Current Osteoporosis Reports

, Volume 15, Issue 4, pp 239–246 | Cite as

Wnt Signaling in Ewing Sarcoma, Osteosarcoma, and Malignant Peripheral Nerve Sheath Tumors

  • Matthew G. Pridgeon
  • Patrick J. Grohar
  • Matthew R. Steensma
  • Bart O. WilliamsEmail author
Cancer-induced Musculoskeletal Diseases (M Reagan and E Keller, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Cancer-induced Musculoskeletal Diseases


Purpose of Review

Wnt signaling plays a central role in development and homeostasis, and its dysregulation is a common event in many types of human cancer. Here we explore in detail the contributions of Wnt signaling to the initiation and maintenance of three types of saroma: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. This review provides an overview of the Wnt signaling pathway and explores in detail the current knowledge about its role in the initiation or maintenance of three tumor types: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors.

Recent Findings

Recent work has assessed the role(s) of Wnt signaling within these cell types. This review provides an overview of the mechanistic insights that have been gained from a number of recent studies to set the foundation for potential therapeutic applications.


Wnt signaling has emerged as a potentially critical pathway in maintaining the growth of these types of tumors. Given the fact that many new inhibitors of the pathway have recently or will soon enter Phase 1 clinical trials, it is likely that assessment of their activity in these tumor types will occur in human patients.


Wnt β-catenin Ewing sarcoma Neurofibromatosis Type 1 Osteosarcoma Malignant peripheral nerve sheath tumors 



Work in these areas is supported by NIH grants to BOW (AR053293) and PJG (CA188314). MRS is supported by the Francis S. Collins Scholars Program in Neurofibromatosis Clinical and Translational Research sponsored by Johns Hopkins University’s Neurofibromatosis Therapeutic Acceleration Program (NTAP). PJG has received additional support from Alex’s Lemonade Stand Reach Award and Lily’s Garden Foundation. We thank Nicole Ethen for assistance with preparation of the figure.

Compliance with Ethical Standards

Conflict of Interest

Matthew Pridgeon, Patrick Grohar, and Matthew Steensma declare no conflict of interest.

Bart Williams reports speaker honoraria from Vertex Pharmaceuticals and personal fees as a member of the board of scientific advisor from Surrozen.

Human and Animal Rights and Informed Consent

This article does not contain any studies that include human or animal subjects performed by any of the authors.


