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Wnt/β-catenin pathway in bone cancers

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Tumor Biology

Abstract

The Wnt signaling pathway regulates some of the crucial aspects of cellular processes. The beta-catenin dependent Wnt signaling (Wnt/β-catenin) pathway controls the expression of key developmental genes, and acts as an intracellular signal transducer. The association of Wnt/β-catenin pathway is often reported with different cancers. In this study, we have reviewed the association of Wnt/β-catenin pathway with bone cancers, focusing on carcinogenesis and therapeutic aspects. Wnt/β-catenin pathway is a highly complex and unique signaling pathway, which has ability to regulate gene expression, cell invasion, migration, proliferation, and differentiation for the initiation and progression of bone cancers, especially osteosarcoma. Association of Wnt/β-catenin pathway with chondrosarcoma, Ewing’s sarcoma and chondroma is also documented. Recently, targeting Wnt/β-catenin pathway has gained significant interests as a potential therapeutic application for the treatment of bone cancers. Small RNA technology to knockdown aberrant Wnt/β-catenin or inhibition of β-catenin expression by natural component has shown promising effects against bone cancers. Advances in understanding the mechanisms of Wnt signaling and new technologies have facilitated the discovery of agents that can target and regulate Wnt/β-catenin signaling pathway, and these may provide a basement for the innovative therapeutic approaches in the treatment of bone cancers.

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References

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4:68–75.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387–98.

    Article  CAS  PubMed  Google Scholar 

  4. Rao TP, Kühl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106:1798–806.

    Article  CAS  PubMed  Google Scholar 

  5. Mao J, Wang J, Liu B, Pan W, Farr 3rd GH, Flynn C, et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell. 2001;7:801–9.

    Article  CAS  PubMed  Google Scholar 

  6. Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development. 2008;135:367–75.

    Article  CAS  PubMed  Google Scholar 

  7. He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004;131:1663–77.

    Article  CAS  PubMed  Google Scholar 

  8. Sakanaka C, Sun TQ, Williams LT. New steps in the Wnt/beta-catenin signal transduction pathway. Recent Prog Horm Res. 2000;55:225–36.

    CAS  PubMed  Google Scholar 

  9. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.

    Article  CAS  PubMed  Google Scholar 

  10. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36:417–22.

    Article  CAS  PubMed  Google Scholar 

  11. Marques C, Ferreira JM, Andronescu E, Ficai D, Sonmez M, Ficai A. Multifunctional materials for bone cancer treatment. Int J Nanomedicine. 2014;9:2713–25.

    PubMed Central  PubMed  Google Scholar 

  12. Rosenberg AE. Robins and cotran pathologic basis of disease. Bone, joints and soft tissue tumors. 8th ed. Philadelphia: WB Saunders; 2010. p. 1203–56.

    Google Scholar 

  13. Kundu ZS. Classification, imaging, biopsy and staging of osteosarcoma. Indian J Orthop. 2014;48:238–46.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.

    Article  PubMed  Google Scholar 

  15. Calvert GT, Randall RL, Jones KB, Cannon-Albright L, Lessnick S, Schiffman JD. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma. 2012;2012:152382.

    PubMed Central  PubMed  Google Scholar 

  16. Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Children’s Oncology Group. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol. 2008;26:633–8.

    Article  CAS  PubMed  Google Scholar 

  17. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776–90.

    Article  PubMed  Google Scholar 

  18. Sakamoto A. The molecular pathogenesis of dedifferentiated chondrosarcoma. Indian J Orthop. 2014;48:262–5.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Darouassi Y, Touati MM, Chihani M, Nadour K, Boussouga M, Ammar H, et al. Chondrosarcoma metastasis in the thyroid gland: a case report. J Med Case Rep. 2014;8:157.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Sridhar H, Vijaya M, Clement W, Srinivas C. Chondrosarcoma arising in an enchondroma of the metacarpal bone—a case report. J Clin Diagn Res. 2014;8:142–3.

    PubMed Central  PubMed  Google Scholar 

  21. Lin PP, Moussallem CD, Deavers MT. Secondary chondrosarcoma. J Am Acad Orthop Surg. 2010;18:608–15.

    PubMed  Google Scholar 

  22. Geng S, Zhang J, Zhang LW, Wu Z, Jia G, Xiao X, et al. Diagnosis and microsurgical treatment of chondromas and chondrosarcomas of the cranial base. Oncol Lett. 2014;8:301–4.

