Wnt Signalling-Targeted Therapy in the CMS2 Tumour Subtype: A New Paradigm in CRC Treatment?

  • Cristina Albuquerque
  • Lucília Pebre Pereira
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1110)


Colorectal cancers (CRC) belonging to the consensus molecular subtype 2 (CMS2) have the highest incidence rate, affect mainly the distal colon and rectum, and are characterized by marked Wnt/β-catenin/Transcription Factor 7-Like 2 (TCF7L2) pathway activation and also by activation of epidermal growth factor receptor (EGFR) signalling. Despite having the highest overall survival, CMS2 tumours are often diagnosed at stage III when an adjuvant chemotherapy-based regimen is recommended. Nevertheless, colorectal cancer stem cells (CSCs) and circulating tumour cells may still evade the current therapeutic options and metastasize, stressing the need to develop more tailored therapeutic strategies. For example, activation of EGFR signalling is being used as a target for tailored therapy, however, therapy resistance is frequently observed. Therefore, targeting the Wnt signalling axis represents an additional therapeutic strategy, considering that CMS2 tumours are “Wnt-addicted”. Several efforts have been made to identify Wnt antagonists, either of synthetic or natural origin. However, an inverse gradient of Wnt/β-catenin/TCF7L2 signalling activity during CRC progression has been suggested, with early stage and metastatic tumours displaying high and low Wnt signalling activities, respectively, which lead us to revisit the “just-right” signalling model. This may pinpoint the use of Wnt signalling agonists instead of antagonists for treatment of metastatic stages, in a context-dependent fashion. Moreover, the poor immunogenicity of these tumours challenges the use of recently emerged immunotherapies. This chapter makes a journey about CMS2 tumour characterization, their conventional treatment, and how modulation of Wnt signalling or immune response may be applied to CRC therapy. It describes the newest findings in this field and indicates where more research is required.


CMS2 therapy Immunomodulation Just-right signalling Nutraceuticals Wnt antagonists/agonists Wnt signalling 



The authors would like to thank the funding from Liga Portuguesa Contra o Cancro – Núcleo Regional do Sul (Portuguese League Against Cancer – South Regional Nucleus) assigned as an Oncology Research Scholarship (LPCC/FUNDAÇÃO PT – 2017) granted to Lucília Pebre Pereira. Support from Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E.), is also acknowledged.


  1. Alam MN, Almoyad M, Huq F (2018) Polyphenols in colorectal cancer: current state of knowledge including clinical trials and molecular mechanism of action. Biomed Res Int 2018:4154185. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Albuquerque C et al (2002) The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Hum Mol Genet 11:1549–1560. CrossRefPubMedGoogle Scholar
  3. Albuquerque C et al (2010) Colorectal cancers show distinct mutation spectra in members of the canonical WNT signaling pathway according to their anatomical location and type of genetic instability. Genes Chromosomes Cancer 49:746–759. CrossRefPubMedGoogle Scholar
  4. Albuquerque C, Bakker ERM, van Veelen W, Smits R (2011) Colorectal cancers choosing sides. Biochim Biophys Acta 1816:219–231. CrossRefPubMedGoogle Scholar
  5. Algars A et al (2017) EGFR gene copy number predicts response to anti-EGFR treatment in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. Int J Cancer 140:922–929. CrossRefPubMedGoogle Scholar
  6. Allegra CJ, Rumble RB, Hamilton SR, Mangu PB, Roach N, Hantel A, Schilsky RL (2016) Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology provisional clinical opinion update 2015. J Clin Oncol 34:179–185. CrossRefPubMedGoogle Scholar
  7. Allen WL et al (2018) Transcriptional subtyping and CD8 immunohistochemistry identifies patients with stage II and III colorectal cancer with poor prognosis who benefit from adjuvant chemotherapy. JCO Precis Oncol:1–15.
