Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2014, Article ID 437096, 11 pages
http://dx.doi.org/10.1155/2014/437096
Review Article

The CCN Family Proteins: Modulators of Bone Development and Novel Targets in Bone-Associated Tumors

1Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
2Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan
3Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan
4Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
5Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan
6Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
7Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan
8Department of Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan

Received 12 November 2013; Accepted 19 December 2013; Published 14 January 2014

Academic Editor: Po-Lin Kuo

Copyright © 2014 Po-Chun Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Aszódi, K. R. Legate, I. Nakchbandi, and R. Fässler, “What mouse mutants teach us about extracellular matrix function,” Annual Review of Cell and Developmental Biology, vol. 22, pp. 591–621, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Y. Chen and C. H. Yao, “Repair of bone defects with gelatin-based composites: a review,” BioMedicine, vol. 1, no. 1, pp. 29–32, 2011. View at Google Scholar
  3. P. Bornstein and E. H. Sage, “Matricellular proteins: extracellular modulators of cell function,” Current Opinion in Cell Biology, vol. 14, no. 5, pp. 608–616, 2002. View at Publisher · View at Google Scholar · View at Scopus
  4. C.-C. Chen and L. F. Lau, “Functions and mechanisms of action of CCN matricellular proteins,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 4, pp. 771–783, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Leask and D. J. Abraham, “All in the CCN family: essential matricellular signaling modulators emerge from the bunker,” Journal of Cell Science, vol. 119, no. 23, pp. 4803–4810, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. K. P. Holbourn, K. R. Acharya, and B. Perbal, “The CCN family of proteins: structure-function relationships,” Trends in Biochemical Sciences, vol. 33, no. 10, pp. 461–473, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. D. R. Brigstock, R. Goldschmeding, K.-I. Katsube et al., “Proposal for a unified CCN nomenclature,” Journal of Clinical Pathology, vol. 56, no. 2, pp. 127–128, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. N. Planque and B. Perbal, “A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis,” Cancer Cell International, vol. 3, article 15, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. P. Bork, “The modular architecture of a new family of growth regulators related to connective tissue growth factor,” FEBS Letters, vol. 327, no. 2, pp. 125–130, 1993. View at Publisher · View at Google Scholar · View at Scopus
  10. D. M. Bradham, A. Igarashi, R. L. Potter, and G. R. Grotendorst, “Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10,” Journal of Cell Biology, vol. 114, no. 6, pp. 1285–1294, 1991. View at Google Scholar · View at Scopus
  11. G. P. Yang and L. F. Lau, “Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface,” Cell Growth & Differentiation, vol. 2, no. 7, pp. 351–357, 1991. View at Google Scholar · View at Scopus
  12. L. F. Lau and S. C.-T. Lam, “The CCN family of angiogenic regulators: the integrin connection,” Experimental Cell Research, vol. 248, no. 1, pp. 44–57, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. A. W. Rachfal and D. R. Brigstock, “Structural and functional properties of CCN proteins,” Vitamins and Hormones, vol. 70, pp. 69–103, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. H. Yeger and B. Perbal, “The CCN family of genes: a perspective on CCN biology and therapeutic potential,” Journal of Cell Communication and Signaling, vol. 1, no. 3-4, pp. 159–164, 2007. View at Google Scholar