    PubMed Central  PubMed  Google Scholar 

  23. Fiorenza F, Abudu A, Grimer RJ, Carter SR, Tillman RM, Ayoub K, et al. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg (Br). 2002;84:93–9.

    Article  CAS  Google Scholar 

  24. Chen B, Yang Y, Chen L, Zhou F, Yang H. Unilateral lateral mass fixation of cervical spinal low-grade chondrosarcoma with intralesional resection: a case report. Oncol Lett. 2014;7:1515–8.

    PubMed Central  PubMed  Google Scholar 

  25. Rossig C. Cellular immunotherapy strategies for Ewing sarcoma. Immunotherapy. 2014;6:611–21.

    Article  CAS  PubMed  Google Scholar 

  26. Iwamoto Y. Diagnosis and treatment of Ewing’s sarcoma. Jpn J Clin Oncol. 2007;37:79–89.

    Article  PubMed  Google Scholar 

  27. Cheung MR. Optimization of predictors of Ewing sarcoma cause-specific survival: a population study. Asian Pac J Cancer Prev. 2014;15:4143–5.

    Article  PubMed  Google Scholar 

  28. Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, et al. Ewing’s sarcoma family of tumors: current management. Oncologist. 2006;11:503–19.

    Article  CAS  PubMed  Google Scholar 

  29. Owen LA, Kowalewski AA, Lessnick SL. EWS/FLI mediate transcriptional repression via NKX2.2 during oncogenic transformation in Ewing’s sarcoma. PLoS One. 2008;3:e1965.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Choi Y, Choi H, Jin KS, Oh JH. A case of auricular chondroma. Korean J Audiol. 2013;17:156–8.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Choi Y, Lim WS, Lee AY, Lee SH. Extraskeletal chondroma of the scalp: an atypical location. Indian J Dermatol Venereol Leprol. 2013;79:435–6.

    Article  PubMed  Google Scholar 

  32. Chung EB, Enzinger FM. Chondroma of soft parts. Cancer. 1978;41:1414–24.

    Article  CAS  PubMed  Google Scholar 

  33. Gungor S, Kamali G, Canat D, Gokdemir G. Soft tissue chondroma of the index finger: clinical, histological and radiological findings in a unique case. Dermatol Online J. 2013;19:18176.

    PubMed  Google Scholar 

  34. Rabbani SA, Arakelian A, Farookhi R. LRP5 knockdown: effect on prostate cancer invasion growth and skeletal metastasis in vitro and in vivo. Cancer Med. 2013;2:625–35.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Chu T, Teng J, Jiang L, Zhong H, Han B. Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation. Biochem Biophys Res Commun. 2014;443:962–8.

    Article  CAS  PubMed  Google Scholar 

  36. Iwaya K, Ogawa H, Kuroda M, Izumi M, Ishida T, Mukai K. Cytoplasmic and/or nuclear staining of beta-catenin is associated with lung metastasis. Clin Exp Metastasis. 2003;20:525–9.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Cai Y, Cai T, Chen Y. Wnt pathway in osteosarcoma, from oncogenic to therapeutic. J Cell Biochem. 2014;115:625–31.

    Article  CAS  PubMed  Google Scholar 

  39. Lin CH, Ji T, Chen CF, Hoang BH. Wnt signaling in osteosarcoma. Adv Exp Med Biol. 2014;804:33–45.

    Article  CAS  PubMed  Google Scholar 

  40. Ma Y, Ren Y, Han EQ, Li H, Chen D, Jacobs JJ, et al. Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun. 2013;431:274–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. 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;119:837–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Cai Y, Mohseny AB, Karperien M, Hogendoorn PC, Zhou G, Cleton-Jansen AM. Inactive Wnt/beta-catenin pathway in conventional high-grade osteosarcoma. J Pathol. 2010;220:24–33.

    Article  CAS  PubMed  Google Scholar 

  43. Wan Y, Zhao W, Jiang Y, Liu D, Meng G, Cai Y. β-catenin is a valuable marker for differential diagnosis of osteoblastoma and osteosarcoma. Hum Pathol. 2014;45:1459–65.

    Article  CAS  PubMed  Google Scholar 

  44. Du X, Yang J, Yang D, Tian W, Zhu Z. The genetic basis for inactivation of Wnt pathway in human osteosarcoma. BMC Cancer. 2014;14:450.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Fanburg-Smith JC, Auerbach A, Marwaha JS, Wang Z, Rushing EJ. Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22 cases. Hum Pathol. 2010;41:653–62.

