016;37(6):349–51.CrossRefPubMedPubMedCentralGoogle Scholar
  237. 237.
    Lehuede C, et al. Metabolic plasticity as a determinant of tumor growth and metastasis. Cancer Res. 2016;76(18):5201–8.CrossRefPubMedPubMedCentralGoogle Scholar
  238. 238.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Shayan G, et al. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology. 2017;6(1):e1261779.CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513–32.CrossRefPubMedPubMedCentralGoogle Scholar
  241. 241.
    Aminuddin A, Ng PY. Promising druggable target in head and neck squamous cell carcinoma: Wnt signaling. Front Pharmacol. 2016;7:244.CrossRefPubMedPubMedCentralGoogle Scholar
  242. 242.
    Tammela T, et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature. 2017;545(7654):355–9.CrossRefPubMedPubMedCentralGoogle Scholar
  243. 243.
    Rudy SF, et al. In vivo Wnt pathway inhibition of human squamous cell carcinoma growth and metastasis in the chick chorioallantoic model. J Otolaryngol Head Neck Surg. 2016;45:26.CrossRefPubMedPubMedCentralGoogle Scholar
  244. 244.
    Madan B, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35(17):2197–207.CrossRefPubMedPubMedCentralGoogle Scholar
  245. 245.
    Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36(11):1461–73.CrossRefPubMedPubMedCentralGoogle Scholar
  246. 246.
    Arensman MD, et al. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther. 2014;13(10):2303–14.CrossRefPubMedPubMedCentralGoogle Scholar
  247. 247.
    Lafyatis R, et al. Inhibition of beta-catenin signaling in the skin rescues cutaneous adipogenesis in systemic sclerosis: a randomized, double-blind, placebo-controlled trial of C-82. J Invest Dermatol. 2017;137:2473–83.CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Kartha VK, et al. PDGFRbeta is a novel marker of stromal activation in oral squamous cell carcinomas. PLoS One. 2016;11(4):e0154645.CrossRefPubMedPubMedCentralGoogle Scholar
  249. 249.
    Barat S, et al. Gamma-secretase inhibitor IX (GSI) impairs concomitant activation of notch and Wnt-beta-catenin pathways in CD44+ gastric cancer stem cells. Stem Cells Transl Med. 2017;6(3):819–29.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular and Cell BiologyBoston University School of Dental MedicineBostonUSA

Personalised recommendations