Could targeting bone delay cancer progression? Potential mechanisms of action of bisphosphonates

Although dissemination may occur early in the course of many cancers, the development of overt metastases depends upon a variety of factors inherent to the cancer cells and the tissue(s) they colonize. The time lag between initial dissemination and established metastases could be several years, during which period the bone marrow may provide an unwitting sanctuary for disseminated tumor cells (DTCs). Survival in a dormant state within the bone marrow may help DTCs weather the effects of anticancer therapies and seed posttreatment relapses. The importance of the bone marrow for facilitating DTC survival may vary depending on the type of cancer and mechanisms of tumor cell dissemination. By altering the bone microenvironment, bisphosphonates may reduce DTC viability. Moreover, some bisphosphonates have demonstrated multiple anticancer activities. These multiple mechanisms may help explain the improvement in disease outcomes with the use of zoledronic acid in malignancies like breast cancer and multiple myeloma.

► The bone microenvironment facilitates distant metastasis from solid tumors. ► Disseminated tumor cells (DTCs) survive in bone marrow niches to seed later metastases. ► Using bisphosphonates (BP) to alter the bone microenvironment may prevent metastasis. ► BP benefits are most evident in cancers where DTCs are prognostic for recurrence. ► The antimetastatic potential of BPs is under investigation in many malignancies.