Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Molecular Determinants of Head and Neck Cancer

Part of the book series: Current Cancer Research ((CUCR))

  • 612 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.

    Article  PubMed  CAS  Google Scholar 

  2. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  6. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006;281(32):22429–33.

    Article  PubMed  CAS  Google Scholar 

  7. Widelitz R. Wnt signaling through canonical and non-canonical pathways: recent progress. Growth Factors. 2005;23(2):111–6.

    Article  PubMed  CAS  Google Scholar 

  8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  9. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. 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, NY

    Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  15. Lapebie P, et al. WNT/beta-catenin signalling and epithelial patterning in the homoscleromorph sponge Oscarella. PLoS One. 2009;4(6):e5823.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kusserow A, et al. Unexpected complexity of the Wnt gene family in a sea anemone. Nature. 2005;433(7022):156–60.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  18. Katoh M. Comparative genomics on SFRP2 orthologs. Oncol Rep. 2005;14(3):783–7.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Hao HX, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012;485(7397):195–200.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–80.

    Article  CAS  PubMed  Google Scholar 

  26. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50.

    Article  PubMed  CAS  Google Scholar 

  27. Korinek V, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science. 1997;275(5307):1784–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  30. Beck TN, Golemis EA. Genomic insights into head and neck cancer. Cancers Head Neck. 2016;1(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gonzalez-Moles MA, et al. Beta-catenin in oral cancer: an update on current knowledge. Oral Oncol. 2014;50(9):818–24.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  43. Li L, et al. Overexpression of beta-catenin induces cisplatin resistance in oral squamous cell carcinoma. Biomed Res Int. 2016;2016:5378567.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  48. Pannone G, et al. WNT pathway in oral cancer: epigenetic inactivation of WNT-inhibitors. Oncol Rep. 2010;24(4):1035–41.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13(12):767–79.

    Article  PubMed  CAS  Google Scholar 

  52. Mikels AJ, Nusse R. Wnts as ligands: processing, secretion and reception. Oncogene. 2006;25(57):7461–8.

    Article  PubMed  CAS  Google Scholar 

  53. Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31(12):2714–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Gottardi CJ, Peifer M. Terminal regions of beta-catenin come into view. Structure. 2008;16(3):336–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Xing Y, et al. Crystal structure of a full-length beta-catenin. Structure. 2008;16(3):478–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  60. Simcha I, et al. Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. J Cell Biol. 1996;133(1):199–209.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  62. Williams BO, Barish GD, Klymkowsky MW, Varmus HE. A comparative evaluation of beta-catenin and plakoglobin signaling activity. Oncogene. 2000;19:5720–8.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  69. Essers MA, et al. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005;308(5725):1181–4.

    Article  PubMed  CAS  Google Scholar 

  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. Hikasa H, et al. Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification. Dev Cell. 2010;19(4):521–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Hoffmeyer K, et al. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549–54.

    Article  CAS  PubMed  Google Scholar 

  74. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19(11):1438–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  80. Varelas X, et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell. 2010;18(4):579–91.

    Article  PubMed  CAS  Google Scholar 

  81. Azzolin L, et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158(1):157–70.

    Article  PubMed  CAS  Google Scholar 

  82. Azzolin L, et al. Role of TAZ as mediator of Wnt signaling. Cell. 2012;151(7):1443–56.

    Article  PubMed  CAS  Google Scholar 

  83. Rosenbluh J, et al. Beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell. 2012;151(7):1457–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Stamos JL, Weis WI. The beta-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5(1):a007898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  88. Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010;2(2):a002915.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Holland JD, et al. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol. 2013;25(2):254–64.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Yang H, et al. Epithelial-Mesenchymal micro-niches govern stem cell lineage choices. Cell. 2017;169(3):483–96. e13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Oskarsson T, Batlle E, Massague J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14(3):306–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Monroe MM, et al. Cancer stem cells in head and neck squamous cell carcinoma. J Oncol. 2011;2011:762780.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Song J, et al. Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling. PLoS One. 2010;5(7):e11456.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  104. Schepers AG, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337(6095):730–5.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Malanchi I, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature. 2008;452(7187):650–3.

