Microenvironmental regulation of epithelial-mesenchymal transitions in cancer

Abstract

The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. Activation of the epithelial-to-mesenchymal transition (EMT) endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The observation that in many cancers distant metastases resemble the epithelial phenotype of primary tumors has led to speculation that the disseminated tumor cells recruited to the target organs undergo mesenchymal-to-epithelial transition (MET). However, the MET cascade has not been recapitulated in vivo, and the cellular and molecular regulators that promote MET remain unknown. In a recent report, using a model of spontaneous breast cancer, we have shown that bone marrow-derived myeloid progenitor cells in the premetastatic lung secrete the proteoglycan versican, which induces MET of metastatic tumor cells and accelerates metastases. This review summarizes recent progress in MET research, outlines a unique paracrine cross-talk between the microenvironment and the cancer cells, which promotes tumor outgrowth in the metastatic organ, and discusses opportunities for novel antimetastatic approaches for cancer therapy.

Figure 1. Schematic depicting the contribution of bone marrow-derived cells to the formation of lung metastases from a primary breast tumor

Bone marrow contributes F4/80⁺ macrophages that express EMT promoting factors in the primary tumor microenvironment, and Ly6C⁺ myeloid progenitor cells in the metastatic lungs that express versican to stimulate MET of disseminated tumor cells. EMT, epithelial to mesenchymal transition; MET, mesenchymal to epithelial transition.