title: Macrophages in multiple myeloma: emerging concepts and therapeutic implications.
abstract: Multiple myeloma, a clonal plasma cell malignancy, has long provided a prototypic model to study regulatory interactions between malignant cells and their microenvironment. Myeloma-associated macrophages have historically received limited scrutiny, but recent work points to central and non-redundant roles in myeloma niche homeostasis. The evidence supports a paradigm of complex, dynamic and often mutable interactions between macrophages and other cellular constituents of the niche. We and others have shown that macrophages support myeloma cell growth, viability and drug resistance through both contact-mediated and non-contact-mediated mechanisms. These tumor-beneficial roles have evolved in opposition to, or in parallel with, intrinsic pro-inflammatory and tumoricidal properties. Thus, simple blockade of protective "don't eat me" signals on the surface of myeloma cells leads to macrophage-mediated myeloma cell killing. Macrophages also enhance the tumor-supportive role of mesenchymal stem/stromal cells (MSCs) in the niche: importantly, this interaction is bidirectional, producing a distinct state of macrophage polarization that we termed "MSC-educated macrophages." The intriguing pattern of cross-talk between macrophages, MSCs and tumor cells highlights the myeloma niche as a dynamic multi-cellular structure. Targeted reprogramming of these interactions harbors significant untapped therapeutic potential, particularly in the setting of minimal residual disease, the main obstacle toward a cure.
authors: Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health , Madison, WI , USA and University of Wisconsin Carbone Cancer Center , Madison, WI , USA.
authors: Fotis
authors: F
authors: Asimakopoulos
authors: Jaehyup
authors: J
authors: Kim
authors: Ryan A
authors: RA
authors: Denu
authors: Chelsea
authors: C
authors: Hope
authors: Jeffrey L
authors: JL
authors: Jensen
authors: Samuel J
authors: SJ
authors: Ollar
authors: Ellen
authors: E
authors: Hebron
authors: Claire
authors: C
authors: Flanagan
authors: Natalie
authors: N
authors: Callander
authors: Peiman
authors: P
authors: Hematti
mesh_terms: D000818:Animals; D002450:Cell Communication; D002470:Cell Survival; D006801:Humans; D007167:Immunotherapy; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D009389:Neovascularization, Pathologic; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human