  15. J.-I. Jun and L. F. Lau, “Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets,” Nature Reviews Drug Discovery, vol. 10, no. 12, pp. 945–963, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. M. L. Kireeva, S. C.-T. Lam, and L. F. Lau, “Adhesion of human umbilical vein endothelial cells to the immediate- early gene product Cyr61 is mediated through integrin αvβ3,” Journal of Biological Chemistry, vol. 273, no. 5, pp. 3090–3096, 1998. View at Publisher · View at Google Scholar · View at Scopus
  17. R. Gao and D. R. Brigstock, “A novel integrin α5β1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells,” Gut, vol. 55, no. 6, pp. 856–862, 2006. View at Publisher · View at Google Scholar · View at Scopus
  18. N. Chen, S.-J. Leu, V. Todorović, S. C.-T. Lam, and L. F. Lau, “Identification of a novel integrin αvβ3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells,” Journal of Biological Chemistry, vol. 279, no. 42, pp. 44166–44176, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. K. Sakamoto, S. Yamaguchi, R. Ando et al., “The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway,” Journal of Biological Chemistry, vol. 277, no. 33, pp. 29399–29405, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Minamizato, K. Sakamoto, T. Liu et al., “CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways,” Biochemical and Biophysical Research Communications, vol. 354, no. 2, pp. 567–573, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. C.-C. Chen, J. L. Young, R. I. Monzon, N. Chen, V. Todorović, and L. F. Lau, “Cytotoxicity of TNFα is regulated by integrin-mediated matrix signaling,” EMBO Journal, vol. 26, no. 5, pp. 1257–1267, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. Chen, D. J. Abraham, X. Shi-Wen et al., “CCN2 (connective tissue growth factor) promotes fibroblast adhesion to fibronectin,” Molecular Biology of the Cell, vol. 15, no. 12, pp. 5635–5646, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. T. Nishida, S. Kubota, T. Fukunaga et al., “CTGF/Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes,” Journal of Cellular Physiology, vol. 196, no. 2, pp. 265–275, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. V. Todorovi, C.-C. Chen, N. Hay, and L. F. Lau, “The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts,” Journal of Cell Biology, vol. 171, no. 3, pp. 559–568, 2005. View at Publisher · View at Google Scholar · View at Scopus
  25. L. Desnoyers, D. Arnott, and D. Pennica, “WISP-1 binds to decorin and biglycan,” Journal of Biological Chemistry, vol. 276, no. 50, pp. 47599–47607, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Mercurio, B. Latinkic, N. Itasaki, R. Krumlauf, and J. C. Smith, “Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex,” Development, vol. 131, no. 9, pp. 2137–2147, 2004. View at Publisher · View at Google Scholar · View at Scopus
  27. R. Gao and D. R. Brigstock, “Low density lipoprotein receptor-related protein (LRP) is a heparin-dependent adhesion receptor for connective tissue growth factor (CTGF) in rat activated hepatic stellate cells,” Hepatology Research, vol. 27, no. 3, pp. 214–220, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. L. A. Edwards, K. Woolard, M. J. Son et al., “Effect of brain- and tumor-derived connective tissue growth factor on glioma invasion,” Journal of the National Cancer Institute, vol. 103, no. 15, pp. 1162–1178, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. N. A. Wahab, B. S. Weston, and R. M. Mason, “Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA,” Journal of the American Society of Nephrology, vol. 16, no. 2, pp. 340–351, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. B. V. Perbal and M. Takigawa, CCN Proteins : A New family of Cell Growth and differentiation Regulators, Imperial College Press, London, UK, 2005.
