A Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma

• DOI: 10.1002/stem.2499
• Publication Date: 2016-09-19T08:51:41Z
• Authors: Masahiko Kanehira; Tohru Fujiwara; Shinji Nakajima; Yoko Okitsu; Yasushi Onishi; Noriko Fukuhara; Ryo Ichinohasama; Yoshinori Okada; Hideo Harigae
• Keywords: Senescence

Mesenchymal stromal cells (MSCs) are multipotent progenitor and there is much interest in how MSCs contribute to the regulation of tumor microenvironment. Whether exert a supportive or suppressive effect on progression still controversial, but likely dependent variety factors that tumor-type dependent. Multiple myeloma (MM) characterized by growth malignant plasma bone marrow. It has been shown MM governed MSCs, which act as stroma cells. Although created via mutual communication between mechanism poorly understood. Here we explored role lysophosphatidic acid (LPA) signaling cellular events where were converted into either MM-supportive MM-suppressive stroma. We found stimulate produce autotaxin, an indispensable enzyme for biosynthesis LPA, LPA receptor 1 (LPA1) 3 (LPA3) transduce opposite signals determine fate MSCs. LPA3-silenced (siLPA3-MSCs) exhibited senescence-related phenotypes vitro, significantly promoted tumor-related angiogenesis vivo. In contrast, siLPA1-MSCs showed resistance senescence efficiently delayed Consistently, anti-MM effects obtained LPA1-silencing completely reproduced systemic administration Ki6425, LPA1 antagonist. Collectively, our results indicate determines potential therapeutic target MM. Stem Cells 2017;35:739-753.