Skip to main content

Association of the metastatic phenotype with CCN family members among breast and oral cancer cells

Journal of Cell Communication and Signaling volume 5, pages 291–299 (2011)Cite this article

Abstract

The CCN family of proteins consists of six members with conserved structural features. These proteins play several roles in the physiology and pathology of cells. Among the pathological roles of the CCN family, one of the most important and controversial ones is their role in the expansion and metastasis of cancer. Up to now a number of reports have described the possible role of each CCN family member independently. In this study, we comprehensively analyzed the roles of all six CCN family members in cell growth, migration and invasion of breast cancer cells in vitro and in vivo. As a result, we found the CCN2/CCN3 ratio to be a parameter that is associated with the metastatic phenotype of breast cancer cells that are highly metastatic to the bone. The same analysis with cell lines from oral squamous carcinomas that are not metastatic to the bone further supported our notion. These results suggest the functional significance of the interplay between CCN family members in regulating the phenotype of cancer cells.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Babic AM, Kireeva ML, Kolesnikova TV, Lau LF (1998) CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA 95:6355–6360

    PubMed  Article  CAS  Google Scholar 

  • Brigstock DR (2003) The CCN family: a new stimulus package. J Endocrinol 178:169–175

    PubMed  Article  CAS  Google Scholar 

  • Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783

    PubMed  Article  CAS  Google Scholar 

  • Espinoza I, Liu H, Busby R, Lupu R (2011). CCN1 a candidate target for zoledronic acid treatment in breast cancer. Mol Cancer Ther in press

  • Fritah A, Saucier C, De Wever O, Bracke M, Bièche I, Lidereau R, Gespach C, Drouot S, Redeuilh G (2008) Role of WISP-2/CCN5 in the maintenance of a differentiated and noninvasive phenotype in human breast cancer cells. Mol Cell Biol 28:1114–1123

    PubMed  Article  CAS  Google Scholar 

  • Guise TA, Mundy GR (1998) Cancer and bone. Endocr Rev 19:18–54

    PubMed  Article  CAS  Google Scholar 

  • Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K, Mansel RE (2004) Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer. Endcr Relat Cancer 11:781–791

    Article  CAS  Google Scholar 

  • Kang Y, Siegel P, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, Guise TA, Massagué J (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 5:537–549

    Article  Google Scholar 

  • Kawaki H, Kubota S, Minato M, Moritani NH, Hattori T, Hanagata H, Kubota M, Miyauchi A, Nakanishi T, Takigawa M (2003) Novel enzyme-linked immunosorbent assay systems for the quantitative analysis of connective tissue growth factor (CTGF/Hcs24/CCN2): detection of HTLV-1 tax-induced CTGF from a human carcinoma cell line. DNA Cell Biol 22:641–648

    PubMed  Article  CAS  Google Scholar 

  • Kawaki H, Kubota S, Suzuki A, Yamada T, Matsumura T, Mandai T, Yao M, Maeda T, Lyons KM, Takigawa M (2008a) Functional requirement of CCN2 for intramembranous bone formation in embryonic mice. Biochem Biophys Res Commun 366:450–456

    PubMed  Article  CAS  Google Scholar 

  • Kawaki H, Kubota S, Suzuki A, Lazar N, Yamada T, Matsumura T, Ohgawara T, Maeda T, Perbal B, Lyons KM, Takigawa M (2008b) Cooperative regulation of chondrocyte differentiation by CCN2 and CCN3 shown by a comprehensive analysis of the CCN family proteins in cartilage. J Bone Miner Res 23:1751–1764

    PubMed  Article  CAS  Google Scholar 

  • Kubota S, Takigawa M (2007) Role of CCN2/CTGF/Hcs24 in bone growth. Int Rev Cytol 257:1–41

    PubMed  Article  CAS  Google Scholar 

  • Kubota S, Takigawa M (2011). The role of CCN2 in cartilage and bone development. J Cell Commun Signal in press

  • Kubota S, Kawata K, Yanagita T, Doi H, Kitoh T, Takigawa M (2004) Abundant retention and release of connective tissue growth factor (CTGF/CCN2) by platelets. J Biochem 136:279–282

    PubMed  Article  CAS  Google Scholar 

  • Leask A (2011). Possible strategies for anti-fibrotic drug intervention in scleroderma. J Cell Commun Signal in press

  • Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803–4810

    PubMed  Article  CAS  Google Scholar 

  • Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY, Lau LF (2003) CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem 278:24200–24208

    PubMed  Article  CAS  Google Scholar 

  • Menendez JA, Vellon L, Mehmi I, Teng PK, Griggs DW, Lupu R (2005) A novel CYR61-triggered ‘CYR61-alphavbeta3 integrin loop’ regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway. Oncogene 2005(24):761–779

    Article  Google Scholar 

  • Nakanishi T, Nishida T, Shimo T, Kobayashi K, Kubo T, Tamatani T, Tezuka K, Takigawa M (2000) Effect of CTGF/Hcs24, a product of a hypertrophic chondrocyte-specific gene, on the proliferation and differentiation of chondrocytes in culture. Endocrinology 141:264–273

    PubMed  Article  CAS  Google Scholar 

  • Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363:62–64

    PubMed  Article  CAS  Google Scholar 

  • Perbal B, Takigawa M (2005) CCN proteins: a new family of cell growth and differentiation regulators. Imperial College Press, London

    Book  Google Scholar 

  • Sasaki A, Boyce BF, Story B, Wright KR, Chapman M, Boyce R, Mundy GR, Yoneda T (1995) Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 55:3551–3557

    PubMed  CAS  Google Scholar 

  • Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M (1999) Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem (Tokyo) 126:137–145

    CAS  Google Scholar 

  • Shimo T, Kubota S, Yoshioka N, Ibaragi S, Isowa S, Eguchi T, Sasaki A, Takigawa M (2006) Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. J Bone Miner Res 21:1045–1059

    PubMed  Article  CAS  Google Scholar 

  • Tsai MS, Bogart DF, Castañeda JM, Li P, Lupu R (2002) Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene 21:817881–817885

    Google Scholar 

  • Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP (2001) Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer Res 61:8917–8923

    PubMed  CAS  Google Scholar 

  • Yanagita T, Kubota S, Kawaki H, Kawata K, Kondo S, Takano-Yamamoto T, Tanaka S, Takigawa M (2007) Expression and physiological role of CCN4/Wnt-induced secreted protein 1 mRNA splicing variants in chondrocytes. FEBS J 274:1655–1665

    PubMed  Article  CAS  Google Scholar 

  • Yoneda T (1998) Cellular and molecular mechanisms of breast and prostate cancer metastasis to bone. Eur J Cancer 34:240–245

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the programs Grants-in-Aid for Scientific Research (S)[to M.T.] and (C) [to S.K.] from Japan Society for the Promotion of Science, and by a grant from the program Grants-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [to M.T.]. Work performed in B. Perbal’s laboratory was funded by French Ministry of Education: EA1556; and by European PROTHETS (Prognosis and Therapeutic Targets of Ewing Family of Tumors, FP6 Contract 503036). We thank Dr. Takanori Eguchi for useful discussions, and Ms. Yoko Tada for valuable secretarial assistance.

Author information

Affiliations

  1. Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan

    Toshihiro Ohgawara, Satoshi Kubota, Harumi Kawaki, Tarek Abd El Kader, Mitsuhiro Hoshijima, Danilo Janune & Masaharu Takigawa

  2. Department of Oral and Maxillofacial Surgery and Biopathological Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

    Toshihiro Ohgawara, Naito Kurio, Tsuyoshi Shimo & Akira Sasaki

  3. Laboratoire d’Oncologie Virale et Moleculaire, Universite Paris 7, D. Diderot, Paris, France

    Bernard Perbal

Authors
  1. Toshihiro Ohgawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoshi Kubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harumi Kawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naito Kurio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tarek Abd El Kader
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mitsuhiro Hoshijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Danilo Janune
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tsuyoshi Shimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bernard Perbal
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akira Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masaharu Takigawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Satoshi Kubota or Masaharu Takigawa.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ohgawara, T., Kubota, S., Kawaki, H. et al. Association of the metastatic phenotype with CCN family members among breast and oral cancer cells. J. Cell Commun. Signal. 5, 291–299 (2011). https://doi.org/10.1007/s12079-011-0133-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-011-0133-3

Keywords

  • CCN family
  • CCN2
  • CCN3
  • Bone metastasis
  • Breast cancer
  • Oral cancer