  8. Amado RG et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634. CrossRefPubMedGoogle Scholar
  9. Anderson EC, Hessman C, Levin TG, Monroe MM, Wong MH (2011) The role of colorectal cancer stem cells in metastatic disease and therapeutic response. Cancers 3:319–339. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Anitha A, Sreeranganathan M, Chennazhi KP, Lakshmanan VK, Jayakumar R (2014) In vitro combinatorial anticancer effects of 5-fluorouracil and curcumin loaded N,O-carboxymethyl chitosan nanoparticles toward colon cancer and in vivo pharmacokinetic studies. Eur J Pharm Biopharm 88:238–251. CrossRefPubMedGoogle Scholar
  11. Arques O et al (2016) Tankyrase inhibition blocks Wnt/beta-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin Cancer Res 22:644–656. CrossRefPubMedGoogle Scholar
  12. Bachmeier BE, Killian PH, Melchart D (2018) The role of curcumin in prevention and management of metastatic disease. Int J Mol Sci 19:1716. CrossRefPubMedCentralGoogle Scholar
  13. Becht E et al (2016) Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res 22:4057–4066. CrossRefPubMedGoogle Scholar
  14. 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 313:1652–1666. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Buhrmann C, Yazdi M, Popper B, Shayan P, Goel A, Aggarwal BB, Shakibaei M (2018) Resveratrol chemosensitizes TNF-beta-induced survival of 5-FU-treated colorectal cancer cells. Nutrients 10:888. CrossRefPubMedCentralGoogle Scholar
  16. Burn J et al (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378:2081–2087. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cao Y et al (2016) Regular aspirin use associates with lower risk of colorectal cancers with low numbers of tumor-infiltrating lymphocytes. Gastroenterology 151:879–892. e874. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Carroll RE et al (2011) Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res 4:354–364. CrossRefGoogle Scholar
  19. Chang LC, Yu YL (2016) Dietary components as epigenetic-regulating agents against cancer. Biomedicine (Taipei) 6:2. CrossRefGoogle Scholar
  20. Chen B et al (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100–107. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chen HJ, Hsu LS, Shia YT, Lin MW, Lin CM (2012) The beta-catenin/TCF complex as a novel target of resveratrol in the Wnt/beta-catenin signaling pathway. Biochem Pharmacol 84:1143–1153. CrossRefPubMedGoogle Scholar
  22. Chen N et al (2015) Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol 10:910–923. CrossRefPubMedGoogle Scholar
  23. Chen Y, Rao X, Huang K, Jiang X, Wang H, Teng L (2017a) FH535 inhibits proliferation and motility of colon cancer cells by targeting Wnt/β-catenin signaling pathway. J Cancer 8:3142–3153. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Chen Y et al (2017b) (−)-Epigallocatechin-3-Gallate inhibits colorectal cancer stem cells by suppressing Wnt/β-catenin pathway. Nutrients 9:572. CrossRefPubMedCentralGoogle Scholar
  25. Christie M et al (2013) Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/beta-catenin signalling thresholds for tumourigenesis. Oncogene 32:4675–4682. CrossRefPubMedGoogle Scholar
  26. Colangelo T et al (2017) Friend or foe? The tumour microenvironment dilemma in colorectal cancer. Biochim Biophys Acta 1867:1–18. CrossRefGoogle Scholar
  27. Croy HE et al (2016) The poly(ADP-ribose) polymerase enzyme Tankyrase antagonizes activity of the beta-catenin destruction complex through ADP-ribosylation of axin and APC2. J Biol Chem 291:12747–12760. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Cunningham D et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345. CrossRefPubMedGoogle Scholar
  29. Dasari A, Gao H, Deaton L, Overman MJ, Hauch S, Kopetz S, Reuben JM (2013) Association of mesenchymal phenotype in circulating tumor cells with poor prognosis in metastatic colorectal cancer. J Clin Oncol 31:e14567–e14567. CrossRefGoogle Scholar
  30. de Gramont A et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947. CrossRefPubMedGoogle Scholar
  31. de Sousa EMF et al (2011) Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 9:476–485. CrossRefGoogle Scholar
  32. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Derer A, Frey B, Fietkau R, Gaipl US (2016) Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol Immunother 65:779–786. CrossRefPubMedGoogle Scholar