    Article  PubMed  CAS  Google Scholar 

  107. Peng Y, et al. The crosstalk between microRNAs and the Wnt/beta-catenin signaling pathway in cancer. Oncotarget. 2017;8(8):14089–106.

    Article  PubMed  Google Scholar 

  108. Huang K, et al. MicroRNA roles in beta-catenin pathway. Mol Cancer. 2010;9:252.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Behrens J, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996;382(6592):638–42.

    Article  PubMed  CAS  Google Scholar 

  110. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8.

    Article  PubMed  CAS  Google Scholar 

  111. Albert M, Peters AH. Genetic and epigenetic control of early mouse development. Curr Opin Genet Dev. 2009;19(2):113–21.

    Article  PubMed  CAS  Google Scholar 

  112. Parker DS, et al. Wingless signaling induces widespread chromatin remodeling of target loci. Mol Cell Biol. 2008;28(5):1815–28.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 2014;105(9):1087–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Li J, et al. CBP/p300 are bimodal regulators of Wnt signaling. EMBO J. 2007;26(9):2284–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Wend P, et al. Wnt signaling in stem and cancer stem cells. Semin Cell Dev Biol. 2010;21(8):855–63.

    Article  PubMed  CAS  Google Scholar 

  119. de Sousa EM, et al. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17(4):647–53.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  122. Chinn SB, Myers JN. Oral cavity carcinoma: current management, controversies, and future directions. J Clin Oncol. 2015;33(29):3269–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Hedberg ML, et al. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. J Clin Invest. 2016;126(4):1606.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  125. Thiery JP, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.

    Article  PubMed  CAS  Google Scholar 

  126. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Ye X, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525(7568):256–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Katoh M. Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs. Oncol Rep. 2005;14(4):1083–6.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  138. Zhang J, Ma L. MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev. 2012;31(3–4):653–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Yan J, et al. Regulation of mesenchymal phenotype by MicroRNAs in cancer. Curr Cancer Drug Targets. 2013;13(9):930–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  151. Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993;9:317–21.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000;36:1607–20.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Whitman M. Smads and early developmental signaling by the TGFbeta superfamily. Genes Dev. 1998;12(16):2445–62.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Akhmetshina A, et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun. 2012;3:735.

    Article  PubMed  CAS  Google Scholar 

  168. Nowell CS, Radtke F. Notch as a tumour suppressor. Nat Rev Cancer. 2017;17(3):145–59.

    Article  PubMed  CAS  Google Scholar 

  169. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Dotto GP. Notch tumor suppressor function. Oncogene. 2008;27(38):5115–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Croagh D, et al. Esophageal stem cells and genetics/epigenetics in esophageal cancer. Ann N Y Acad Sci. 2014;1325:8–14.

    Article  PubMed  Google Scholar 

  172. Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Lawrence MS, et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  176. Munoz-Chapuli R, Perez-Pomares JM. Cardiogenesis: an embryological perspective. J Cardiovasc Transl Res. 2010;3(1):37–48.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Camargo FD, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Current biology : CB. 2007;17(23):2054–60.

    Article  PubMed  CAS  Google Scholar 

  181. Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15(2):73–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  185. Hiemer SE, Varelas X. Stem cell regulation by the Hippo pathway. Biochim Biophys Acta. 2012;18:2323–2334.

    Google Scholar 

  186. Mauviel A, Nallet-Staub F, Varelas X. Integrating developmental signals: a Hippo in the (path)way. Oncogene. 2012;31(14):1743–56.

    Article  PubMed  CAS  Google Scholar 

  187. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642–56.

