Dormancy in the Tumor Microenvironment.

Tumor cells frequently disseminate to distant organ sites, where they encounter permissive or restrictive environments that enable them to grow and colonize or enter a dormant state. Tumor dormancy is not strictly defined, but generally describes a tumor cell that is non-proliferative or in a state of balanced equilibrium, in which the proliferation rate of the tumor cell or cells is equal to its rate of cell death. The mechanisms that regulate tumor cell entry into and exit from dormancy are poorly understood, but microenvironmental features as well as tumor cell intrinsic factors play an important role in mediating this transition. Upon homing to distant metastatic sites, tumor cells may disseminate into various niches, most frequently the perivascular, hematopoietic stem cell, or endosteal/osteogenic niche. Tumor cells sense the cytokines, growth factors, and chemo-attractants from each of these niches, and tumor cell expression of cognate ligands and receptors can determine whether a tumor cell enters or exits dormancy. In addition to the secreted factors and cell-cell interactions that regulate dormancy, the cellular milieu also impacts upon disseminated tumor cells to promote or restrain their growth in distant metastatic sites. In this chapter we will discuss the role of the osteogenic and perivascular niche on dormant tumor cells, as well as the impact of hypoxia (low oxygen tensions) and the immune system on the restriction and outgrowth of dormant, disseminated tumor cells.