Every year about 500,000 people in the United States die as a result of cancer. Among them, 90% exhibit systemic disease with metastasis. Considering this high rate of incidence and mortality, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy. In recent years, two broad mechanisms for metastasis have received significant attention: epithelial-to-mesenchymal transition (EMT) and tumor microenvironment interactions. EMT is believed to be a major mechanism by which cancer cells become migratory and invasive. Various cancer cells--both in vivo and in vitro--demonstrate features of epithelial-to-mesenchymal-like transition. In addition, many steps of metastasis are influenced by host contributions from the tumor microenvironment, which help determine the course and severity of metastasis. Here we evaluate the diverse mechanisms of EMT and tumor microenvironment interactions in the progression of cancer, and construct a rational argument for targeting these pathways to control metastasis.

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As appreciation grows for the contribution of the tumor microenvironment to the progression of cancer, new evidence accumulates to support that the participation of stromal cells can extend beyond the local environment. Recently, Elkabets and colleagues demonstrated a systemic interaction between cancer cells and distant bone marrow cells to support the growth of otherwise indolent tumor cells at a secondary site, raising thought-provoking questions regarding the involvement of stromal cells in maintaining metastatic dormancy.