  34. Di Gennaro E et al (2010) Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase. Br J Cancer 103:1680–1691. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J (2017) Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer 17:79–92. CrossRefPubMedGoogle Scholar
  36. Dou H et al (2017) Curcumin suppresses the colon cancer proliferation by inhibiting Wnt/beta-catenin pathways via miR-130a. Front Pharmacol 8:877. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Douillard JY et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047. CrossRefPubMedGoogle Scholar
  38. Dow LE, O’Rourke KP, Simon J, Tschaharganeh DF, van Es JH, Clevers H, Lowe SW (2015) Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal. Cancer Cell 161:1539–1552. CrossRefGoogle Scholar
  39. Dylla SJ et al (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One 3:e2428. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Emami KH et al (2004) A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription. Proc Natl Acad Sci U S A 101:12682–12687. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Fang L et al (2016) A small-molecule antagonist of the beta-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis. Cancer Res 76:891–901. CrossRefPubMedGoogle Scholar
  42. Fazzone W, Wilson PM, Labonte MJ, Lenz HJ, Ladner RD (2009) Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells. Int J Cancer 125:463–473. CrossRefPubMedGoogle Scholar
  43. Fu C et al (2015) Beta-catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci U S A 112:2823–2828. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Gajewski TF (2015) The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin Oncol 42:663–671. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Gala MK, Chan AT (2015) Molecular pathways: aspirin and Wnt signaling-a molecularly targeted approach to cancer prevention and treatment. Clin Cancer Res 21:1543–1548. CrossRefPubMedGoogle Scholar
  46. Galon J et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964. CrossRefGoogle Scholar
  47. Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886. CrossRefPubMedGoogle Scholar
  48. Gaspar C, Fodde R (2004) APC dosage effects in tumorigenesis and stem cell differentiation. Int J Dev Biol 48:377–386. CrossRefPubMedGoogle Scholar
  49. Grothey A, Sargent D, Goldberg RM, Schmoll HJ (2004) Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209–1214. CrossRefPubMedGoogle Scholar
  50. Guinney J et al (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21:1350–1356. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Gurney A et al (2012) Wnt pathway inhibition via the targeting of frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A 109:11717–11722. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Handeli S, Simon JA (2008) A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities. Mol Cancer Ther 7:521–529. CrossRefPubMedGoogle Scholar
  53. Hopirtean C, Nagy V (2018) Optimizing the use of anti VEGF targeted therapies in patients with metastatic colorectal cancer: review of literature. Clujul Med 91:12–17. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Huang SM et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620. CrossRefPubMedGoogle Scholar
  55. Hurwitz H et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342. CrossRefPubMedGoogle Scholar
  56. Hurwitz H et al (2017) Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): interim data from my pathway. J Clin Oncol 35:676–676. CrossRefGoogle Scholar
  57. Inamura K (2018) Colorectal cancers: an update on their molecular pathology. Cancers 10:26. CrossRefPubMedCentralGoogle Scholar
  58. Irving GR et al (2015) Combining curcumin (C3-complex, Sabinsa) with standard care FOLFOX chemotherapy in patients with inoperable colorectal cancer (CUFOX): study protocol for a randomised control trial. Trials 16:110. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Isella C et al (2017) Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer. Nat Commun 8:15107. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Jackie Oh S, Lee W, Lockhart AC (2016) A promising road in colorectal cancer treatment: personalized immunotherapy based on molecular and immune classification system. Transl Cancer Res 5:327–329. CrossRefGoogle Scholar
  61. Jackson H et al (2016) Novel bispecific domain antibody to LRP6 inhibits Wnt and R-spondin ligand-induced Wnt signaling and tumor growth. Mol Cancer Res 14:859–868. CrossRefPubMedGoogle Scholar
