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The Role of Osteoblast-Derived Cytokines in Bone Metastatic Breast Cancer

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Annual summary rept. 1 Mar 2006-31 Dec 2008

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Breast cancer BC metastasizes to bone. While the mechanism for directed metastasis is unknown, the bone microenvironment likely provides a fertile soil for metastatic BC cells. Our purpose is to determine how OB-derived cytokines influence BC metastases to bone. Goals include investigating the production of OB-derived cytokines in response to BC cells or their conditioned medium CM, the production of bone-derived cytokines in response to BC cells in vivo, the presence of functional cytokine receptors on OBs and BC cells, and the chemoattractant effect of OB-derived cytokines on BC metastasis. OB and BC cells expressed IL-6, KCGRO-945, MIP-2IL-8, and VEGF, but only OBs produced MCP-1. OB-derived cytokine production increased with direct co-culture of BC cells or CM treatment. OB CM was a chemoattractant for BC cells. BC cells cultured with OBs enhanced TRAP positive multi-nucleated OC formation in vitro. Concentrations of IL-6, VEGF, and MCP-1 increased in cancer-bearing mice, but MIP-2 and KC were expressed in negligible amounts. MCP-1 and VEGF were localized in the trabecular bone matrix, while IL-6 was expressed in the bone marrow. MCP-1 and VEGF were not detected adjacent to BC cells. Human VEGF expression increased with increasing tumor size. Megakaryocyte numbers in the bone marrow cavity were increased in cancer-bearing mice. These data suggest that OBs are an important source of cytokines in bone metastatic breast cancer. These findings implicate the importance of the bone microenvironment and cancer cell modulation in facilitating metastatic tumor cell colonization and survival.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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