  31. C.-C. Chen, N. Chen, and L. F. Lau, “The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts,” Journal of Biological Chemistry, vol. 276, no. 13, pp. 10443–10452, 2001. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Liu, W. Dong, Z. Lin et al., “CCN4 regulates vascular smooth muscle cell migration and proliferation,” Molecules and Cells, vol. 36, no. 2, pp. 112–118, 2013. View at Google Scholar
  33. A. C. Lake and J. J. Castellot Jr., “CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells,” Cell Communication and Signaling, vol. 1, article 5, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. N. Schütze, R. Schenk, J. Fiedler, T. Mattes, F. Jakob, and R. E. Brenner, “CYR61/CCN1 and WISP3/CCN6 are chemoattractive ligands for human multipotent mesenchymal stroma cells,” BMC Cell Biology, vol. 8, article 45, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. S.-J. Leu, S. C.-T. Lam, and L. F. Lau, “Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins αvβ3 and α6β1 in human umbilical vein endothelial cells,” Journal of Biological Chemistry, vol. 277, no. 48, pp. 46248–46255, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. M. L. Kireeva, F.-E. Mo, G. P. Yang, and L. F. Lau, “Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion,” Molecular and Cellular Biology, vol. 16, no. 4, pp. 1326–1334, 1996. View at Google Scholar · View at Scopus
  37. G. Yosimichi, T. Nakanishi, T. Nishida, T. Hattori, T. Takano-Yamamoto, and M. Takigawa, “Ctgf/hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38mapk), and proliferation through a p44/42 mapk/extracellular-signal regulated kinase (erk),” European Journal of Biochemistry, vol. 268, no. 23, pp. 6058–6065, 2001. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Baguma-Nibasheka and B. Kablar, “Pulmonary hypoplasia in the connective tissue growth factor (Ctgf) null mouse,” Developmental Dynamics, vol. 237, no. 2, pp. 485–493, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. B. Perbal, “NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues,” Journal of Clinical Pathology, vol. 54, no. 2, pp. 57–79, 2001. View at Publisher · View at Google Scholar · View at Scopus
  40. G. W. Zuo, C. D. Kohls, B. C. He et al., “The CCN proteins: important signaling mediators in stem cell differentiation and tumorigenesis,” Histology and Histopathology, vol. 25, no. 6, pp. 795–806, 2010. View at Google Scholar
  41. S. Kubota and M. Takigawa, “CCN family proteins and angiogenesis: from embryo to adulthood,” Angiogenesis, vol. 10, no. 1, pp. 1–11, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. F.-E. Mo, A. G. Muntean, C.-C. Chen, D. B. Stolz, S. C. Watkins, and L. F. Lau, “CYR61 (CCN1) is essential for placental development and vascular integrity,” Molecular and Cellular Biology, vol. 22, no. 24, pp. 8709–8720, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Ivkovic, B. S. Yoon, S. N. Popoff et al., “Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development,” Development, vol. 130, no. 12, pp. 2779–2791, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. C. G. Lin, S.-J. Leu, N. Chen et al., “CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family,” Journal of Biological Chemistry, vol. 278, no. 26, pp. 24200–24208, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. L. Kular, J. Pakradouni, P. Kitabgi, M. Laurent, and C. Martinerie, “The CCN family: a new class of inflammation modulators?” Biochimie, vol. 93, no. 3, pp. 377–388, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. T. Bai, C.-C. Chen, and L. F. Lau, “Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages,” Journal of Immunology, vol. 184, no. 6, pp. 3223–3232, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Takigawa, T. Nakanishi, S. Kubota, and T. Nishida, “Role of CTGF/HCS24/ecogenin in skeletal growth control,” Journal of Cellular Physiology, vol. 194, no. 3, pp. 256–266, 2003. View at Publisher · View at Google Scholar · View at Scopus