  62. Jalili-Nik M, Soltani A, Moussavi S, Ghayour-Mobarhan M, Ferns GA, Hassanian SM, Avan A (2018) Current status and future prospective of curcumin as a potential therapeutic agent in the treatment of colorectal cancer. J Cell Physiol 233:6337–6345. CrossRefPubMedGoogle Scholar
  63. James MI et al (2015) Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett 364:135–141. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Jansson EA, Are A, Greicius G, Kuo IC, Kelly D, Arulampalam V, Pettersson S (2005) The Wnt/beta-catenin signaling pathway targets PPARgamma activity in colon cancer cells. Proc Natl Acad Sci U S A 102:1460–1465. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Ji Q et al (2013) Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/beta-catenin signal pathway. PLoS One 8:e78700. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Ju J et al (2005) Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea. Cancer Res 65:10623–10631. CrossRefPubMedGoogle Scholar
  67. Kamel KM, Khalil IA, Rateb ME, Elgendy H, Elhawary S (2017) Chitosan-coated cinnamon/oregano-loaded solid lipid nanoparticles to augment 5-fluorouracil cytotoxicity for colorectal cancer: extract standardization, nanoparticle optimization, and cytotoxicity evaluation. J Agric Food Chem 65:7966–7981. CrossRefPubMedGoogle Scholar
  68. Kanterman J et al (2014) Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res 74:6022–6035. CrossRefPubMedGoogle Scholar
  69. Karapetis CS et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765. CrossRefPubMedGoogle Scholar
  70. Karpinski P, Rossowska J, Sasiadek MM (2017) Immunological landscape of consensus clusters in colorectal cancer. Oncotarget 8:105299–105311. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Kavuri SM et al (2015) HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov 5:832–841. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Kikuchi A, Yamamoto H, Sato A, Matsumoto S (2011) New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol 291:21–71. CrossRefPubMedGoogle Scholar
  73. Kresty LA, Mallery SR, Stoner GD (2016) Black raspberries in cancer clinical trials: past, present and future. J Berry Res 6:251–261. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Krishnamurthy N, Kurzrock R (2018) Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev 62:50–60. CrossRefPubMedGoogle Scholar
  75. Kuppusamy P, Yusoff MM, Maniam GP, Ichwan SJ, Soundharrajan I, Govindan N (2014) Nutraceuticals as potential therapeutic agents for colon cancer: a review. Acta Pharm Sin B 4:173–181. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandala M, Cervantes A, Arnold D (2013) Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(Suppl 6):vi64–vi72. CrossRefPubMedGoogle Scholar
  77. Lal N et al (2018) KRAS mutation and consensus molecular subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer. Clin Cancer Res 24:224–233. CrossRefPubMedGoogle Scholar
  78. Lanou AJ, Svenson B (2011) Reduced cancer risk in vegetarians: an analysis of recent reports. Cancer Manag Res 3:1–8. CrossRefGoogle Scholar
  79. Lau T et al (2013) A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res 73:3132–3144. CrossRefPubMedGoogle Scholar
  80. Le DT et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. CrossRefPubMedPubMedCentralGoogle Scholar
  81. Lee N-K, Zhang Y, Su Y, Bidlingmaier S, Sherbenou DW, Ha KD, Liu B (2018) Cell-type specific potent Wnt signaling blockade by bispecific antibody. Sci Rep 8:766. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Lehtio L, Chi NW, Krauss S (2013) Tankyrases as drug targets. FEBS J 280:3576–3593. CrossRefPubMedGoogle Scholar
  83. Lin C-M, Chen H-H, Lin C-A, Wu H-C, Sheu JJ-C, Chen H-J (2017) Apigenin-induced lysosomal degradation of β-catenin in Wnt/β-catenin signaling. Sci Rep 7:372. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Linnekamp JF et al (2018) Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models. Cell Death Differ 25:616–633. CrossRefPubMedGoogle Scholar
  85. Liu RH (2004) Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr 134:3479S–3485S. CrossRefPubMedGoogle Scholar
  86. Liu K-P et al (2012) Glycogen synthase kinase 3β inhibitor (2′Z,3′E)-6-Bromo-indirubin- 3′-oxime enhances drug resistance to 5-fluorouracil chemotherapy in colon cancer cells. Chin J Cancer Res 24:116–123. CrossRefPubMedPubMedCentralGoogle Scholar
