title: Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma.
abstract: We previously showed that macrophages (MΦs) infiltrate the bone marrow (BM) of patients with myeloma and may play a role in drug resistance. This study analyzed chemokines expressed by myeloma BM that are responsible for recruiting monocytes to the tumor bed. We found that chemokines CCL3, CCL14, and CCL2 were highly expressed by myeloma and BM cells, and the levels of CCL14 and CCL3 in myeloma BM positively correlated with the percentage of BM-infiltrating MΦs. In vitro, these chemokines were responsible for chemoattracting human monocytes to tumor sites and in vivo for MΦ infiltration into myeloma-bearing BM in the 5TGM1 mouse model. Surprisingly, we also found that these chemokines stimulated MΦ in vitro proliferation induced by myeloma cells and in vivo in a human myeloma xenograft SCID mouse model. The chemokines also activated normal MΦ polarization and differentiation into myeloma-associated MΦs. Western blot analysis revealed that these chemokines promoted growth and survival signaling in MΦs via activating the PI3K/Akt and ERK MAPK pathways and c-myc expression. Thus, this study provides novel insight into the mechanism of MΦ infiltration of BM and also potential targets for improving the efficacy of chemotherapy in myeloma.
authors.affiliation: Bone Marrow Transplantation Center, Department of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.|Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Hematology, Sichuan University, West China School of Medicine, Chengdu, Sichuan, China.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Enguang
authors.initials: E
authors.lastname: Bi
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Maojie
authors.initials: M
authors.lastname: Yang
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Reu
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Bone Marrow Transplantation Center, Department of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000502:physiology*; D054405:Chemokine CCL3 / Q000502:physiology*; D019742:Chemokines, CC / Q000502:physiology*; D002633:Chemotaxis; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: C097720:CCL14 protein, human; C111835:CCL2 protein, human; C515429:CCL3 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D019742:Chemokines, CC
keywords: bone marrow; chemokine; macrophage; multiple myeloma