BOW has received honoraria from Amgen and Vertex Pharmaceuticals. BOW serves on the Board of Scientific Advisors for, and owns stock inSurrozen.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Joiner DM, Ke J, Zhong Z, Xu HE, Williams BO. LRP5 and LRP6 in development and disease. Trends Endocrinol Metab. 2013;24(1):31–9.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Zhong Z, Ethen NJ, Williams BO. WNT signaling in bone development and homeostasis. Wiley Interdiscip Rev Dev Biol. 2014;3(6):489–500.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Song X, Wang S, Li L. New insights into the regulation of Axin function in canonical Wnt signaling pathway. Protein Cell. 2014;5(3):186–93.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Hrckulak D, Kolar M, Strnad H, Korinek V. TCF/LEF transcription factors: an update from the internet resources. Cancers (Basel). 2016;8(7).PubMedCentralGoogle Scholar
  5. 5.
    Acebron SP, Niehrs C. beta-Catenin-independent roles of Wnt/LRP6 signaling. Trends Cell Biol. 2016;26(12):956–67.PubMedGoogle Scholar
  6. 6.
    Yang Y, Mlodzik M. Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt). Annu Rev Cell Dev Biol. 2015;31:623–46.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell. 2003;5(3):367–77.PubMedGoogle Scholar
  8. 8.
    Green J, Nusse R, van Amerongen R. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb Perspect Biol. 2014;01:6(2).Google Scholar
  9. 9.
    Kuhl M. The WNT/calcium pathway: biochemical mediators, tools and future requirements. Front Biosci. 2004;9:967–74.PubMedGoogle Scholar
  10. 10.
    Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 2003;116(Pt 13):2627–34.PubMedGoogle Scholar
  11. 11.
    Mason JJ, Williams BO. SOST and DKK: antagonists of LRP family signaling as targets for treating bone disease. J Osteoporos. 2010;01:2010.Google Scholar
  12. 12.
    Zhang X, Cheong SM, Amado NG, Reis AH, MacDonald BT, Zebisch M, et al. Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation. Dev Cell. 2015;32(6):719–30.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kakugawa S, Langton PF, Zebisch M, Howell SA, Chang TH, Liu Y, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015;519(7542):187–92.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang X, Abreu JG, Yokota C, MacDonald BT, Singh S, Coburn KL, et al. Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell. 2012;149(7):1565–77.PubMedPubMedCentralGoogle Scholar
  15. 15.
    de Lau W, Peng WC, Gros P, Clevers H. The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 2014;28(4):305–16.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Streich Jr FC, Haas AL. Activation of ubiquitin and ubiquitin-like proteins. Subcell Biochem. 2010;54:1–16.PubMedGoogle Scholar
  17. 17.
    Cadigan KM. Receptor endocytosis: Frizzled joins the ubiquitin club. EMBO J. 2010;29(13):2099–100.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Mukai A, Yamamoto-Hino M, Awano W, Watanabe W, Komada M, Goto S. Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt. EMBO J. 2010;29(13):2114–25.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Goh LK, Sorkin A. Endocytosis of receptor tyrosine kinases. Cold Spring Harb Perspect Biol. 2013;5(5):a017459.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Knight MN, Hankenson KD. R-spondins: novel matricellular regulators of the skeleton. Matrix Biol. 2014;37:157–61.PubMedGoogle Scholar
  21. 21.
    Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 2012;01:4(5).Google Scholar
  22. 22.
    •• Hao HX, Jiang X, Cong F. Control of Wnt receptor turnover by R-spondin-ZNRF3/RNF43 signaling module and its dysregulation in cancer. Cancers (Basel). 2016;8(6). This review provides an outstanding overview of the recently elucidated genetic changes that increase Wnt receptor availability on the cell surface which may drive tumorigenesis.PubMedCentralGoogle Scholar
  23. 23.
    Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36(11):1461–73.PubMedGoogle Scholar
  24. 24.
    Cironi L, Petricevic T, Fernandes Vieira V, Provero P, Fusco C, Cornaz S, et al. The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma. Sci Rep. 2016;6:22113.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Nielsen TO, Poulin NM, Ladanyi M. Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy. Cancer Discov. 2015;5(2):124–34.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Trautmann M, Sievers E, Aretz S, Kindler D, Michels S, Friedrichs N, et al. SS18-SSX fusion protein-induced Wnt/beta-catenin signaling is a therapeutic target in synovial sarcoma. Oncogene. 2014;33(42):5006–16.PubMedGoogle Scholar