  48. Q. Luo, Q. Kang, W. Si et al., “Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells,” Journal of Biological Chemistry, vol. 279, no. 53, pp. 55958–55968, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. N. Schutze, U. Noth, J. Schneidereit, C. Hendrich, and F. Jakob, “Differential expression of CCN-family members in primary human bone marrow-derived mesenchymal stem cells during osteogenic, chondrogenic and adipogenic differentiation,” Cell Communication and Signaling, vol. 3, article 5, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. W. Si, Q. Kang, H. H. Luu et al., “CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells,” Molecular and Cellular Biology, vol. 26, no. 8, pp. 2955–2964, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. V. Ouellet and P. M. Siegel, “CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis,” Journal of Cell Communication and Signaling, vol. 6, no. 2, pp. 73–85, 2012. View at Google Scholar
  52. M. Wong, M. L. Kireeva, T. V. Kolesnikova, and L. F. Lau, “Cyr61, product of a growth factor-inducible immediate-early gene, regulates chondrogenesis in mouse limb bud mesenchymal cells,” Developmental Biology, vol. 192, no. 2, pp. 492–508, 1997. View at Publisher · View at Google Scholar · View at Scopus
  53. J. C. Crockett, N. Schütze, D. Tosh et al., “The matricellular protein CYR61 inhibits osteoclastogenesis by a mechanism independent of αvβ3 and αvβ5,” Endocrinology, vol. 148, no. 12, pp. 5761–5768, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. K.-I. Katsube, K. Sakamoto, Y. Tamamura, and A. Yamaguchi, “Role of CCN, a vertebrate specific gene family, in development,” Development Growth and Differentiation, vol. 51, no. 1, pp. 55–67, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. T. Nishida, T. Nakanishi, M. Asano et al., “Effects of CTGF/Hcs24, a hypertrophic chondrocyte-specific gene product, on the proliferation and differentiation of osteoblastic cells in vitro,” Journal of Cellular Physiology, vol. 184, no. 2, pp. 197–206, 2000. View at Google Scholar
  56. T. Shimo, M. Kanyama, C. Wu et al., “Expression and roles of connective tissue growth factor in Meckel's cartilage development,” Developmental Dynamics, vol. 231, no. 1, pp. 136–147, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Maeda, “An impact of CCN2-BMP-2 complex upon chondrocyte biology: evoking a signalling pathway bypasses ERK and Smads?” Journal of Biochemistry, vol. 150, no. 3, pp. 219–221, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. J. G. Abreu, N. I. Ketpura, B. Reversade, and E. M. De Robertis, “Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β,” Nature Cell Biology, vol. 4, no. 8, pp. 599–604, 2002. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Rydziel, L. Stadmeyer, S. Zanotti, D. Durant, A. Smerdel-Ramoya, and E. Canalis, “Nephroblastoma overexpressed (Nov) inhibits osteoblastogenesis and causes osteopenia,” Journal of Biological Chemistry, vol. 282, no. 27, pp. 19762–19772, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. E. Canalis, “Nephroblastoma overexpressed (Nov) is a novel bone morphogenetic protein antagonist,” Annals of the New York Academy of Sciences, vol. 1116, pp. 50–58, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. T.-W. Tan, Y.-L. Huang, J.-T. Chang et al., “CCN3 increases BMP-4 expression and bone mineralization in osteoblasts,” Journal of Cellular Physiology, vol. 227, no. 6, pp. 2531–2541, 2012. View at Publisher · View at Google Scholar · View at Scopus
  62. A. A. Sabile, M. J. E. Arlt, R. Muff et al., “Cyr61 expression in osteosarcoma indicates poor prognosis and promotes intratibial growth and lung metastasis in mice,” Journal of Bone and Mineral Research, vol. 27, no. 1, pp. 58–67, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. O. Fromigue, Z. Hamidouche, P. Vaudin et al., “CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis,” Journal of Bone and Mineral Research, vol. 26, no. 7, pp. 1533–1542, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. M. C. Manara, B. Perbal, S. Benini et al., “The expression of CCN3(NOV) gene in musculoskeletal tumors,” The American Journal of Pathology, vol. 160, no. 3, pp. 849–859, 2002. View at Google Scholar · View at Scopus
  65. C. L. Wu, H. C. Tsai, Z. W. Chen et al., “Ras activation mediates WISP-1-induced increases in cell motility and matrix metalloproteinase expression in human osteosarcoma,” Cellular Signalling, vol. 25, no. 12, pp. 2812–2822, 2013. View at Google Scholar