    PubMed  PubMed Central  CAS  Google Scholar 

  188. Attisano L, Wrana JL. Signal integration in TGF-beta, WNT, and Hippo pathways. F1000Prime Rep. 2013;5:17.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Li J, et al. LATS2 suppresses oncogenic Wnt signaling by disrupting beta-catenin/BCL9 interaction. Cell Rep. 2013;5(6):1650–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Heallen T, et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332(6028):458–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Park HW, et al. Alternative Wnt signaling activates YAP/TAZ. Cell. 2015;162(4):780–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  193. Hu T, Li C. Convergence between Wnt-beta-catenin and EGFR signaling in cancer. Mol Cancer. 2010;9:236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  197. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol. 2009;10(7):445–57.

    Article  PubMed  CAS  Google Scholar 

  198. Whitman M, et al. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332(6165):644–6.

    Article  PubMed  CAS  Google Scholar 

  199. Locasale JW, Cantley LC. Altered metabolism in cancer. BMC Biol. 2010;8:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269–70.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  206. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.

    Article  PubMed  CAS  Google Scholar 

  207. Mazumdar J, et al. O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol. 2010;12(10):1007–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15(9):540–55.

    Article  PubMed  CAS  Google Scholar 

  210. Gillies RJ, Gatenby RA. Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr. 2007;39(3):251–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Junk DJ, et al. Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene. 2017;36(28):4001–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582–98.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Gopal S, et al. Fibronectin-guided migration of carcinoma collectives. Nat Commun. 2017;8:14105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Bais MV, Kukuruzinska M, Trackman PC. Orthotopic non-metastatic and metastatic oral cancer mouse models. Oral Oncol. 2015;51(5):476–82.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  229. van Loosdregt J, et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity. 2013;39(2):298–310.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  231. Spranger S, Gajewski TF. A new paradigm for tumor immune escape: beta-catenin-driven immune exclusion. J Immunother Cancer. 2015;3:43.

    Article  PubMed  PubMed Central  Google Scholar 

  232. Pai SG, et al. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017;10(1):101.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  234. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.

    Article  CAS  PubMed  Google Scholar 

  235. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.

    PubMed  CAS  Google Scholar 

  236. Spranger S. Tumor heterogeneity and tumor immunity: a chicken-and-egg problem. Trends Immunol. 2016;37(6):349–51.

    Article  PubMed  CAS  Google Scholar 

  237. Lehuede C, et al. Metabolic plasticity as a determinant of tumor growth and metastasis. Cancer Res. 2016;76(18):5201–8.

    Article  PubMed  CAS  Google Scholar 

  238. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  240. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Aminuddin A, Ng PY. Promising druggable target in head and neck squamous cell carcinoma: Wnt signaling. Front Pharmacol. 2016;7:244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  242. Tammela T, et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature. 2017;545(7654):355–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  244. Madan B, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35(17):2197–207.

    Article  PubMed  CAS  Google Scholar 

  245. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36(11):1461–73.

    Article  PubMed  CAS  Google Scholar 

  246. Arensman MD, et al. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther. 2014;13(10):2303–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Kartha VK, et al. PDGFRbeta is a novel marker of stromal activation in oral squamous cell carcinomas. PLoS One. 2016;11(4):e0154645.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, MA, USA

    Khalid Alamoud & Maria A. Kukuruzinska

Authors
  1. Khalid Alamoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria A. Kukuruzinska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria A. Kukuruzinska .

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Barbara Burtness

  2. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

    Erica A. Golemis

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Alamoud, K., Kukuruzinska, M.A. (2018). Diversity of Wnt/β-Catenin Signaling in Head and Neck Cancer: Cancer Stem Cells, Epithelial-to-Mesenchymal Transition, and Tumor Microenvironment. In: Burtness, B., Golemis, E. (eds) Molecular Determinants of Head and Neck Cancer. Current Cancer Research. Humana Press, Cham. https://doi.org/10.1007/978-3-319-78762-6_18

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-78762-6_18

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-78761-9

  • Online ISBN: 978-3-319-78762-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation