title: Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone.
abstract: Multiple myeloma (MM) cells reside in the bone marrow microenvironment and form complicated interactions with nonneoplastic, resident stromal cells. We previously found that aggressive MM cells shift osteoblast progenitors toward adipogenesis. In addition, adipocytes are among the most common cell types in the adult skeleton; both mature adipocytes and preadipocytes serve as endocrine cells that secrete a number of soluble molecules into the microenvironment. Therefore, we used a combination of in vivo and in vitro methods to test the hypothesis that an increase in adipocyte lineage cells feeds back to promote MM progression. The results of this study revealed that bone marrow from patients with MM indeed contains increased preadipocytes and significantly larger mature adipocytes than normal bone marrow. We also found that preadipocytes and mature adipocytes secrete many molecules important for supporting MM cells in the bone marrow and directly recruit MM cells through both monocyte chemotactic protein-1 and stromal cell-derived factor-1α. Co-culture experiments found that preadipocytes activate Wnt signaling and decrease cleaved caspase-3, whereas mature adipocytes activate ERK signaling in MM cells. Furthermore, mature adipocyte conditioned medium promotes MM growth, whereas co-culture with preadipocytes results in enhanced MM cell chemotaxis in vitro and increased tumor growth in bone in vivo. Combined, these data reveal the importance of preadipocytes and mature adipocytes on MM progression and represent a unique target in the bone marrow microenvironment.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Trotter
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gibson
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tshering Lama
authors.initials: TL
authors.lastname: Sherpa
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Pramod S
authors.initials: PS
authors.lastname: Gowda
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Deniz
authors.initials: D
authors.lastname: Peker
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Comprehensive Cancer Center and the Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: yangyang@uabmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D050156:Adipogenesis; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D053148:Caspase 3