Dormancy and recurrence of cancer stem cells in bone: Role of bone morphogenetic proteins

Abstract

Metastatic disease is the leading cause of death in cancer patients. Despite signifi cant advancement in understanding the pathological process at cellular and molecular level, there is no effective cure to this devastating disease till date. Dissemination of cancer cell into the blood is considered to occur even at an early stage in cancer progression that eventually leads to formation of secondary tumor or metastasis after remaining dormant for a long or short period of time. This variation in time period can be attributed to the properties of both disseminated tumor cells and the new homing microenvironment at the metastatic sites. Increasing line of evidences indicate that the disseminated cells possess cancer stem cell like properties that render them with the ability to disseminate from primary tumor and remain dormant in the new microenvironment at the distant organs. However, it is not clear about how and when these cancer stemlike cells (CSCs) are able to switch into proliferative state to manifest as recurrent disease. CSCs must adopt different genetic and epigenetic changes to potentiate themselves with proliferative phenotype leading to recurred tumor. On the other hand, immediate microenvironment of CSCs exerts restrictive barrier for growth of these cells or even induce cell death. To evade from the inhibitory signaling from the microenvironment, these disseminated CSCs switch to dormant phenotype. It hasbeen recently found that bone morphogenetic proteins (BMPs) released by microenvironmental cells plays a critical role in inducing dormancy and deprivation of BMPs leads to reversal of dormancy and increase in proliferation of dormant cells. Role of BMPs in the dormancy-recurrence axis may offer a therapeutic approach to retain the disseminated CSCs in perpetual dormant state. Therefore, comprehensive understanding of the role of BMPs in various microenvironment of disseminated tumor cell is considered to open a new avenue for the treatment of cancer metastasis.