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2021 Fiscal Year Final Research Report

Role of the angiocrine factor Egfl7 in multiple myeloma progression and drug resistance

Research Project

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Project/Area Number 19K08857
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionJuntendo University

Principal Investigator

Heissig Beate  順天堂大学, 大学院医学研究科, 特任准教授 (30372931)

Co-Investigator(Kenkyū-buntansha) 服部 浩一  順天堂大学, 大学院医学研究科, 特任先任准教授 (10360116)
Project Period (FY) 2019-04-01 – 2022-03-31
Keywordsmultiple myeloma / angiocrine factor / proliferation / integrin
Outline of Final Research Achievements

We showed malignant plasma cells express angiocrine factor EGF like-7 (EGFL7) mRNA and protein. MM cells expressed the functional EGFL7 receptor integrin b 3 (ITGB3), resulting in ITGB3 phosphorylation and FAK activation. Overexpression of ITGB3 or EGFL7 enhanced MM cell adhesion and proliferation. ITGB3 overexpression upregulated the transcription factor Kr¨uppel-like factor 2 (KLF2), which further enhanced EGFL7 transcription in MM cells, thereby establishing an EGFL7-ITGB3-KLF2-EGFL7 amplication loop that supports MM cell survival and proliferation.. NOD.scid./J mice transplanted with MM cells showed elevated human plasma EGFL7 levels. EGFL7 knockdown in patient-derived MM cells and treatment with neutralizing antibodies against EGFL7 inhibited MM cell growth in vivo. The MM drug bortezomib upregulates EGFL7, ITGB3, and KLF2 expression in MM cells. Inhibition of EGFL7 signaling in synergy with BTZ may provide a novel strategy for inhibiting MM cell proliferation.

Free Research Field

造血

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫(MM)は、造血器の悪性腫瘍としては2番目に高頻度であり、さらには治療薬自体の副作用、また抵抗性が問題となり、5年生存率は概ね50%、長期無病生存は5%以下と予後不良で完治の難しい疾患に該当します。従って、治療法のオプションは多い程良く、また新しい分子標的が常に望まれている疾患と言えます。本研究成果は、血管内皮から分泌されるアンジオクライン因子を通じたMMの病態制御機構という、これまでに無い、新しい観点からの疾患病態へのアプローチという点で、学術的にも極めて有意義なものと考えます。今後の臨床応用への展開が強く期待される内容と、当方らは判断致しております。

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Published: 2023-01-30  

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