Skip to main content
SpringerLink
Log in

Targeting Wnt Signalling in Cancer

  • Chapter
  • First Online:
Targeting the Wnt Pathway in Cancer

  • 934 Accesses

Abstract

The modular nature of the Wnt pathway provides multiple potential points of intervention to alter its activity. In this chapter we review potential opportunities to inhibit Wnt signalling at various levels, including the synthesis and secretion of Wnt ligands, activation of the Wnt receptor complex, degradation of cytoplasmic β-catenin and finally the nuclear complex between β-catenin and other transcription factors and co-activators. We also discuss the possibility of therapies targeting downstream Wnt target genes and a number of approaches with less defined mechanisms, whose anti-oncogenic properties may be mediated by Wnt pathway suppression. This review mainly focusses on canonical Wnt-β-catenin signalling, although a number of non-canonical Wnt pathways are also discussed, mainly in relation to their role in canonical Wnt pathway inhibition.

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

  • Arenas RB, Fichera A, Mok P, Blanco MC, Michelassi F (1996) Introduction of human ­adenomatous polyposis coli gene into Min mice via cationic liposomes. Surgery 120(4):712

    Article  CAS  PubMed  Google Scholar 

  • Bachar-Dahan L, Goltzmann J, Yaniv A, Gazit A (2006) Engrailed-1 negatively regulates beta-Catenin transcriptional activity by destabilizing beta-Catenin via a glycogen synthase kinase-­3independent pathway. Mol Biol Cell 17(6):2572

    Article  CAS  PubMed  Google Scholar 

  • Barker N, Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5(12):997

    Article  CAS  PubMed  Google Scholar 

  • Barker N et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003

    Article  CAS  PubMed  Google Scholar 

  • Barker N et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457(7229):608

    Article  CAS  PubMed  Google Scholar 

  • Benetti R et al (2005) The calpain system is involved in the constitutive regulation of beta-catenin signaling functions. J Biol Chem 280(23):22070

    Article  CAS  PubMed  Google Scholar 

  • Blanc E, Goldschneider D, Douc-Rasy S, Bénard J, Raguénez G (2005) Wnt-5a gene expression in malignant human neuroblasts. Cancer Lett 228(1–2):117

    Article  CAS  PubMed  Google Scholar 

  • Bordonaro M, Lazarova DL, Sartorelli AC (2007) The activation of beta-catenin by Wnt signaling mediates the effects of histone deacetylase inhibitors. Exp Cell Res 313(8):1652

    Article  CAS  PubMed  Google Scholar 

  • Cadigan KM, Liu YI (2006) Wnt signaling: complexity at the surface. J Cell Sci 119(3):395

    Article  CAS  PubMed  Google Scholar 

  • Chan TA, Wang Z, Dang LH, Vogelstein B, Kinzler KW (2002) Targeted inactivation of CTNNB1 reveals unexpected effects of β-catenin mutation. Proc Natl Acad Sci USA 99(12):8265

    Article  CAS  PubMed  Google Scholar 

  • Chan DW, Chan C, Yam JW, Ching Y, Ng IO (2006) Prickle-1 negatively regulates Wnt/β-Catenin pathway by promoting dishevelled Ubiquitination/Degradation in liver cancer. Gastroenterology 131(4):1218

    Article  CAS  PubMed  Google Scholar 

  • Chen B et al (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5(2):100

    Article  CAS  PubMed  Google Scholar 

  • Chiu S et al (2009) Over-expression of EphB3 enhances cell-cell contacts and suppresses tumor growth in HT-29 human colon cancer cells. Carcinogenesis 30(9):1475

    Article  CAS  PubMed  Google Scholar 

  • Choi H et al (2010) Murrayafoline A attenuates the Wnt/β-catenin pathway by promoting the degradation of intracellular β-catenin proteins. Biochem Biophys Res Commun 391(1):915

    Article  CAS  PubMed  Google Scholar 

  • Clevers H (2006a) Colon cancer – understanding how NSAIDs work. N Engl J Med 354(7):761

    Article  CAS  PubMed  Google Scholar 

  • Clevers H (2006b) Wnt/β-Catenin signaling in development and disease. Cell 127(3):469

    Article  CAS  PubMed  Google Scholar 

  • Clevers H, Batlle E (2006) EphB/EphrinB receptors and Wnt signaling in colorectal cancer. Cancer Res 66(1):2

    Article  CAS  PubMed  Google Scholar 

  • Courey AJ, Jia S (2001) Transcriptional repression: the long and the short of it. Genes Dev 15(21):2786

    CAS  PubMed  Google Scholar 

  • Dayyani F et al (2008) Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival. Blood 111(8):4338

