Virchows Archiv

, Volume 443, Issue 2, pp 146–151 | Cite as

Expression of osteoprotegerin correlates with aggressiveness and poor prognosis of gastric carcinoma

  • Reiko Ito
  • Hirofumi Nakayama
  • Kazuhiro Yoshida
  • Kazuya Kuraoka
  • Junichi Motoshita
  • Noriko Oda
  • Naohide Oue
  • Wataru Yasui
Original Article


Osteoprotegerin (OPG), identical with osteoclastogenesis inhibitory factor, is a member of a subgroup of the tumor necrosis factor (TNF)-receptor superfamily, which functions as a soluble decoy receptor. It has been reported that OPG expression is associated with bone metastasis of cancer of the breast and prostate. In the present study, we examined the expression of OPG in gastric carcinomas using immunohistochemistry and reverse-transcription polymerase chain reaction methods, and compared with clinicopathological parameters. The expression of OPG mRNA was confirmed in a gastric carcinoma cell line (MKN-7) and gastric carcinoma tissues. Immunohistochemically, strongly positive staining of OPG was found in 65% (67/103) of gastric carcinomas, whereas OPG protein was not detected in non-neoplastic mucosal epithelia. The expression of OPG protein in gastric carcinoma tissues correlates significantly with depth of tumor invasion, nodal metastases and advanced tumor stage. Furthermore, the prognosis of the cases with strong OPG expression was significantly worse than those with weak or no expression of OPG. These results suggest that OPG may participate in stomach carcinogenesis, invasion and metastasis, and may serve as a novel molecular marker for aggressive gastric cancer.


Osteoprotegerin Aggressiveness Gastric carcinoma 



This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Culture, Sports, and Technology of Japan, and the Ministry of Health, Labor, and Welfare of Japan. The authors thank Masayoshi Takatani and Mutsumi Ueda for their skillful technical assistance. The authors are also grateful to Noriko Sagawa for her secretarial assistance.


  1. 1.
    Brown JM, Corey E, Lee ZD, True LD, Yun TJ, Tondravi M, Vessella RL (2001) Osteoprotegerin and rank ligand expression in prostate cancer. Urology 57:611–616CrossRefPubMedGoogle Scholar
  2. 2.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268PubMedGoogle Scholar
  3. 3.
    Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273:14363–14367PubMedGoogle Scholar
  4. 4.
    Griffith TS, Wiley SR, Kubin MZ, Sedger LM, Maliszewski CR, Fanger NA (1999) Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine TRAIL. J Exp Med 189:1343–1354CrossRefPubMedGoogle Scholar
  5. 5.
    Holen I, Croucher PI, Hamdy FC, Eaton CL (2002) Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res 62:1619–1623PubMedGoogle Scholar
  6. 6.
    Ito R, Kitadai Y, Kyo E, Yokozaki H, Yasui W, Yamashita U, Nikai H, Tahara E (1993) Interleukin 1 alpha acts as an autocrine growth stimulator for human gastric carcinoma cells. Cancer Res 53:4102–4106PubMedGoogle Scholar
  7. 7.
    Japanese Research Society for Gastric Cancer (ed) (1995) Japanese Classification of Gastric Carcinoma, 1st English edn. Kanehara & Co., Ltd, Tokyo, pp 38–65Google Scholar
  8. 8.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176PubMedGoogle Scholar
  9. 9.
    Lin DL, Tarnowski CP, Zhang J, Dai J, Rohn E, Patel AH, Morris MD, Keller ET (2001) Bone metastatic LNCaP-derivative C4–2B prostate cancer cell line mineralizes in vitro. Prostate 47:212–221CrossRefPubMedGoogle Scholar
  10. 10.
    Michigami T, Ihara-Watanabe M, Yamazaki M, Ozono K (2001) Receptor activator of nuclear factor kappaB ligand (RANKL) is a key molecule of osteoclast formation for bone metastasis in a newly developed model of human neuroblastoma. Cancer Res 61:1637–1644PubMedGoogle Scholar
  11. 11.
    Morony S, Capparelli C, Sarosi I, Lacey DL, Dunstan CR, Kostenuik PJ (2001) Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res 61:4432–4436PubMedGoogle Scholar
  12. 12.
    Ochiai A, Yasui W, Tahara E (1985) Establishment and characterization of human signet ring cell gastric carcinoma cell lines with amplification of the c-myc oncogene. Cancer Res 57:3669–3671Google Scholar
  13. 13.
    Penno H, Silfversward CJ, Frost A, Brandstrom H, Nilsson O, Ljunggren O (2002) Osteoprotegerin secretion from prostate cancer is stimulated by cytokines, in vitro. Biochem Biophys Res Commun 293:451–455CrossRefPubMedGoogle Scholar
  14. 14.
    Scatena M, Giachelli C (2002) The alpha(v)beta3 integrin, NF-kappaB, osteoprotegerin endothelial cell survival pathway. Potential role in angiogenesis. Trends Cardiovasc Med 12:83–88CrossRefPubMedGoogle Scholar
  15. 15.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319PubMedGoogle Scholar
  16. 16.
    Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA et al (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673–682PubMedGoogle Scholar
  17. 17.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 95:3597–3602PubMedGoogle Scholar
  18. 18.
    Zhang J, Dai J, Qi Y, Lin DL, Smith P, Strayhorn C, Mizokami A, Fu Z, Westman J, Keller ET (2001) Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Invest 107:1235–1244PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Reiko Ito
    • 1
  • Hirofumi Nakayama
    • 1
  • Kazuhiro Yoshida
    • 2
  • Kazuya Kuraoka
    • 1
  • Junichi Motoshita
    • 1
  • Noriko Oda
    • 3
  • Naohide Oue
    • 1
  • Wataru Yasui
    • 1
  1. 1.Department of Molecular PathologyHiroshima University Graduate School of Biomedical SciencesJapan
  2. 2.Department of Surgery, Research Institute for Nuclear Medicine and BiologyHiroshima UniversityHiroshima Japan
  3. 3.Department of Human Nutrition, Faculty of Human SciencesHiroshima Bunkyo Women's UniversityHiroshima Japan

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