  27. 27.
    Barham W, Frump AL, Sherrill TP, Garcia CB, Saito-Diaz K, VanSaun MN, et al. Targeting the Wnt pathway in synovial sarcoma models. Cancer Discov. 2013;3(11):1286–301.PubMedGoogle Scholar
  28. 28.
    Chen C, Zhao M, Tian A, Zhang X, Yao Z, Ma X. Aberrant activation of Wnt/beta-catenin signaling drives proliferation of bone sarcoma cells. Oncotarget. 2015;6(19):17570–83.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Vijayakumar S, Liu G, Rus IA, Yao S, Chen Y, Akiri G, et al. High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/beta-catenin target gene, CDC25A. Cancer Cell. 2011;19(5):601–12.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Uren A, Wolf V, Sun YF, Azari A, Rubin JS, Toretsky JA. Wnt/Frizzled signaling in Ewing sarcoma. Pediatr Blood Cancer. 2004;43(3):243–9.PubMedGoogle Scholar
  31. 31.
    Baird K, Davis S, Antonescu CR, Harper UL, Walker RL, Chen Y, et al. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005;65(20):9226–35.PubMedGoogle Scholar
  32. 32.
    Gibault L, Perot G, Chibon F, Bonnin S, Lagarde P, Terrier P, et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol. 2011;223(1):64–71.PubMedGoogle Scholar
  33. 33.
    Kelleher FC, O'Sullivan H. FOXM1 in sarcoma: role in cell cycle, pluripotency genes and stem cell pathways. Oncotarget. 2016;7(27):42792–804.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Dancsok AR, Asleh-Aburaya K, Nielsen TO. Advances in sarcoma diagnostics and treatment. Oncotarget. 2017;8(4):7068–93.PubMedGoogle Scholar
  35. 35.
    Esiashvili N, Goodman M, Marcus Jr RB. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: surveillance epidemiology and end results data. J Pediatr Hematol Oncol. 2008;30(6):425–30.PubMedGoogle Scholar
  36. 36.
    Pizzo PA, Poplack DG. Principles and practice of pediatric oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.Google Scholar
  37. 37.
    Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O. Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 2007;11(5):421–9.PubMedGoogle Scholar
  38. 38.
    von Levetzow C, Jiang X, Gwye Y, von Levetzow G, Hung L, Cooper A, et al. Modeling initiation of Ewing sarcoma in human neural crest cells. PLoS One. 2011;6(4), e19305.Google Scholar
  39. 39.
    Staege MS, Hutter C, Neumann I, Foja S, Hattenhorst UE, Hansen G, et al. DNA microarrays reveal relationship of Ewing family tumors to both endothelial and fetal neural crest-derived cells and define novel targets. Cancer Res. 2004;64(22):8213–21.PubMedGoogle Scholar
  40. 40.
    Minas TZ, Surdez D, Javaheri T, Tanaka M, Howarth M, Kang HJ, et al. Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model. Oncotarget. 2016.Google Scholar
  41. 41.
    Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359(6391):162–5.PubMedGoogle Scholar
  42. 42.
    Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, et al. The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994;331(5):294–9.PubMedGoogle Scholar
  43. 43.
    Kauer M, Ban J, Kofler R, Walker B, Davis S, Meltzer P, et al. A molecular function map of Ewing's sarcoma. PLoS One. 2009;4(4), e5415.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, et al. The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014;10(7), e1004475.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Crompton BD, Stewart C, Taylor-Weiner A, Alexe G, Kurek KC, Calicchio ML, et al. The genomic landscape of pediatric ewing sarcoma. Cancer Discov. 2014;4(11):1326–41.PubMedGoogle Scholar
  46. 46.
    Tirode F, Surdez D, Ma X, Parker M, Le Deley MC, Bahrami A, et al. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov. 2014;4(11):1342–53.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Vijayaragavan K, Szabo E, Bosse M, Ramos-Mejia V, Moon RT, Bhatia M. Noncanonical Wnt signaling orchestrates early developmental events toward hematopoietic cell fate from human embryonic stem cells. Cell Stem Cell. 2009;4(3):248–62.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Tanaka M, Yamazaki Y, Kanno Y, Igarashi K, Aisaki K, Kanno J, et al. Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors. J Clin Invest. 2014;124(7):3061–74.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Javaheri T, Kazemi Z, Pencik J, Pham HT, Kauer M, Noorizadeh R, et al. Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation. Cell Death Dis. 2016;7(10), e2419.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Leacock SW, Basse AN, Chandler GL, Kirk AM, Rakheja D, Amatruda JF. A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis. Dis Model Mech. 2012;5(1):95–106.PubMedGoogle Scholar
