Bone metastatic breast cancer cell-derived extracellular vesicles block osteoblast mineralization through MAPK signaling

Research Project

Project/Area Number	18K09522
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 57010:Oral biological science-related
Research Institution	Kyushu University
Principal Investigator	Uehara Norihisa 九州大学, 歯学研究院, 助教 (30368211)
Project Period (FY)	2018-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000) Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	細胞外小胞 / 骨細胞 / 骨芽細胞 / 破骨細胞 / 骨転移 / 酸化ストレス / 糖化コラーゲン / 骨吸収
Outline of Final Research Achievements	The interplay between breast cancer cells and bone cells in bone marrow microenvironments play an important role in tumor progression through the secreting factors. Although extracellular vesicles (EVs) released from cancer cells have shown to regulate the many types of cancer progression, In this study, we explored the implications of bone metastatic breast cancer cell-derived EVs in the regulation of osteoblast differentiation and mineralization. Treatment of MC3T3-E1 and ST2 osteoblastic cells with mouse bone metastatic (4T1) mammary tumor cell-derived EVs (4T1-EV) inhibited mineralization, which associated with the decreased in the expression of ATF4 . 4T1-EV treatment attenuated the activation of ERK, JNK and p38MAPK phosphorylation in ST2 cells. Our results demonstrate the implication of 4T1-EV-mediated osteoblast maturation and mineralization through MAPK pathways.
Academic Significance and Societal Importance of the Research Achievements	本研究では、骨転移性乳癌細胞由来細胞外小胞（EV)が、骨芽細胞の石灰化を著しく抑制すること見出し、その分子機序としてMAPキナーゼ活性化抑制を介していることを明らかにした。この発見は、骨転移に伴う骨破壊の制御メカニズムにおける、骨転移性乳癌細胞由来EVの機能の新たな発見に加え、EVをターゲットとした骨破壊のマーカー探索への応用に有用な知見を与えうるものと考えられた。