    Article  CAS  PubMed  Google Scholar 

  • Eastman Q, Grosschedl R (1999) Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol 11(2):233

    Article  CAS  PubMed  Google Scholar 

  • Emami KH et al (2004) A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. Proc Natl Acad Sci USA 101(34):12682

    Article  CAS  PubMed  Google Scholar 

  • Ewan KBR, Dale TC (2008) The potential for targeting oncogenic WNT/beta- catenin signaling in therapy. Curr Drug Targets 9(7):532

    Article  CAS  PubMed  Google Scholar 

  • Fraga MF et al (2008) Epigenetic inactivation of the Groucho homologue gene TLE1 in hematologic malignancies. Cancer Res 68(11):4116

    Article  CAS  PubMed  Google Scholar 

  • Framson PE, Sage EH (2004) SPARC and tumor growth: Where the seed meets the soil? J Cell Biochem 92(4):679

    Article  CAS  PubMed  Google Scholar 

  • Fujii N et al (2007) An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res 67(2):573

    Article  CAS  PubMed  Google Scholar 

  • Garcia MI et al (2009) LGR5 deficiency deregulates Wnt signaling and leads to precocious paneth cell differentiation in the fetal intestine. Dev Biol 331(1):58

    Article  CAS  PubMed  Google Scholar 

  • Gaspar C et al (2009) A targeted constitutive mutation in the Apc tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet 5(7):e1000547

    Article  PubMed  Google Scholar 

  • Gasperowicz M, Otto F (2005) Mammalian Groucho homologs: redundancy or specificity? J Cell Biochem 95(4):670

    Article  CAS  PubMed  Google Scholar 

  • Harris DM, Go VLW (2004) Vitamin D and colon carcinogenesis. J Nutr 134(12):3463S

    CAS  PubMed  Google Scholar 

  • He T et al (1998) Identification of c-MYC as a target of the APC pathway. Science 281(5382):1509

    Article  CAS  PubMed  Google Scholar 

  • He B et al (2004) A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia 6(1):7

    CAS  PubMed  Google Scholar 

  • He B et al (2005) Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene 24(18):3054

    Article  CAS  PubMed  Google Scholar 

  • Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R (2000) The p300/CBP acetyltransferases function as transcriptional coactivators of β-catenin in vertebrates. EMBO J 19(8):1839

    Article  CAS  PubMed  Google Scholar 

  • Holcombe RF et al (2002) Expression of Wnt ligands and Frizzled receptors in colonic mucosa and in colon carcinoma. Mol Pathol 55(4):220

    Article  CAS  PubMed  Google Scholar 

  • Huang SA et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614

    Article  CAS  PubMed  Google Scholar 

  • Ireland H et al (2004) Inducible cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of β-catenin. Gastroenterology 126(5):1236

    Article  CAS  PubMed  Google Scholar 

  • Ishitani T et al (2003a) The TAK1-NLK Mitogen-Activated protein kinase cascade functions in the Wnt-5a/Ca2+ pathway to antagonize Wnt/beta-Catenin signaling. Mol Cell Biol 23(1):131

    Article  CAS  PubMed  Google Scholar 

  • Ishitani T, Ninomiya-Tsuji J, Matsumoto K (2003b) Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in Wnt/β-catenin signaling. Mol Cell Biol 23(4):1379

    Article  CAS  PubMed  Google Scholar 

  • Iversen PL, Arora V, Acker AJ, Mason DH, Devi GR (2003) Efficacy of antisense morpholino oligomer targeted to C-MYC in prostate cancer xenograft murine model and a phase I safety study in humans. Clin Cancer Res 9(7):2510

    CAS  PubMed  Google Scholar 

  • Jonsson M, Dejmek J, Bendahl P, Andersson T (2002) Loss of WNT-5A protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res 62(2):409

    CAS  PubMed  Google Scholar 

  • Jubb AM et al (2006) Achaete-scute like 2 (ascl2) is a target of wnt signaling and is upregulated in intestinal neoplasia. Oncogene 25(24):3445

    Article  CAS  PubMed  Google Scholar 

  • Kim JK, Diehl JA (2009) Nuclear Cyclin D1: an oncogenic driver in human cancer. J Cell Physiol 220(2):292

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Crooks H, Foxworth A, Waldman T (2002) Proof-of-principle: oncogenic beta-catenin is a valid molecular target for the development of pharmacological inhibitors. Mol Cancer Ther 1(14):1355

