Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jul;85(1):78–84. doi: 10.1054/bjoc.2001.1856

Cellular mechanisms of bone resorption in breast carcinoma

N C A Hunt 1, Y Fujikawa 2, A Sabokbar 2, I Itonaga 2, A Harris 3, N A Athanasou 2
PMCID: PMC2363911  PMID: 11437406

Abstract

The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear. Osteoclasts are marrow-derived cells which form by fusion of mononuclear phagocyte precursors that circulate in the monocyte fraction. In this study we have determined whether circulating osteoclast precursors are increased in number or have an increased sensitivity to humoral factors for osteoclastogenesis in breast cancer patients with skeletal metastases (± hypercalcaemia) compared to patients with primary breast cancer and age-matched normal controls. Monocytes were isolated and cocultured with UMR 106 osteoblastic cells in the presence of 1,25 dihydroxyvitamin D3[1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF) on coverslips and dentine slices. Limiting dilution experiments showed that there was no increase in the number of circulating osteoclast precursors in breast cancer patients with skeletal metastases (± hypercalcaemia) compared to controls. Osteoclast precursors in these patients also did not exhibit increased sensitivity to 1,25(OH)2D3 or M-CSF in terms of osteoclast formation. The addition of parathyroid hormone-related protein and interleukin-6 did not increase osteoclast formation. The addition of the supernatant of cultured breast cancer cell lines (MCF-7 and MDA-MB-435), however, significantly increased monocyte-osteoclast formation in a dose-dependent fashion. These results indicate that the increase in osteoclast formation in breast cancer is not due to an increase in the number/nature of circulating osteoclast precursors. They also suggest that tumour cells promote osteoclast formation in the bone microenvironment by secreting soluble osteoclastogenic factor(s). © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: metastasis, breast cancer, osteoclast, bone resorption

