Tumor osteolysis: A role for interleukin-8

Breast cancer shows a predilection for metastasis to bone. Approximately 80% of patients with metastatic breast cancer also develop bone metastases and these are a major cause of morbidity for the patients. An understanding of the factors contributing to the metastatic and osteolytic potential of breast cancer cells to bone will enhance the prospect of developing new therapies that impede this process.; In this study, we used an in vivo selection scheme to identify a highly metastatic and osteolytic breast cancer cell line (MDA-MET) from a less metastatic and osteolytic parental cell line (MDA-231). Analysis of the gene expression profile in the MDA-MET versus MDA-231 cells identified relatively few genes whose expression was altered >2 fold. An important difference between the two cell lines was the elevated expression by MDA-MET cell of the cytokine interleukin-8 (IL-8). Increased expression of IL-8 by a breast cancer cell line with bone metastatic and osteolytic potential (MDA-MET) prompted further investigation into the role of IL-8 in the osteolytic process.; IL-8 directly stimulated the differentiation of human peripheral blood mononuclear cells into osteoclasts. In these cultures, IL-8 stimulated both human osteoclast formation and osteoclastic bone resorption independent of receptor activator of NFκB ligand (RANKL). In addition, IL-8 stimulated RANKL expression by stromal osteoblastic cells. The effect of IL-8 on osteoclasts and their progenitors was presumably mediated via the cell surface expression of the specific IL-8 receptor (CXCR1). These results demonstrated a direct effect of IL-8 on osteoclast differentiation and activity and implicated IL-8 in osteolysis associated with metastatic breast cancer.; To test the above hypothesis we attempted to neutralize IL-8 secreted by the MDA-MET cells by use of an IL-8 neutralizing antibody or to reduce its secretion by transfecting MDA-MET cells with an IL-8 antisense cDNA construct. Treatment of animals with IL-8 neutralizing antibody or use of MDA-MET IL-8 antisense cells for intratibial injection significantly reduced tumor osteolysis and tumor size.; The data obtained from this study indicates a clear role for IL-8 in MDA-MET induced osteolysis and has important implications in the management of patients with osteolysis due to metastatic breast cancer.