Generation of Soluble Receptor Activator of NF-KappaB Ligand Is Critical for Osteolytic Bone Metastasis

摘要

The tropism of breast cancer cells for bone and their tendency to induce the osteolytic phenotype is a result of interactions between breast cancer cells and bone stromal cells and is of paramount importance for bone metastasis. The capacity of breast cancer cells to collaborate with bone stromal cells is likely to be mediated by specific molecules. The underlying molecular mechanisms of tumor-stromal interaction in bone metastasis remain poorly understood. In our study, we examined whether interaction between breast cancer cells and stromal cells in the bone microenvironment play a critical role in the tumor-induced osteolysis and whether inhibition of such interactions using targeted therapeutics will inhibit osteolysis during bone metastasis. We used microarray analysis for gene expression profiling at the tumor bone interface versus the tumor alone area from syngenic mice injected with three different mammary tumor cell lines that differ in their metastatic potential. Upregulation of mRNA and protein expression of receptor activator of nuclear factor kB ligand (RANKL) and matrix metalloproteinase (MMP)-13 at the tumor bone interface in all three groups was observed. Collectively our studies demonstrated that identifying the molecules involved in osteolytic bone metastasis and developing therapeutic strategies to target these molecules may help to inhibit mammary tumor induced osteolysis.