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 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.

The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis

“…The importance of these particles in systemic signalling is supported by the finding that their circulating levels in tumour-bearing hosts seem to be higher than the levels observed in cell culture experiments where microvesicle-induced effects have been clearly observed 65 .…”

“…Likewise, renal-carcinoma-derived exosomes were found to promote angiogenesis in lung tumour metastases 64 . Additionally, a study of murine mammary carcinoma demonstrated that osteopontin, carried through the circulation by tumour-derived microparticles, was necessary to mobilize pro-angiogenic cells from the bone marrow 65 . Interestingly, in these experiments, the mammary tumours produced microparticles as a result of paclitaxel chemotherapy, which was consistent with the authors’ clinical observations that circulating microparticle numbers were elevated in some cancer patients following chemotherapy.…”

Membrane microparticles: shedding new light into cancer cell communication

“…Although OPN depletion from MP is not sufficient to reduce tumor growth, they observed that when bone marrow-derived pro-angiogenic cells (BMDC) from paclitaxel-treated mice were injected into OPN-depleted tumor-bearing mice, tumor growth and BMDC infiltration were greatly inhibited (Fremder et al 2014). These data suggest that OPN-loaded MPs may play important roles in tumor homing and BMDC mobilization, which facilitates angiogenesis.…”

“…Recently, Fremder et al (2014) detected a high OPN content in tumor cell-derived MP. Although OPN depletion from MP is not sufficient to reduce tumor growth, they observed that when bone marrow-derived pro-angiogenic cells (BMDC) from paclitaxel-treated mice were injected into OPN-depleted tumor-bearing mice, tumor growth and BMDC infiltration were greatly inhibited (Fremder et al 2014).…”

Extracellular vesicle cross-talk in the bone marrow microenvironment: implications in multiple myeloma

“…It has been shown that microparticles from paclitaxel treated breast carcinoma cells contain osteopontin by which they induce BM-derived pro-angiogenic cell mobilization and colonization, leading to microvessel sprouting and increased angiogenesis, which ultimately accelerates tumor growth [86]. In a different study, the anti-VEGF-A antibody B20 reduced the level of VEGF-A enclosed in breast cancer cell-secreted microparticles and these vesicles were unable to activate endothelial cells and could not promote BM-derived pro-angiogenic cell colonization [87].…”