FIGURE 1: EPI and NOR (E/N, blue square) are released in the BM microenvironment from SNS fibers entering the bone with blood vessels. EPI and NOR influence interaction of tumor cells with b-ARs -expressing BM niche cells, e.g. CXCL12 abundant reticular (CAR) cells, osteoblasts and osteoclasts through different axis. In response to adrenergic signaling niche cells release (1) CXCL16 chemokine (red) that interacts with CXCR6 expressed on the surface of several tumor cells types, (2) CXCL12 (orange) that chemoattracts CXCR4 expressing cancer cells and (3) RANKL (green) protein that binds RANK-expressing malignant cells. In addition, adrenergic signaling in osteoblasts and also directly in tumor cells themselves can promote release of angiogenic factors thus promoting BM colonization by tumor cells through increased blood vessel density.