  87. Liu J et al (2013) Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proc Natl Acad Sci U S A 110:20224–20229. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Liu K, Li J, Wu X, Chen M, Luo F (2017) GSK-3beta inhibitor 6-bromo-indirubin-3′-oxime promotes both adhesive activity and drug resistance in colorectal cancer cells. Int J Oncol 51:1821–1830. CrossRefPubMedGoogle Scholar
  89. Lu B, Green BA, Farr JM, Lopes FC, Van Raay TJ (2016) Wnt drug discovery: weaving through the screens, patents and clinical trials. Cancers 8:82. CrossRefPubMedCentralGoogle Scholar
  90. MacDonald BT, Tamai K, He X (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Mah AT, Yan KS, Kuo CJ (2016) Wnt pathway regulation of intestinal stem cells. J Physiol 594:4837–4847. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Mariotti L, Pollock K, Guettler S (2017) Regulation of Wnt/beta-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding. Br J Pharmacol 174:4611–4636. CrossRefPubMedPubMedCentralGoogle Scholar
  93. Martino-Echarri E, Brocardo MG, Mills KM, Henderson BR (2016) Tankyrase inhibitors stimulate the ability of Tankyrases to bind axin and drive assembly of beta-catenin degradation-competent axin puncta. PLoS One 11:e0150484. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Masuda M, Sawa M, Yamada T (2015) Therapeutic targets in the Wnt signaling pathway: feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther 156:1–9. CrossRefPubMedGoogle Scholar
  95. Masuda M et al (2016) TNIK inhibition abrogates colorectal cancer stemness. Nat Commun 7:12586. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Mertins SD (2014) Cancer stem cells: a systems biology view of their role in prognosis and therapy. Anti-Cancer Drugs 25:353–367. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Morrone S, Cheng Z, Moon RT, Cong F, Xu W (2012) Crystal structure of a Tankyrase-Axin complex and its implications for Axin turnover and Tankyrase substrate recruitment. Proc Natl Acad Sci U S A 109:1500–1505. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Nair HB, Sung B, Yadav VR, Kannappan R, Chaturvedi MM, Aggarwal BB (2010) Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer. Biochem Pharmacol 80:1833–1843. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Ndolo KM, Park KR, Lee HJ, Yoon KB, Kim YC, Han SY (2017) Characterization of the indirubin derivative LDD970 as a small molecule aurora kinase a inhibitor in human colorectal cancer cells. Immune Netw 17:110–115. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Network TCGA (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337. CrossRefGoogle Scholar
  101. Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C, Holcombe RF (2009) Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res 1:25–37. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Novellasdemunt L, Antas P, Li VS (2015) Targeting Wnt signaling in colorectal cancer. A review in the theme: cell signaling: proteins, pathways and mechanisms. Am J Physiol Cell Physiol 309:C511–C521. CrossRefPubMedPubMedCentralGoogle Scholar
  103. O’Connell MJ et al (2008) Survival following recurrence in stage II and III colon cancer: findings from the ACCENT data set. J Clin Oncol 26:2336–2341. CrossRefPubMedGoogle Scholar
  104. Okada-Iwasaki R, Takahashi Y, Watanabe Y, Ishida H, Saito J, Nakai R, Asai A (2016) The discovery and characterization of K-756, a novel Wnt/beta-catenin pathway inhibitor targeting Tankyrase. Mol Cancer Ther 15:1525–1534. CrossRefPubMedGoogle Scholar
  105. Orner GA et al (2002) Response of Apc(min) and A33 (delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutat Res 506–507:121–127. CrossRefPubMedGoogle Scholar
  106. Ostrup O et al (2017) Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget 8:76290–76304. CrossRefPubMedPubMedCentralGoogle Scholar
  107. Pai SG et al (2017) Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol 10:101. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Pan MH, Lai CS, Wu JC, Ho CT (2011) Molecular mechanisms for chemoprevention of colorectal cancer by natural dietary compounds. Mol Nutr Food Res 55:32–45. CrossRefPubMedGoogle Scholar
  109. Park JE, Sun Y, Lim SK, Tam JP, Dekker M, Chen H, Sze SK (2017) Dietary phytochemical PEITC restricts tumor development via modulation of epigenetic writers and erasers. Sci Rep 7:40569. CrossRefPubMedPubMedCentralGoogle Scholar
  110. Patel S et al (2016) Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. Oncotarget 7:59087–59097. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Patil H, Saxena SG, Barrow CJ, Kanwar JR, Kapat A, Kanwar RK (2017) Chasing the personalized medicine dream through biomarker validation in colorectal cancer. Drug Discov Today 22:111–119. CrossRefPubMedGoogle Scholar
  112. Pereira CV (2016) Effect of citrus bioactive compounds on targeting human colorectal cancer stem cells. Master thesis, Faculty of Sciences and Technology, New University of Lisbon, Caparica, Portugal;
  113. Pereira LP, Silva P, Duarte M, Rodrigues L, Duarte CM, Albuquerque C, Serra AT (2017) Targeting colorectal cancer proliferation, stemness and metastatic potential using Brassicaceae extracts enriched in isothiocyanates: a 3D cell model-based study. Nutrients 9:368. CrossRefPubMedCentralGoogle Scholar
  114. Pericleous M, Mandair D, Caplin ME (2013) Diet and supplements and their impact on colorectal cancer. J Gastrointest Oncol 4:409–423. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Pfirschke C et al (2016) Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44:343–354. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Phesse T, Flanagan D, Vincan E (2016) Frizzled7: a promising Achilles’ heel for targeting the Wnt receptor complex to treat cancer. Cancers 8:50. CrossRefPubMedCentralGoogle Scholar
  117. Pistollato F, Giampieri F, Battino M (2015) The use of plant-derived bioactive compounds to target cancer stem cells and modulate tumor microenvironment. Food Chem Toxicol 75:58–70. CrossRefPubMedGoogle Scholar
  118. Priyadarsini RV, Nagini S (2012) Cancer chemoprevention by dietary phytochemicals: promises and pitfalls. Curr Pharm Biotechnol 13:125–136. CrossRefPubMedGoogle Scholar
  119. Qu Y et al (2018) Small molecule promotes beta-catenin citrullination and inhibits Wnt signaling in cancer. Nat Chem Biol 14:94–101. CrossRefPubMedGoogle Scholar
  120. Quackenbush KS et al (2016) The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance. Oncotarget 7:28273–28285. CrossRefPubMedPubMedCentralGoogle Scholar
  121. Reddivari L, Charepalli V, Radhakrishnan S, Vadde R, Elias RJ, Lambert JD, Vanamala JKP (2016) Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. BMC Complement Altern Med 16:278. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Redondo-Blanco S, Fernández J, Gutiérrez-del-Río I, Villar CJ, Lombó F (2017) New insights toward colorectal cancer chemotherapy using natural bioactive compounds. Front Pharmacol 8:109. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Riley JM, Cross AW, Paulos CM, Rubinstein MP, Wrangle J, Camp ER (2018) The clinical implications of immunogenomics in colorectal cancer: a path for precision medicine. Cancer 124:1650–1659. CrossRefPubMedGoogle Scholar
  124. Roelands J et al (2017) Immunogenomic classification of colorectal cancer and therapeutic implications. Int J Mol Sci 18:2229. CrossRefPubMedCentralGoogle Scholar
  125. Ruiz de Porras V et al (2016) Curcumin mediates oxaliplatin-acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-kappaB signalling pathway. Sci Rep 6:24675. CrossRefPubMedPubMedCentralGoogle Scholar
  126. Sartore-Bianchi A et al (2016) Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 17:738–746. CrossRefPubMedGoogle Scholar
  127. Sauer R et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740. CrossRefPubMedGoogle Scholar
  128. Sawada K, Kotani D, Bando H (2018) The clinical landscape of circulating tumor DNA in gastrointestinal malignancies. Front Oncol 8:263. CrossRefPubMedPubMedCentralGoogle Scholar
  129. Schoumacher M et al (2014) Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling. Cancer Res 74:3294–3305. CrossRefPubMedGoogle Scholar
  130. Serman L, Martic TN, Serman A, Vranic S (2014) Epigenetic alterations of the Wnt signaling pathway in cancer: a mini review. Bosn J Basic Med Sci 14:191–194. CrossRefPubMedPubMedCentralGoogle Scholar
  131. Seth C, Ruiz I Altaba A (2016) Metastases and colon cancer tumor growth display divergent responses to modulation of canonical WNT signaling. PLoS One 11:e0150697. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Shakibaei M, Kraehe P, Popper B, Shayan P, Goel A, Buhrmann C (2015) Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancer. BMC Cancer 15:250. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Shin SH et al (2017) A small molecule inhibitor of the beta-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo. EBioMedicine 25:22–31. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Shitashige M et al (2010) Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res 70:5024–5033. CrossRefPubMedGoogle Scholar