Full Text

The Full Text of this article is available as a PDF (212.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akatsu T., Murakami T., Ono K., Nishikawa M., Tsuda E., Mochizuki S. I., Fujise N., Higashio K., Motoyoshi K., Yamamoto M. Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. Bone. 1998 Dec;23(6):495–498. doi: 10.1016/s8756-3282(98)00141-0. [DOI] [PubMed] [Google Scholar]
  2. Akatsu T., Ono K., Katayama Y., Tamura T., Nishikawa M., Kugai N., Yamamoto M., Nagata N. The mouse mammary tumor cell line, MMT060562, produces prostaglandin E2 and leukemia inhibitory factor and supports osteoclast formation in vitro via a stromal cell-dependent pathway. J Bone Miner Res. 1998 Mar;13(3):400–408. doi: 10.1359/jbmr.1998.13.3.400. [DOI] [PubMed] [Google Scholar]
  3. Athanasou N. A. Cellular biology of bone-resorbing cells. J Bone Joint Surg Am. 1996 Jul;78(7):1096–1112. doi: 10.2106/00004623-199607000-00016. [DOI] [PubMed] [Google Scholar]
  4. Athanasou N. A., Quinn J. Immunophenotypic differences between osteoclasts and macrophage polykaryons: immunohistological distinction and implications for osteoclast ontogeny and function. J Clin Pathol. 1990 Dec;43(12):997–1003. doi: 10.1136/jcp.43.12.997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boyde A., Ali N. N., Jones S. J. Resorption of dentine by isolated osteoclasts in vitro. Br Dent J. 1984 Mar 24;156(6):216–220. doi: 10.1038/sj.bdj.4805313. [DOI] [PubMed] [Google Scholar]
  6. Bugelski P. J., Corwin S. P., North S. M., Kirsh R. L., Nicolson G. L., Poste G. Macrophage content of spontaneous metastases at different stages of growth. Cancer Res. 1987 Aug 1;47(15):4141–4145. [PubMed] [Google Scholar]
  7. Clohisy D. R., Ogilvie C. M., Carpenter R. J., Ramnaraine M. L. Localized, tumor-associated osteolysis involves the recruitment and activation of osteoclasts. J Orthop Res. 1996 Jan;14(1):2–6. doi: 10.1002/jor.1100140103. [DOI] [PubMed] [Google Scholar]
  8. Clohisy D. R., Palkert D., Ramnaraine M. L., Pekurovsky I., Oursler M. J. Human breast cancer induces osteoclast activation and increases the number of osteoclasts at sites of tumor osteolysis. J Orthop Res. 1996 May;14(3):396–402. doi: 10.1002/jor.1100140309. [DOI] [PubMed] [Google Scholar]
  9. Clohisy D. R., Ramnaraine M. L. Osteoclasts are required for bone tumors to grow and destroy bone. J Orthop Res. 1998 Nov;16(6):660–666. doi: 10.1002/jor.1100160606. [DOI] [PubMed] [Google Scholar]
  10. Dodwell D. J. Malignant bone resorption: cellular and biochemical mechanisms. Ann Oncol. 1992 Apr;3(4):257–267. doi: 10.1093/oxfordjournals.annonc.a058175. [DOI] [PubMed] [Google Scholar]
  11. Fujikawa Y., Quinn J. M., Sabokbar A., McGee J. O., Athanasou N. A. The human osteoclast precursor circulates in the monocyte fraction. Endocrinology. 1996 Sep;137(9):4058–4060. doi: 10.1210/endo.137.9.8756585. [DOI] [PubMed] [Google Scholar]
  12. Grano M., Mori G., Minielli V., Cantatore F. P., Colucci S., Zallone A. Z. Breast cancer cell line MDA-231 stimulates osteoclastogenesis and bone resorption in human osteoclasts. Biochem Biophys Res Commun. 2000 Apr 21;270(3):1097–1100. doi: 10.1006/bbrc.2000.2569. [DOI] [PubMed] [Google Scholar]
  13. Horton M. A., Lewis D., McNulty K., Pringle J. A., Chambers T. J. Monoclonal antibodies to osteoclastomas (giant cell bone tumors): definition of osteoclast-specific cellular antigens. Cancer Res. 1985 Nov;45(11 Pt 2):5663–5669. [PubMed] [Google Scholar]
  14. Kacinski B. M. CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann Med. 1995 Feb;27(1):79–85. doi: 10.3109/07853899509031941. [DOI] [PubMed] [Google Scholar]
  15. Lee M. Y., Eyre D. R., Osborne W. R. Isolation of a murine osteoclast colony-stimulating factor. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8500–8504. doi: 10.1073/pnas.88.19.8500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mantovani A., Bottazzi B., Colotta F., Sozzani S., Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992 Jul;13(7):265–270. doi: 10.1016/0167-5699(92)90008-U. [DOI] [PubMed] [Google Scholar]
  17. Nakagawa N., Kinosaki M., Yamaguchi K., Shima N., Yasuda H., Yano K., Morinaga T., Higashio K. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998 Dec 18;253(2):395–400. doi: 10.1006/bbrc.1998.9788. [DOI] [PubMed] [Google Scholar]
  18. Ono K., Akatsu T., Murakami T., Wada S., Nishikawa M., Kugai N., Yamamoto M., Matsuura N., Nagata N. Mouse mammary carcinoma cell line (BALB/c-MC) stimulates osteoclast formation from mouse bone marrow cells through cell-to-cell contact. Bone. 1998 Jul;23(1):27–32. doi: 10.1016/s8756-3282(98)00065-9. [DOI] [PubMed] [Google Scholar]
  19. Partridge N. C., Alcorn D., Michelangeli V. P., Kemp B. E., Ryan G. B., Martin T. J. Functional properties of hormonally responsive cultured normal and malignant rat osteoblastic cells. Endocrinology. 1981 Jan;108(1):213–219. doi: 10.1210/endo-108-1-213. [DOI] [PubMed] [Google Scholar]
  20. Price J. E., Polyzos A., Zhang R. D., Daniels L. M. Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res. 1990 Feb 1;50(3):717–721. [PubMed] [Google Scholar]
  21. Quinn J. M., Matsumura Y., Tarin D., McGee J. O., Athanasou N. A. Cellular and hormonal mechanisms associated with malignant bone resorption. Lab Invest. 1994 Oct;71(4):465–471. [PubMed] [Google Scholar]
  22. Quinn J. M., McGee J. O., Athanasou N. A. Human tumour-associated macrophages differentiate into osteoclastic bone-resorbing cells. J Pathol. 1998 Jan;184(1):31–36. doi: 10.1002/(SICI)1096-9896(199801)184:1<31::AID-PATH962>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
  23. Quinn J. M., Sabokbar A., Athanasou N. A. Cells of the mononuclear phagocyte series differentiate into osteoclastic lacunar bone resorbing cells. J Pathol. 1996 May;179(1):106–111. doi: 10.1002/(SICI)1096-9896(199605)179:1<106::AID-PATH535>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  24. Rosol T. J., Capen C. C. Mechanisms of cancer-induced hypercalcemia. Lab Invest. 1992 Dec;67(6):680–702. [PubMed] [Google Scholar]
  25. Shalhoub V., Elliott G., Chiu L., Manoukian R., Kelley M., Hawkins N., Davy E., Shimamoto G., Beck J., Kaufman S. A. Characterization of osteoclast precursors in human blood. Br J Haematol. 2000 Nov;111(2):501–512. doi: 10.1046/j.1365-2141.2000.02379.x. [DOI] [PubMed] [Google Scholar]
  26. Soule H. D., Vazguez J., Long A., Albert S., Brennan M. A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst. 1973 Nov;51(5):1409–1416. doi: 10.1093/jnci/51.5.1409. [DOI] [PubMed] [Google Scholar]
  27. Tanaka S., Takahashi N., Udagawa N., Tamura T., Akatsu T., Stanley E. R., Kurokawa T., Suda T. Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest. 1993 Jan;91(1):257–263. doi: 10.1172/JCI116179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Taube T., Elomaa I., Blomqvist C., Beneton M. N., Kanis J. A. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone. 1994 Mar-Apr;15(2):161–166. doi: 10.1016/8756-3282(94)90703-x. [DOI] [PubMed] [Google Scholar]
  29. Udagawa N., Takahashi N., Akatsu T., Tanaka H., Sasaki T., Nishihara T., Koga T., Martin T. J., Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7260–7264. doi: 10.1073/pnas.87.18.7260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Yasuda H., Shima N., Nakagawa N., Yamaguchi K., Kinosaki M., Mochizuki S., Tomoyasu A., Yano K., Goto M., Murakami A. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3597–3602. doi: 10.1073/pnas.95.7.3597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. van Ravenswaay Claasen H. H., Kluin P. M., Fleuren G. J. Tumor infiltrating cells in human cancer. On the possible role of CD16+ macrophages in antitumor cytotoxicity. Lab Invest. 1992 Aug;67(2):166–174. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES