Role of Osteoblast-Derived Inflammatory Cytokines in Bone Metastatic Breast Cancer; Annual summary rept. 1 Mar 2007-28 Feb 2008

摘要

Breast cancer (BC) has a predilection for bone metastases. While the mechanism for directional metastasis is unknown, the bone microenvironment likely provides a fertile soil for metastatic BC cells. Besides affecting osteoblast (OB) and osteoclast (OC) properties, we have evidence that metastatic BC cells further create a unique bone niche by co-opting osteoblasts to increase production of inflammatory cytokines that may be chemoattractants, growth, or maintenance factors for cancer cells or OCs. 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. Using murine osteoblasts and human non-osteoblast variants, we found that BC CM treatment increased osteoblast-derived cytokine secretion of IL-6, KC, VEGF, MIP-2, and MCP-1. Maximum induction of osteoblast-derived cytokine secretion occurred with 20 day old cells. Human metastatic BC cells produce very small quantities of MCP-1. When osteoblasts and non- osteoblasts were placed in a co-culture system, nonosteoblast- derived cytokine production decreased significantly from baseline amounts. Murine bone cell- derived cytokine production increased when human metastatic cancer cells were present in the bone microenvironment.