  135. Singh CK, Liu X, Ahmad N (2015a) Resveratrol, in its natural combination in whole grape, for health promotion and disease management. Ann N Y Acad Sci 1348:150–160. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Singh PP, Sharma PK, Krishnan G, Lockhart AC (2015b) Immune checkpoints and immunotherapy for colorectal cancer. Gastroenterol Rep 3:289–297. CrossRefGoogle Scholar
  137. Smeby J et al (2018) CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. Ann Oncol 29:1227–1234. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Song M, Garrett WS, Chan AT (2015) Nutrients, foods, and colorectal cancer prevention. Gastroenterology 148:1244–1260. CrossRefPubMedPubMedCentralGoogle Scholar
  139. Spranger S, Gajewski TF (2015) A new paradigm for tumor immune escape: β-catenin-driven immune exclusion. J Immunother Cancer 3:43. CrossRefPubMedPubMedCentralGoogle Scholar
  140. Stamos JL, Weis WI (2013) The beta-catenin destruction complex. Cold Spring Harb Perspect Biol 5:a007898. CrossRefPubMedPubMedCentralGoogle Scholar
  141. Sun X et al (2017) Colorectal cancer cells suppress CD4+ T cells immunity through canonical Wnt signaling. Oncotarget 8:15168–15181. CrossRefPubMedPubMedCentralGoogle Scholar
  142. Sveen A et al (2018) Colorectal cancer consensus molecular subtypes translated to preclinical models uncover potentially targetable cancer cell dependencies. Clin Cancer Res 24:794–806. CrossRefPubMedGoogle Scholar
  143. Takada R et al (2006) Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell 11:791–801. CrossRefPubMedGoogle Scholar
  144. Tanaka N et al (2017) APC mutations as a potential biomarker for sensitivity to Tankyrase inhibitors in colorectal cancer. Mol Cancer Ther 16:752–762. CrossRefPubMedGoogle Scholar
  145. Tejpar S et al (2016) Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 3:194–201. CrossRefGoogle Scholar
  146. Thanki K et al (2017) Consensus molecular subtypes of colorectal cancer and their clinical implications. Int Biol Biomed J 3:105–111PubMedPubMedCentralGoogle Scholar
  147. Thorvaldsen TE et al (2015) Structure, dynamics, and functionality of Tankyrase inhibitor-induced degradasomes. Mol Cancer Res 13:1487–1501. CrossRefPubMedGoogle Scholar
  148. Tian W et al (2012) Structure-based discovery of a novel inhibitor targeting the beta-catenin/Tcf4 interaction. Biochemistry 51:724–731. CrossRefPubMedGoogle Scholar
  149. Toden S et al (2015) Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis 36:355–367. CrossRefPubMedPubMedCentralGoogle Scholar
  150. Toden S, Tran HM, Tovar-Camargo OA, Okugawa Y, Goel A (2016) Epigallocatechin-3-gallate targets cancer stem-like cells and enhances 5-fluorouracil chemosensitivity in colorectal cancer. Oncotarget 7:16158–16171. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Tome-Carneiro J, Larrosa M, Gonzalez-Sarrias A, Tomas-Barberan FA, Garcia-Conesa MT, Espin JC (2013) Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des 19:6064–6093. CrossRefPubMedPubMedCentralGoogle Scholar
  152. Tournigand C et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237. CrossRefPubMedGoogle Scholar
  153. Trumpi K et al (2017) Neoadjuvant chemotherapy affects molecular classification of colorectal tumors. Oncogenesis 6:e357. CrossRefPubMedPubMedCentralGoogle Scholar
  154. Twyman-Saint Victor C et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377. CrossRefGoogle Scholar
  155. Ueno K et al (2009) Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells. Br J Cancer 101:1374–1381. CrossRefPubMedPubMedCentralGoogle Scholar
  156. Vaiopoulos AG, Athanasoula K, Papavassiliou AG (2014) Epigenetic modifications in colorectal cancer: molecular insights and therapeutic challenges. Biochim Biophys Acta 1842:971–980. CrossRefPubMedGoogle Scholar
  157. Van Cutsem E et al (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29:2011–2019. CrossRefPubMedGoogle Scholar
  158. Van Cutsem E et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27:1386–1422. CrossRefPubMedGoogle Scholar
  159. van de Wetering M et al (2015) Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–945. CrossRefPubMedGoogle Scholar