  66. B. Perbal, N. Lazar, D. Zambelli et al., “Prognostic relevance of CCN3 in Ewing sarcoma,” Human Pathology, vol. 40, no. 10, pp. 1479–1486, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Benini, B. Perbal, D. Zambelli et al., “In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type,” Oncogene, vol. 24, no. 27, pp. 4349–4361, 2005. View at Publisher · View at Google Scholar · View at Scopus
  68. T.-W. Tan, W.-H. Yang, Y.-T. Lin et al., “Cyr61 increases migration and MMP-13 expression via αvβ3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells,” Carcinogenesis, vol. 30, no. 2, pp. 258–268, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. T.-W. Tan, C.-H. Lai, C.-Y. Huang et al., “CTGF enhances migration and MMP-13 up-regulation via αvβ3 integrin, FAK, ERK, and NF-κB-dependent pathway in human chondrosarcoma cells,” Journal of Cellular Biochemistry, vol. 107, no. 2, pp. 345–356, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. H.-E. Tzeng, J.-C. Chen, C.-H. Tsai et al., “CCN3 increases cell motility and MMP-13 expression in human chondrosarcoma through integrin-dependent pathway,” Journal of Cellular Physiology, vol. 226, no. 12, pp. 3181–3189, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. C.-H. Hou, Y.-C. Chiang, Y.-C. Fong, and C.-H. Tang, “WISP-1 increases MMP-2 expression and cell motility in human chondrosarcoma cells,” Biochemical Pharmacology, vol. 81, no. 11, pp. 1286–1295, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. Y.-C. Fong, C.-Y. Lin, Y.-C. Su et al., “CCN6 enhances ICAM-1 expression and cell motility in human chondrosarcoma cells,” Journal of Cellular Physiology, vol. 227, no. 1, pp. 223–232, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. T. A. Damron, W. G. Ward, and A. Stewart, “Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: national cancer data base report,” Clinical Orthopaedics and Related Research, no. 459, pp. 40–47, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. H. D. Dorfman and B. Czerniak, “Bone cancers,” Cancer, vol. 75, no. 1, pp. 203–210, 1995. View at Google Scholar · View at Scopus
  75. R. Sweetnam, “Osteosarcoma,” British Journal of Hospital Medicine, vol. 28, no. 2, pp. 112–121, 1982. View at Google Scholar · View at Scopus
  76. R. M. Terek, G. K. Schwartz, K. Devaney et al., “Chemotherapy and P-glycoprotein expression in chondrosarcoma,” Journal of Orthopaedic Research, vol. 16, no. 5, pp. 585–590, 1998. View at Publisher · View at Google Scholar · View at Scopus
  77. C. H. Tang, “Molecular mechanisms of chondrosarcoma metastasis,” BioMedicine, vol. 2, no. 3, pp. 92–98, 2012. View at Google Scholar
  78. C. A. Hamm, J. W. Stevens, H. Xie et al., “Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors,” BMC Cancer, vol. 10, article 471, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. W. G. Jiang, G. Watkins, O. Fodstad, A. Douglas-Jones, K. Mokbel, and R. E. Mansel, “Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer,” Endocrine-Related Cancer, vol. 11, no. 4, pp. 781–791, 2004. View at Publisher · View at Google Scholar · View at Scopus
  80. I. Espinoza, H. Liu, R. Busby, and R. Lupu, “CCN1, a candidate target for zoledronic acid treatment in breast cancer,” Molecular Cancer Therapeutics, vol. 10, no. 5, pp. 732–741, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. J. Lin, R. Huo, L. Wang et al., “A novel anti-Cyr61 antibody inhibits breast cancer growth and metastasis in vivo,” Cancer Immunology, Immunotherapy, vol. 61, no. 5, pp. 677–687, 2012. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Casimiro, I. Luis, A. Fernandes et al., “Analysis of a bone metastasis gene expression signature in patients with bone metastasis from solid tumors,” Clinical and Experimental Metastasis, vol. 29, no. 2, pp. 155–164, 2012. View at Publisher · View at Google Scholar · View at Scopus
  83. T. R. Cawthorn, E. Amir, R. Broom et al., “Mechanisms and pathways of bone metastasis: challenges and pitfalls of performing molecular research on patient samples,” Clinical and Experimental Metastasis, vol. 26, no. 8, pp. 935–943, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Shimo, S. Kubota, N. Yoshioka et al., “Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer,” Journal of Bone and Mineral Research, vol. 21, no. 7, pp. 1045–1059, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. Y. Kang, P. M. Siegel, W. Shu et al., “A multigenic program mediating breast cancer metastasis to bone,” Cancer Cell, vol. 3, no. 6, pp. 537–549, 2003. View at Publisher · View at Google Scholar · View at Scopus