  51. 51.
    Navarro D, Agra N, Pestana A, Alonso J, Gonzalez-Sancho JM. The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes beta-catenin/TCF-mediated transcription. Carcinogenesis. 2010;31(3):394–401.PubMedGoogle Scholar
  52. 52.
    •• Pedersen EA, Menon R, Bailey KM, Thomas DG, Van Noord RA, Tran J, et al. Activation of Wnt/beta-Catenin in Ewing sarcoma cells antagonizes EWS/ETS function and promotes phenotypic transition to more metastatic cell states. Cancer Res. 2016;76(17):5040–53. This manuscript presents novel concepts in terms of the relationship between heterogenous activation of Wnt signaling within subpopulations of tumors and disease progression. PubMedPubMedCentralGoogle Scholar
  53. 53.
    Scannell CA, Pedersen EA, Mosher JT, Krook MA, Nicholls LA, Wilky BA, et al. LGR5 is expressed by Ewing sarcoma and potentiates Wnt/beta-Catenin signaling. Front Oncol. 2013;3:81.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Endo Y, Beauchamp E, Woods D, Taylor WG, Toretsky JA, Uren A, et al. Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3- and c-Jun N-terminal kinase-dependent mechanism. Mol Cell Biol. 2008;28(7):2368–79.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Jin Z, Zhao C, Han X, Han Y. Wnt5a promotes ewing sarcoma cell migration through upregulating CXCR4 expression. BMC Cancer. 2012;12:480.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Techavichit P, Gao Y, Kurenbekova L, Shuck R, Donehower LA, Yustein JT. Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential. BMC Cancer. 2016;16(1):869.PubMedPubMedCentralGoogle Scholar
  57. 57.
    von Heyking K, Roth L, Ertl M, Schmidt O, Calzada-Wack J, Neff F, et al. The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma. Oncotarget. 2016;7(27):41767–41780.Google Scholar
  58. 58.
    Baker EK, Taylor S, Gupte A, Chalk AM, Bhattacharya S, Green AC, et al. Wnt inhibitory factor 1 (WIF1) is a marker of osteoblastic differentiation stage and is not silenced by DNA methylation in osteosarcoma. Bone. 2015;73:223–32.PubMedGoogle Scholar
  59. 59.
    Kansara M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest. 2009;119(4):837–51.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Hoang BH, Kubo T, Healey JH, Yang R, Nathan SS, Kolb EA, et al. Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Cancer Res. 2004;64(8):2734–9.PubMedGoogle Scholar
  61. 61.
    Lin CH, Guo Y, Ghaffar S, McQueen P, Pourmorady J, Christ A, et al. Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma. Sarcoma. 2013;2013:147541.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Zhao S, Kurenbekova L, Gao Y, Roos A, Creighton CJ, Rao P, et al. NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma. Oncogene. 2015;34(39):5069–79.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Li Z, Li Y, Wang N, Yang L, Zhao W, Zeng X. miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis in osteosarcoma cells. Biochem Biophys Res Commun. 2016;471(4):479–85.PubMedGoogle Scholar
  64. 64.
    Martins-Neves SR, Paiva-Oliveira DI, Wijers-Koster PM, Abrunhosa AJ, Fontes-Ribeiro C, Bovee JV, et al. Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/beta-catenin signaling. Cancer Lett. 2016;370(2):286–95.PubMedGoogle Scholar
  65. 65.
    Scholten 2nd DJ, Timmer CM, Peacock JD, Pelle DW, Williams BO, Steensma MR. Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. PLoS One. 2014;9(10), e111431.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Ma Y, Ren Y, Han EQ, Li H, Chen D, Jacobs JJ, et al. Inhibition of the Wnt-beta-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun. 2013;431(2):274–9.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell. 2012;149(3):515–24.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Wang Q, Cai J, Cai XH, Chen L. miR-346 regulates osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by targeting the Wnt/beta-catenin pathway. PLoS One. 2013;8(9):e72266.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Vanas V, Haigl B, Stockhammer V, Sutterluty-Fall H. MicroRNA-21 increases proliferation and cisplatin sensitivity of osteosarcoma-derived cells. PLoS One. 2016;11(8), e0161023.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Zhu Z, Tang J, Wang J, Duan G, Zhou L, Zhou X. MiR-138 acts as a tumor suppressor by targeting EZH2 and enhances cisplatin-induced apoptosis in osteosarcoma cells. PLoS One. 2016;11(3), e0150026.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Geng S, Gu L, Ju F, Zhang H, Wang Y, Tang H, et al. MicroRNA-224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1. J Cell Mol Med. 2016;20(9):1611–9.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Wei R, Cao G, Deng Z, Su J, Cai L. miR-140-5p attenuates chemotherapeutic drug-induced cell death by regulating autophagy through inositol 1,4,5-trisphosphate kinase 2 (IP3k2) in human osteosarcoma cells. Biosci Rep. 2016;36(5).PubMedPubMedCentralGoogle Scholar