    Article  CAS  PubMed  Google Scholar 

  46. Uren A, Wolf V, Sun YF, Azari A, Rubin JS, Toretsky JA. Wnt/Frizzled signaling in Ewing sarcoma. Pediatr Blood Cancer. 2004;43:243–9.

    Article  PubMed  Google Scholar 

  47. 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;28:2368–79.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8:727–38.

    Article  CAS  PubMed  Google Scholar 

  49. Yuasa T, Kondo N, Yasuhara R, Shimono K, Mackem S, Pacifici M, et al. Transient activation of Wnt/{beta}-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice. Am J Pathol. 2009;175:1993–2003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8:739–50.

    Article  CAS  PubMed  Google Scholar 

  51. Cantley L, Saunders C, Guttenberg M, Candela ME, Ohta Y, Yasuhara R, et al. Loss of β-catenin induces multifocal periosteal chondroma-like masses in mice. Am J Pathol. 2013;182:917–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Richardson RB. Age-specific bone tumour incidence rates are governed by stem cell exhaustion influencing the supply and demand of progenitor cells. Mech Ageing Dev. 2014;139C:31–40.

    Article  Google Scholar 

  53. Jin S, Shen JN, Wang J, Huang G, Zhou JG. Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells. Cancer Biol Ther. 2007;6:261–8.

    Article  CAS  PubMed  Google Scholar 

  54. Liu Y, Liu YZ, Zhang RX, Wang X, Meng ZJ, Huang J, et al. Oridonin inhibits the proliferation of human osteosarcoma cells by suppressing Wnt/β-catenin signaling. Int J Oncol. 2014;45:795–803.

    CAS  PubMed  Google Scholar 

  55. Zhang F, Chen A, Chen J, Yu T, Guo F. SiRNA-mediated silencing of beta-catenin suppresses invasion and chemosensitivity to doxorubicin in MG-63 osteosarcoma cells. Asian Pac J Cancer Prev. 2011;12:239–45.

    PubMed  Google Scholar 

  56. Xia JJ, Pei LB, Zhuang JP, Ji Y, Xu GP, Zhang ZP, et al. Celecoxib inhibits β-catenin-dependent survival of the human osteosarcoma MG-63 cell line. J Int Med Res. 2010;38:1294–304.

    Article  CAS  PubMed  Google Scholar 

  57. Leow PC, Tian Q, Ong ZY, Yang Z, Ee PL. Antitumor activity of natural compounds, curcumin and p KF118–310, as Wnt/β-catenin antagonists against human osteosarcoma cells. Investig New Drugs. 2010;28:766–82.

    Article  CAS  Google Scholar 

  58. Leow PC, Bahety P, Boon CP, Lee CY, Tan KL, Yang T, et al. Functionalized curcumin analogs as potent modulators of the Wnt/β-catenin signaling pathway. Eur J Med Chem. 2014;71:67–80.

    Article  CAS  PubMed  Google Scholar 

  59. Liu Y, Wang W, Xu J, Li L, Dong Q, Shi Q, et al. Dihydroartemisinin inhibits tumor growth of human osteosarcoma cells by suppressing Wnt/β-catenin signaling. Oncol Rep. 2013;30:1723–30.

    CAS  PubMed  Google Scholar 

  60. Zeng L, Wang W, Rong XF, Zhong Y, Jia P, Zhou GQ, et al. Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model. Int Immunopharmacol. 2014;18:175–81.

    Article  CAS  PubMed  Google Scholar 

  61. Fuerer C, Habib SJ, Nusse R. A study on the interactions between heparin sulfate proteoglycans and Wnt proteins. Dev Dyn. 2010;239:184–90.

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81201420, 81272034), the Provincial Science Foundation of Hunan (No. 14JJ3032), the Scientific Research Project of the Development and Reform Commission of Hunan Province ([2013]1199), the Scientific Research Project of Science and Technology Office of Hunan Province (2013SK2018), and the Doctoral Scientific Fund Project of the Ministry of Education of China (20120162110036).

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Authors and Affiliations

  1. Department of Orthopaedics, Xiangya Hospital, Central South University, #87 Xiangya Road, Changsha, Hunan, 410008, China

    Jian Tian, Hongbo He & Guanghua Lei

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  1. Jian Tian
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  2. Hongbo He
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  3. Guanghua Lei
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Correspondence to Guanghua Lei.

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Tian, J., He, H. & Lei, G. Wnt/β-catenin pathway in bone cancers. Tumor Biol. 35, 9439–9445 (2014). https://doi.org/10.1007/s13277-014-2433-8

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