| Project/Area Number |
19K19220
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 57060:Surgical dentistry-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
ANNAN DORCAS 北海道大学, 歯学研究院, 学術研究員 (30837240)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | Tumor endothelial cell / Glutaminolysis / Glutamate / Glutathione / Tumor amgiogenesis / Oxidative stress / Sulfasalazine / Slc7a11/System -xc / Slc7a11 / glutamate / tumor endothelial cell / sulfasalazine / oxidative stress / bioenergetics / Tumor angiogenesis / Glutamine metabolism / Amino acid transporters / angiogenesis / metabolism / tumor |
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| Outline of Research at the Start |
The purpose of this study is to identify a glutaminolysis metabolic crosstalk between tumor endothelial cells and tumor cells which when interrupted can inhibit tumor growth and metastasis, in order to develope tumor endothelial specific drug which has no side effect on normal blood vessels.
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| Outline of Final Research Achievements |
Tumor endothelial cells are the main focus of tumor angiogenesis studies. Compared to normal endothelial cells (NECs), TECs have a unique biology, which offers an explorable hub for new drug targets without the adverse side effects observed with common antiangiogenic drugs. The study examined the roles of glutamine metabolism and mitochondria in TECs. TECs had fewer mitochondria than NECs and produced more ATP from glycolysis than oxidative phosphorylation. Spare respiratory capacity was lower in TECs than in NECs. Glutamine utilization by TECs produced larger quantities of glutamate than other glutaminolysis metabolites. Consistently inhibition of the cystine/glutamate antiporter Slc7a11 with sulfasalazine (SSZ) decreased TEC proliferation more significantly than NECs after 72h although glutathione levels were rapidly decreased in all cells upon exposure. In the mouse tumor models, SSZ treatment decreased both tumor angiogenesis and tumor growth.
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| Academic Significance and Societal Importance of the Research Achievements |
社会経済と人類の健康に癌が及ぼす悪い影響を取り除くためにも，癌の新しい治療戦略構築に関する研究の発展が望まれる．近年，癌細胞の代謝経路の標的化は創薬上重要な戦略と認識されている．本研究により，癌細胞のみならず腫瘍血管内皮細胞の代謝の特性も治療標的として有望であることが明らかになった．また，既存の血管新生阻害剤と異なり，より腫瘍血管に特異的な治療薬のための標的をこの研究にて提案することができた．このことにより，創薬研究分野に新たな知見を提供し，同時に新しい癌治療の展望をもたらした．
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