    CAS  PubMed  Google Scholar 

  • Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2):89

    Article  CAS  PubMed  Google Scholar 

  • Lepourcelet M et al (2004) Small-molecule antagonists of the oncogenic TCF/β-catenin protein complex. Cancer Cell 5(1):91

    Article  CAS  PubMed  Google Scholar 

  • Li G, Iyengar R (2002) Calpain as an effector of the G_q signaling pathway for inhibition of Wnt/β-catenin-regulated cell proliferation. Proc Natl Acad Sci USA 99(20):13254

    Article  CAS  PubMed  Google Scholar 

  • Li J, Wang C (2008) TBL1-TBLR1 and β-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol 10(2):160

    Article  CAS  PubMed  Google Scholar 

  • Liu J et al (2001) Siah-1 mediates a novel β-Catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell 7(5):927

    Article  CAS  PubMed  Google Scholar 

  • MacDonald BT, Tamai K, He X (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9

    Article  CAS  PubMed  Google Scholar 

  • Malliri A et al (2006) The Rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. J Biol Chem 281(1):543

    Article  CAS  PubMed  Google Scholar 

  • Matsukawa Y et al (1997) Effects of quercetin and/or restraint stress on formation of aberrant crypt foci induced by azoxymethane in rat colons. Oncology 54(2):118

    Article  CAS  PubMed  Google Scholar 

  • May R et al (2008) Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM Kinase-Like-1, following radiation injury and in adenomatous polyposis Coli/Multiple intestinal neoplasia mice. Stem Cells 26(3):630

    Article  PubMed  Google Scholar 

  • Mazieres J et al (2005) Wnt2 as a new therapeutic target in malignant pleural mesothelioma. Int J Cancer 117(2):326

    Article  CAS  PubMed  Google Scholar 

  • Merle P et al (2004) Functional consequences of Frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 127(4):1110

    Article  CAS  PubMed  Google Scholar 

  • Mikels AJ, Nusse R (2006) Purified WNT5A protein activates or inhibits β-Catenin/TCF signaling depending on receptor context. PLoS Biol 4(4):e115

    Article  PubMed  Google Scholar 

  • Mikels A, Minami Y, Nusse R (2009) Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling. J Biol Chem 284(44):30167

    Article  CAS  PubMed  Google Scholar 

  • Mikheev AM, Mikheeva SA, Rostomily R, Zarbl H (2007) Dickkopf-1 activates cell death in MDA-MB435 melanoma cells. Biochem Biophys Res Commun 352(3):675

    Article  CAS  PubMed  Google Scholar 

  • Mikheev A et al (2008) Dickkopf-1 mediated tumor suppression in human breast carcinoma cells. Breast Cancer Res Treat 112(2):263

    Article  CAS  PubMed  Google Scholar 

  • Møllersen L, Paulsen JE, Olstorn HB, Knutsen HK, Alexander J (2004) Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (Min)/+ mice. Carcinogenesis 25(1):149

    Article  PubMed  Google Scholar 

  • Moon RT, Kohn AD, Ferrari GVD, Kaykas A (2004) WNT and β-catenin signalling: diseases and therapies. Nat Rev Genet 5(9):691

    Article  CAS  PubMed  Google Scholar 

  • Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC (2005) Interaction of nuclear receptors with the Wnt/beta-Catenin/TCF signaling axis: Wnt you like to know? Endocr Rev 26(7):898

    Article  CAS  PubMed  Google Scholar 

  • Nagayama S et al (2005) Therapeutic potential of antibodies against FZD10, a cell-surface protein, for synovial sarcomas. Oncogene 24(41):6201

    Article  CAS  PubMed  Google Scholar 

  • Park CH et al (2005) Quercetin, a potent inhibitor against β-catenin/TCF signaling in SW480 colon cancer cells. Biochem Biophys Res Commun 328(1):227

    Article  CAS  PubMed  Google Scholar 

  • Park S et al (2006) Hexachlorophene inhibits Wnt/beta-catenin pathway by promoting siah-mediated beta-catenin degradation. Mol Pharmacol 70(3):960

    Article  CAS  PubMed  Google Scholar 

  • Phesse TJ et al (2008) Deficiency of Mbd2 attenuates Wnt signaling. Mol Cell Biol 28(19):6094

    Article  CAS  PubMed  Google Scholar 

  • Phillips RKS et al (2002) A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50(6):857

    Article  CAS  PubMed  Google Scholar 

  • Prokhortchouk A et al (2006) Kaiso-Deficient mice show resistance to intestinal cancer. Mol Cell Biol 26(1):199

    Article  CAS  PubMed  Google Scholar 

  • Säfholm A et al (2008) The Wnt-5a-derived hexapeptide foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin Cancer Res 14(20):6556