  86. X. H.-F. Zhang, Q. Wang, W. Gerald et al., “Latent bone metastasis in breast cancer tied to Src-dependent survival signals,” Cancer Cell, vol. 16, no. 1, pp. 67–78, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. V. Ouellet, K. Tiedemann, A. Mourskaia et al., “CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone,” The American Journal of Pathology, vol. 178, no. 5, pp. 2377–2388, 2011. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Pal, W. Huang, X. Li et al., “CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer,” Cancer Research, vol. 72, no. 18, pp. 4818–4828, 2012. View at Google Scholar
  89. Z.-J. Sun, Y. Wang, Z. Cai, P.-P. Chen, X.-J. Tong, and D. Xie, “Involvement of Cyr61 in growth, migration, and metastasis of prostate cancer cells,” British Journal of Cancer, vol. 99, no. 10, pp. 1656–1667, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. P.-C. Chen, T.-H. Lin, H.-C. Cheng, and C.-H. Tang, “CCN3 increases cell motility and ICAM-1 expression in prostate cancer cells,” Carcinogenesis, vol. 33, no. 4, pp. 937–945, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. P. C. Chen, H. C. Cheng, and C. H. Tang, “CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway,” Carcinogenesis, vol. 34, no. 7, pp. 1669–1679, 2013. View at Google Scholar
  92. M. Ono, C. A. Inkson, R. Sonn et al., “WISP1/CCN4: a potential target for inhibiting prostate cancer growth and spread to bone,” PLoS ONE, vol. 8, no. 8, Article ID e71709, 2013. View at Google Scholar
  93. R. E. Coleman, R. Roodman, S. Smith, B. Body, S. Suva, and V. Vessella, “Clinical features of metastatic bone disease and risk of skeletal morbidity,” Clinical Cancer Research, vol. 12, no. 20, pp. 6243s–6249s, 2006. View at Publisher · View at Google Scholar · View at Scopus
  94. L. G. Harris, L. K. Pannell, S. Singh, R. S. Samant, and L. A. Shevde, “Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61,” Oncogene, vol. 31, pp. 3370–3380, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. W. Huang, M. E. Gonzalez, K. A. Toy, M. Banerjee, and C. G. Kleer, “Blockade of CCN6 (WISP3) activates growth factor-independent survival and resistance to anoikis in human mammary epithelial cells,” Cancer Research, vol. 70, no. 8, pp. 3340–3350, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. R. B. Shah, R. Mehra, A. M. Chinnaiyan et al., “Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program,” Cancer Research, vol. 64, no. 24, pp. 9209–9216, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. R. J. Bryant and F. C. Hamdy, “Screening for prostate cancer: an update,” European Urology, vol. 53, no. 1, pp. 37–44, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. B. Cipolla, J. Y. Bansard, J. P. Ecalard et al., “Treating metastatic castration-resistant prostate cancer with novel polyamine-free oral nutritional supplementation: phase I study,” BioMedicine, vol. 3, no. 3, pp. 114–119, 2013. View at Google Scholar
  99. S. R. Larson, X. Zhang, R. Dumpit et al., “Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases,” Prostate, vol. 73, no. 9, pp. 932–940, 2013. View at Google Scholar
  100. E. T. Keller and J. Brown, “Prostate cancer bone metastases promote both osteolytic and osteoblastic activity,” Journal of Cellular Biochemistry, vol. 91, no. 4, pp. 718–729, 2004. View at Publisher · View at Google Scholar · View at Scopus
  101. M. P. Roudier, L. D. True, C. S. Higano et al., “Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone,” Human Pathology, vol. 34, no. 7, pp. 646–653, 2003. View at Publisher · View at Google Scholar · View at Scopus
  102. N. Dornhöfer, S. Spong, K. Bennewith et al., “Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis,” Cancer Research, vol. 66, no. 11, pp. 5816–5827, 2006. View at Publisher · View at Google Scholar · View at Scopus
  103. T. Aikawa, J. Gunn, S. M. Spong, S. J. Klaus, and M. Korc, “Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer,” Molecular Cancer Therapeutics, vol. 5, no. 5, pp. 1108–1116, 2006. View at Publisher · View at Google Scholar · View at Scopus