An Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma. (29th September 2016)

• Record Type: Journal Article
• Authors: Kanehira, Masahiko; Fujiwara, Tohru; Nakajima, Shinji; Okitsu, Yoko; Onishi, Yasushi; Fukuhara, Noriko; Ichinohasama, Ryo; Okada, Yoshinori; Harigae, Hideo
• Is Part Of: Stem cells. Volume 35:Number 3(2017:Mar.)
• Page Start: 739
• Page End: 753
• Publication Date: 2016-09-29
• Subjects: Hematologic malignancies -- Marrow stromal stem cells -- Mesenchymal stem cells -- Marrow stromal cells -- Tissue‐specific stem cells -- Adult stem cells -- Bone marrow stromal cells; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2499
• Languages: English
• ISSNs: 1066-5099

Abstract

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 Abstract : The signaling through lysophosphatidic acid receptor 1 (LPA1) and 3 (LPA3) in bone marrow mesenchymal stromal cells (MSCs) is an important determinant in multiple myeloma (MM) progression. LPA3‐silenced MSCs exhibit pro‐senescent phenotypes and promote MM progression and tumor‐related angiogenesis via transdifferentiation into tumor‐associated fibroblasts (TAFs) and FGF2 production. Conversely, LPA1‐silenced MSCs exhibit anti‐senescent phenotypes and delay MM progression. These results suggest that LPA1/3 axis is a crucial regulator of formation of tumor microenvironment and a novel conceptual target for MM therapy.