  73. 73.
    Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol. 2005;141(1):71–4.PubMedGoogle Scholar
  74. 74.
    Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A(2):327–32.PubMedGoogle Scholar
  75. 75.
    Widemann BC. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep. 2009;11(4):322–8.PubMedPubMedCentralGoogle Scholar
  76. 76.
    McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Montalto G, Cervello M, et al. Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget. 2012;3(9):954–87.PubMedPubMedCentralGoogle Scholar
  77. 77.
    •• Rahrmann EP, Watson AL, Keng VW, Choi K, Moriarity BS, Beckmann DA, et al. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat Genet. 2013;45(7):756–66. This study helped establish Wnt/B-catenin signaling as a potential tumorigenic driver in NF1.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Thomas LE, Winston J, Rad E, Mort M, Dodd KM, Tee AR, et al. Evaluation of copy number variation and gene expression in neurofibromatosis type-1-associated malignant peripheral nerve sheath tumours. Hum Genomics. 2015;9:3.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Watson AL, Rahrmann EP, Moriarity BS, Choi K, Conboy CB, Greeley AD, et al. Canonical Wnt/beta-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance. Cancer Discov. 2013;3(6):674–89.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Luscan A, Shackleford G, Masliah-Planchon J, Laurendeau I, Ortonne N, Varin J, et al. The activation of the WNT signaling pathway is a Hallmark in neurofibromatosis type 1 tumorigenesis. Clin Cancer Res. 2014;20(2):358–71.PubMedGoogle Scholar
  81. 81.
    Rey JP, Ellies DL. Wnt modulators in the biotech pipeline. Dev Dyn. 2010;239(1):102–14.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Serafino A, Sferrazza G, Colini Baldeschi A, Nicotera G, Andreola F, Pittaluga E, et al. Developing drugs that target the Wnt pathway: recent approaches in cancer and neurodegenerative diseases. Expert Opin Drug Discovery. 2017;12(2):169–86.Google Scholar
  83. 83.
    Serafino A, Moroni N, Zonfrillo M, Andreola F, Mercuri L, Nicotera G, et al. WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer. Oncotarget. 2014;5(4):978–92.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Lu B, Green BA, Farr JM, Lopes FC, Van Raay TJ. Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials. Cancers (Basel). 2016;8(9).PubMedCentralGoogle Scholar
  85. 85.
    Ahmed K, Shaw HV, Koval A, Katanaev VL. A second WNT for old drugs: drug repositioning against WNT-dependent cancers. Cancers (Basel). 2016;8(7).PubMedCentralGoogle Scholar
  86. 86.
    Ke J, Xu HE, Williams BO. Lipid modification in Wnt structure and function. Curr Opin Lipidol. 2013;24(2):129–33.PubMedGoogle Scholar
  87. 87.
    Tauriello DV, Maurice MM. The various roles of ubiquitin in Wnt pathway regulation. Cell Cycle. 2010;9(18):3700–9.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Cadigan KM, Waterman ML. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. 2012;01:4(11).Google Scholar
  89. 89.
    Surana R, Sikka S, Cai W, Shin EM, Warrier SR, Tan HJ, et al. Secreted frizzled related proteins: implications in cancers. Biochim Biophys Acta. 2014;1845(1):53–65.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Matthew G. Pridgeon
    • 1
    • 2
    • 3
  • Patrick J. Grohar
    • 2
    • 3
    • 4
    • 5
  • Matthew R. Steensma
    • 2
    • 3
    • 5
    • 6
  • Bart O. Williams
    • 5
    Email author
  1. 1.Grand Rapids Medical Education PartnersGrand RapidsUSA
  2. 2.Spectrum Health Cancer CenterSpectrum Health SystemGrand RapidsUSA
  3. 3.Helen De Vos Children’s HospitalGrand RapidsUSA
  4. 4.Department of PediatricsMichigan State UniversityGrand RapidsUSA
  5. 5.Center for Cancer and Cell BiologyVan Andel Research InstituteGrand RapidsUSA
  6. 6.Department of SurgeryMichigan State University College of Human MedicineGrand RapidsUSA

Personalised recommendations