Tumor-derived microparticles induce bone marrow-derived cell mobilization and tumor homing: A process regulated by osteopontin

Abstract

Acute chemotherapy can induce rapid bone-marrow derived pro-angiogenic cell (BMDC) mobilization and tumor homing, contributing to tumor regrowth. To study the contribution of tumor cells to tumor regrowth following therapy, we focused on tumor-derived microparticles (TMPs). EMT/6 murine-mammary carcinoma cells exposed to paclitaxel chemotherapy exhibited an increased number of TMPs and significantly altered their angiogenic properties. Similarly, breast cancer patients had increased levels of plasma MUC-1(+) TMPs following chemotherapy. In addition, TMPs from cells exposed to paclitaxel induced higher BMDC mobilization and colonization, but had no increased effect on angiogenesis in Matrigel plugs and tumors than TMPs from untreated cells. Since TMPs abundantly express osteopontin, a protein known to participate in BMDC trafficking, the impact of osteopontin-depleted TMPs on BMDC mobilization, colonization, and tumor angiogenesis was examined. Although EMT/6 tumors grown in mice inoculated with osteopontin-depleted TMPs had lower numbers of BMDC infiltration and microvessel density when compared with EMT/6 tumors grown in mice inoculated with wild-type TMPs, no significant difference in tumor growth was seen between the two groups. However, when BMDCs from paclitaxel-treated mice were injected into wild-type EMT/6-bearing mice, a substantial increase in tumor growth and BMDC infiltration was detected compared to osteopontin-depleted EMT/6-bearing mice injected with BMDCs from paclitaxel-treated mice. Collectively, our results suggest that osteopontin expressed by TMPs play an important role in BMDC mobilization and colonization of tumors, but is not sufficient to enhance the angiogenic activity in tumors.