Hypothesized mechanism of role of hypoxia in the dissemination of MM. Tumor progression induces hypoxia in the MM cells and other cells in the BM microenvironment. Hypoxia activates EMT-related machinery in MM cells and stromal cells, including activation of HIFs, activation of SNAIL, and decreased expression of E-cadherin, which leads to decreased adhesion of MM cells to the BM, decreased SDF1α secretion from stroma, and enhanced egress of MM cells to the circulation. In parallel, hypoxia increases the expression of CXCR4, and consequently increases the migration and homing of MM cells in to the BM to form metastasis to new BM niches. Taken from Figure 8 in the article by Azab et al that begins on page 5782.