  160. Varnat F, Siegl-Cachedenier I, Malerba M, Gervaz P, Ruiz i Altaba A (2010) Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas. EMBO Mol Med 2:440–457. CrossRefPubMedPubMedCentralGoogle Scholar
  161. Vincan E, Darcy PK, Smyth MJ, Thompson EW, Thomas RJ, Phillips WA, Ramsay RG (2005) Frizzled-7 receptor ectodomain expression in a colon cancer cell line induces morphological change and attenuates tumor growth. Differentiation 73:142–153. CrossRefPubMedGoogle Scholar
  162. Waaler J et al (2011) Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. Cancer Res 71:197–205. CrossRefPubMedGoogle Scholar
  163. Waaler J et al (2012) A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res 72:2822–2832. CrossRefPubMedGoogle Scholar
  164. Wang H, Li Q, Chen H (2012) Genistein affects histone modifications on Dickkopf-related protein 1 (DKK1) gene in SW480 human colon cancer cell line. PLoS One 7:e40955. CrossRefPubMedPubMedCentralGoogle Scholar
  165. Wang LS et al (2014a) A phase Ib study of the effects of black raspberries on rectal polyps in patients with familial adenomatous polyposis. Cancer Prev Res 7:666–674. CrossRefGoogle Scholar
  166. Wang S, Su R, Nie S, Sun M, Zhang J, Wu D, Moustaid-Moussa N (2014b) Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. J Nutr Biochem 25:363–376. CrossRefPubMedGoogle Scholar
  167. Wee P, Wang Z (2017) Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel) 9(5):E52. CrossRefGoogle Scholar
  168. Wei Y, Yang P, Cao S, Zhao L (2018) The combination of curcumin and 5-fluorouracil in cancer therapy. Arch Pharm Res 41:1–13. CrossRefPubMedGoogle Scholar
  169. Weickhardt AJ et al (2012) Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J Clin Oncol 30:1505–1512. CrossRefPubMedGoogle Scholar
  170. Wilson PM et al (2010) A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy. Cancer Chemother Pharmacol 65:979–988. CrossRefPubMedGoogle Scholar
  171. Wu X, Luo F, Li J, Zhong X, Liu K (2016) Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway. Int J Oncol 48:1333–1340. CrossRefPubMedPubMedCentralGoogle Scholar
  172. Xu M, Wang S, Song YU, Yao J, Huang K, Zhu X (2016) Apigenin suppresses colorectal cancer cell proliferation, migration and invasion via inhibition of the Wnt/beta-catenin signaling pathway. Oncol Lett 11:3075–3080. CrossRefPubMedPubMedCentralGoogle Scholar
  173. Yan M, Li G, An J (2017) Discovery of small molecule inhibitors of the Wnt/beta-catenin signaling pathway by targeting beta-catenin/Tcf4 interactions. Exp Biol Med 242:1185–1197. CrossRefGoogle Scholar
  174. Yang D, Torres CM, Bardhan K, Zimmerman M, McGaha TL, Liu K (2012) Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo. J Immunol 188:4441–4449. CrossRefPubMedPubMedCentralGoogle Scholar
  175. Ye Q et al (2015) A novel ent-kaurane diterpenoid executes antitumor function in colorectal cancer cells by inhibiting Wnt/beta-catenin signaling. Carcinogenesis 36:318–326. CrossRefPubMedGoogle Scholar
  176. Zhan T, Rindtorff N, Boutros M (2016) Wnt signaling in cancer. Oncogene 36:1461–1473. CrossRefPubMedPubMedCentralGoogle Scholar
  177. Zhang Z et al (2016) Curcumin inhibits tumor epithelial-mesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells. Oncol Rep 35:2615–2623. CrossRefPubMedPubMedCentralGoogle Scholar
  178. Zhao B et al (2017a) Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget 8:3980–4000. CrossRefPubMedPubMedCentralGoogle Scholar
  179. Zhao R et al (2017b) Expression and clinical relevance of epithelial and mesenchymal markers in circulating tumor cells from colorectal cancer. Oncotarget 8:9293–9302. CrossRefPubMedGoogle Scholar
  180. Zheng H et al (2016) HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res 22:4119–4132. CrossRefPubMedPubMedCentralGoogle Scholar
  181. Zhong Y et al (2016) Tankyrase inhibition causes reversible intestinal toxicity in mice with a therapeutic index < 1. Toxicol Pathol 44:267–278. CrossRefPubMedGoogle Scholar
  182. Zhu N, Qin L, Luo Z, Guo Q, Yang L, Liao D (2014) Challenging role of Wnt5a and its signaling pathway in cancer metastasis. Exp Ther Med 8:3–8. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Cristina Albuquerque
    • 1
  • Lucília Pebre Pereira
    • 1
  1. 1.Molecular Pathobiology Research UnitPortuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E.LisbonPortugal

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