Bone metastasis is a frequent occurrence in cancer patients, with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolyitc bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Many of these interactions are mediated by tumor derived growth factors, cytokines, proteases, and other secreted and exosomal proteins. Using gene expression profiling and proteomic analysis, we identified several key protein components of metastatic tumor secretome and exosomes that were uniquely associated with bone metastasis. We then incorporated bioinformatic analyses of large clinical metastasis datasets and functional studies in animal models to identify novel bone metastasis proteins. Several selected and exosomal proteins are found to strongly promote in vivo bone metastasis, including i) exosomal c-MET, ii) soluble ICAM1 and VCAM1; iii) matrix metalloprotease MMP1 and ADAMTS1, iv) the salivary cystatins CST1, CST2, and CST4; and v) the plasminogen activators PLAT and PLAU; or vi) the collagen functionality proteins PLOD2 and COL6A1. These findings underscore the importance secreted and exosomal proteins in mediating tumor-stromal interactions that drive osteoclastogenesis and bone destruction during metastasis.
17 May 2014 - 20 May 2014