title: Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype.
abstract: Multiple myeloma (MM) cells specifically attract peripheral-blood monocytes, while interaction of MM with bone marrow stromal cells (BMSCs) significantly increased monocyte recruitment (p<0.01). The CXCL12 chemokine, produced by both the MM and BMSCs, was found to be a critical regulator of monocyte migration. CXCL12 production was up-regulated under MM-BMSCs co-culture conditions, whereas blockage with anti-CXCR4 antibodies significantly abrogated monocyte recruitment toward a MM-derived conditioned medium (p<0.01). Furthermore, elevated levels of CXCL12 were detected in MM, but not in normal BM samples, whereas malignant MM cells often represented the source of increased CXCL12 in the BM. Blood-derived macrophages effectively supported MM cells proliferation and protected them from chemotherapy-induced apoptosis. Importantly, MM cells affected macrophage polarization, elevating the expression of M2-related scavenger receptor CD206 in macrophages and blocking LPS-induced TNFα secretion (a hallmark of M1 response). Of note, MM-educated macrophages suppressed T-cell proliferation and IFNγ production in response to activation. Finally, increased numbers of CXCR4-expressing CD163+CD206+ macrophages were detected in the BM of MM patients (n=25) in comparison to MGUS (n=11) and normal specimens (n=8). Taken together, these results identify macrophages as important players in MM tumorogenicity, and recognize the CXCR4/CXCL12 axis as a critical regulator of MM-stroma interactions and microenvironment formation.
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Katia
authors.initials: K
authors.lastname: Beider
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bitner
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Leiba
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Odit
authors.initials: O
authors.lastname: Gutwein
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Koren-Michowitz
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Ostrovsky
authors.affiliation: Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Abraham
authors.affiliation: Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Wald
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4