title: An Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma.
abstract: Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells. Although stroma is created via mutual communication between myeloma cells and MSCs, the mechanism is poorly understood. Here we explored the role of lysophosphatidic acid (LPA) signaling in cellular events where MSCs were converted into either MM-supportive or MM-suppressive stroma. We found that myeloma cells stimulate MSCs to produce autotaxin, an indispensable enzyme for the biosynthesis of LPA, and LPA receptor 1 (LPA1) and 3 (LPA3) transduce opposite signals to MSCs to determine the fate of MSCs. LPA3-silenced MSCs (siLPA3-MSCs) exhibited cellular senescence-related phenotypes in vitro, and significantly promoted progression of MM and tumor-related angiogenesis in vivo. In contrast, siLPA1-MSCs showed resistance to cellular senescence in vitro, and efficiently delayed progression of MM and tumor-related angiogenesis in vivo. Consistently, anti-MM effects obtained by LPA1-silencing in MSCs were completely reproduced by systemic administration of Ki6425, an LPA1 antagonist. Collectively, our results indicate that LPA signaling determines the fate of MSCs and has potential as a therapeutic target in MM. Stem Cells 2017;35:739-753.
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kanehira
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.|Molecular Hematology/Oncology, Hebita, Ishinomaki, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Japanese Red Cross Ishinomaki Hospital, Hebita, Ishinomaki, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okitsu
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Fukuhara
authors.affiliation: Division of Hematopathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ichinohasama
authors.affiliation: Department of Thoracic surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Miyagi, Japan.|Molecular Hematology/Oncology, Hebita, Ishinomaki, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D016922:Cellular Senescence; D018450:Disease Progression; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D
keywords: Adult stem cells; Bone marrow stromal cells; Hematologic malignancies; Marrow stromal cells; Marrow stromal stem cells; Mesenchymal stem cells; Tissue-specific stem cells