Chemokines CCL2,3,14Regulate Macrophage Bone Marrow Homing,Proliferation And Polarization In Multiple Myeloma

Multiple myeloma (MM) is a hematologic malignancy derived from B cells in bone marrow, characterized by abnormal proliferation of plasma cells.Besides traditional chemotherapy, treatment based on new agent such as proteosome inhibtors, immune regulators combined with autologus stem cell transplantation offerd us a new strategy for the management of MM. Also progress has been made in the last decade, MM still remains an incurable disease and drug resistance cause for the major failure.Therefore, new options are needed to solve this challenge and improve the clinic outcome for MM patients.Our previous study have demonstrate that macrphage (MO) is abundant in MM BM and protect MM cells from drug induced apoptosis. Clinic data also shown that the infiltration of MΦs in MM BM is associated with poor prognosis. However, why MM BM harbors more MΦs is not well understood. It is widely accepted that MM associated macrophage (mMΦ) are derived from circulating monocytes (MOs), recruited to tissues by chemokines secrected by tumor cells or tumor microenviromentTo investigate which chemokines regulate MOs/MΦs infiltration in MM BM, firstly we examined a panel of MOs chemokines expression in MM BM.We shown that MM BM over-expressed CCL2.CCL3and CCL14compared with healthy BM.More important, the levels of CCL3and CCL14in MM BM plasma positively correlated with the numbers of BM-infiltrating MΦs in MM patients.Both MM cells and BM stromal cells (BMSCs) expressed CCL2,CCL3and CCL14, and MM cells further enhanced BMSC secretion of these chemokines. In vitro migration assay indicated that coculture of MM cells with BMSCs resulted in chemoattraction of monocytes, which was inhibited by neutralizing antibodies to these3chemokines. Similarly, MM5TGM tumor-bearing mice had increased numbers of MΦDs in the BM, and murine BM cells from the tumor-bearing mice expressed more CCL3and CCL2than cells from tumor-free mice. Neutralizing antibodies to murine CCL3or CCL2inhibited MΦs infiltration into BM in this model. Therefore, this study firstly demonstrate CCL2,3,14are crucial chemokines regulate MOs/MΦs infiltration in MM BM.Some study indicated that MΦs could "self-renew" and proliferate as some stem cells, leading to the abundant MOs/MΦs in the tunor environment.In this study,we firstly found that MM stimulated MOs/MΦ proliferation in vitro and in vivo in tumor bed of SCID mice xenografted with human MM cells. Moreover, recent research have revealed that chemokines are associated with the progression,invasion and migration of tumor cells.The chemokines CCL2,3,14were involved in MOs/MΦ proliferation regulation. Meanwhile, addition of each chemokine alone was sufficient to promote survival/proliferation cell signaling PI3K-Akt and MAPK/Erk pathways, as well as the mMΦs characteristic c-myc gene expression. Therefore, our data suggest that CCL2,3,14are not only MOs/MΦ chemoattractant in MM-BM, but also mMΦs activation factors.In conclusion, our data analyzed MOs/MΦs chemokines expressed in MM BM, and indentified CCL2,CCL3and CCL14as functional chemokines resposible for increased mMOs infiltration. We also found that those chemokines promoted mMΦs proliferation and polarization in myeloma tumor bed via activation of PI3K/Akt and MAPK/Erk signalling pathways and c-myc expression. MΦs infiltration is the high risk in MM prognosis. Therefore, a better understanding for the interaction between chemokines and mMΦs in MM is needed,targeting those chemokines may prevent MΦs infiltration in tumor bed, therefore benefit MM chemotherapy.