    Article  PubMed  Google Scholar 

  • Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40(7):915

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ et al (2003) Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat Genet 34(2):145

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ et al (2004) Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18(12):1385

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ et al (2007a) Myc deletion rescues Apc deficiency in the small intestine. Nature 446(7136):676

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ, Mansergh FC, Evans MJ, Wilkins JA, Clarke AR (2007b) Deficiency of SPARC suppresses intestinal tumorigenesis in APCMin/+ mice. Gut 56(10):1410

    Article  CAS  PubMed  Google Scholar 

  • Sato H et al (2007) Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis 28(12):2459

    Article  CAS  PubMed  Google Scholar 

  • Sekhon HS, London CA, Sekhon M, Iversen PL, Devi GR (2008) c-MYC antisense phosphosphorodiamidate morpholino oligomer inhibits lung metastasis in a murine tumor model. Lung Cancer 60(3):347

    Article  PubMed  Google Scholar 

  • Shan B, Wang MX, Li RQ (2009) Quercetin inhibit human SW480 colon cancer growth in association with inhibition of Cyclin D1 and surviving expression through Wnt/beta-catenin ­signaling pathway. Cancer Investig 27(6):604

    Article  CAS  Google Scholar 

  • Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31(1):27

    Article  CAS  PubMed  Google Scholar 

  • Solomon DH et al (2006) Cardiovascular outcomes in new users of coxibs and non-steroidal anti-inflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum 54(5):1378

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36(4):417

    Article  CAS  PubMed  Google Scholar 

  • Takahashi-Yanaga F, Sasaguri T (2009) Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: inhibitors of the wnt/beta-catenin signaling pathway as novel anticancer drugs. J Pharmacol Sci 109(2):179

    Article  CAS  PubMed  Google Scholar 

  • Uematsu K et al (2003a) Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene 22(46):7218

    Article  CAS  PubMed  Google Scholar 

  • Uematsu K et al (2003b) Wnt pathway activation in mesothelioma: Evidence of dishevelled overexpression and transcriptional activity of beta-Catenin. Cancer Res 63(15):4547

    CAS  PubMed  Google Scholar 

  • van de Wetering M et al (2002) The β-Catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111(2):241

    Article  PubMed  Google Scholar 

  • van der Flier LG et al (2009a) Transcription factor Achaete Scute-Like 2 controls intestinal stem cell fate. Cell 136(5):903

    Article  PubMed  Google Scholar 

  • van der Flier LG, Haegebarth A, Stange DE, van de Wetering M, Clevers H (2009b) OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137(1):15

    Article  PubMed  Google Scholar 

  • Weeraratna AT et al (2002) Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 1(3):279

    Article  CAS  PubMed  Google Scholar 

  • Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea–a paradigm shift. Cancer Res 66(4):1883

    Article  CAS  PubMed  Google Scholar 

  • Wilding J et al (2002) Cyclin D1 is not an essential target of beta-Catenin signaling during intestinal tumorigenesis, but it may act as a modifier of disease severity in multiple intestinal neoplasia (Min) mice. Cancer Res 62(16):4562

    CAS  PubMed  Google Scholar 

  • Williams JL et al (2001) Nitric oxide-releasing nonsteroidal antiinflammatory drugs (NSAIDs) alter the kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: implications for colon cancer chemoprevention. Cancer Res 61(8):3285

    CAS  PubMed  Google Scholar 

  • Williams JL et al (2004) NO-donating aspirin inhibits intestinal carcinogenesis in min (APC(Min/+)) mice. Biochem Biophys Res Commun 313(3):784

    Article  CAS  PubMed  Google Scholar 

  • Yamada M et al (2006) NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). J Biol Chem 281(30):20749

    Article  CAS  PubMed  Google Scholar 

  • Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by Cyclin D1 ablation. Nature 411(6841):1017

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK

    Alan R. Clarke

Authors
  1. Aliaksei Holik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan R. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan R. Clarke .

Editor information

Editors and Affiliations

  1. Medical Center, Dept. Surgery, University of Chicago, S. Maryland Ave. 5841, Chicago, 60637-5026, Illinois, USA

    Kathleen H. Goss

  2. Eli & Edythe Broad Center for, Regenerative Medicine &, University of Southern California, San Pablo Street 1501, Los Angeles, 90033, California, USA

    Michael Kahn

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Holik, A., Clarke, A.R. (2011). Targeting Wnt Signalling in Cancer. In: Goss, K., Kahn, M. (eds) Targeting the Wnt Pathway in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8023-6_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-8023-6_8

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-8022-9

  • Online ISBN: 978-1-4419-8023-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation