Study of the tumor microenvironment during progression and acquisition of treatment resistance of renal cell carcinoma
| Project/Area Number |
16K08657
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Keio University |
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Principal Investigator |
Mikami Shuji 慶應義塾大学, 医学部(信濃町), 講師 (20338180)
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| Co-Investigator(Kenkyū-buntansha) |
小坂 威雄 慶應義塾大学, 医学部(信濃町), 講師 (30445407)
水野 隆一 慶應義塾大学, 医学部(信濃町), 講師 (60383824)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 腎細胞癌 / 微小環境 / プレシージョンメディスン / PD-1 / PD-L1 / VASH1 / 微小血管密度 / 腫瘍免疫 / 免疫チェックポイント阻害剤 / 分子標的治療 / コンパニオン診断 / VEGF-TKI / スニチニブ / ソラフェニブ / 免疫 / 耐性 / 血管新生 / 薬剤耐性 |
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| Outline of Final Research Achievements |
VEGF-TKIs have become the first-line drugs for the treatment of metastatic and unresectable renal cell carcinoma. However, most cases become resistant to the treatment about 1 year after the initiation of the treatment. Therefore, elucidation of the molecular mechanism of the treatment resistance is important for the development of effective treatment. In this study, we focused on tumor micro-environment to investigate the molecular mechanism of the progression and acquisition of treatment resistance. As a result, it was found that expression of VASH1, a regulator of angiogenesis, in endothelial cells and PD-1/PD-L1 expression in tumor infiltrating immune cells were involved in resistance to VEGF-TKIs. This study suggested that targeting these molecules might be effective treatment for VEGF-TKI-resistant renal cell carcinoma.
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| Academic Significance and Societal Importance of the Research Achievements |
進行性腎細胞癌の第一選択はVEGF-TKI阻害剤であるが、治療開始後約１年で大部分の症例が治療抵抗性になる。そのため、薬剤耐性の分子機構の解明が腎細胞癌の根治には重要である。本研究課題では、病理医と泌尿器科医が共同で腎細胞癌の臨床所見、病理学的所見に基づき、VEGF-TKI耐性に関与する腎細胞癌のがん微小環境を系統的に解析した。その結果、血管内皮細胞における血管制御因子VASH1発現および免疫担当細胞におけるPD-1/PD-L1発現がVEGF-TKI治療耐性に関与していることが判明したため、これらの分子を標的とした治療がVEGF-TKI抵抗性腎細胞癌の効果的な治療につながると考えられる。
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] Clinical significance of PD-1 and PD-L1 expression in the tumor microenvironment of clear cell renal cell carcinoma.2019
Author(s)
Mikami S, Mizuno R, Kondo T, Shinohara N, Nonomura N, Ozono S, Eto M, Tatsugami K, Takayama T, Matsuyama H, Kishida T, Oya M
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma.2019
Author(s)
Ito K, Masunaga A, Tanaka N, Mizuno R, Shirotake S, Yasumizu Y, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Momma T, Masuda T, Nakagawa K, Oyama M, Asano T, Oya M.
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Journal Title
Jpn J Clin Oncol.
Volume: 49(1)
Pages: 69-76
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Evaluation of prostate-specific antigen density in the diagnosis of prostate cancer combined with magnetic resonance imaging before biopsy in men aged 70 years and older with elevated PSA.2018
Author(s)
Yanai Y, Kosaka T, Hongo H, Matsumoto K, Shinojima T, Kikuchi E, Miyajima A, Mizuno R, Mikami S, Jinzaki M, Oya M.
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Journal Title
Mol Clin Oncol.
Volume: 9
Pages: 656-660
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12)2017
Author(s)
Kuroda N, Yorita K, Sasaki N, Ishihara A, Matsuura K, Daa T, Mori S, Sasaki A, Mikami S, Shigematsu K, Nagashima Y.
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Journal Title
Pol J Pathol
Volume: 68(1)
Pages: 66-72
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Endoscopic morphologic features of ulcerative colitis-associated dysplasia classified according to the SCENIC consensus statement.2017
Author(s)
Sugimoto S, Naganuma M, Iwao Y, Matsuoka K, Shimoda M, Mikami S, Mizuno S, Nakazato Y, Nanki K, Inoue N, Ogata H, Kanai T.
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Journal Title
Gastrointest Endosc
Volume: 85(3)
Pages: 639-46
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model.2017
Author(s)
Tanaka N, Mizuno R, Yasumizu Y, Ito K, Shirotake S, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Oya M
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Journal Title
Urol Oncol.
Volume: 35(2)
Pages: 19-39
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32 dysregulation.2016
Author(s)
Tanaka N, Kosaka T, Miyazaki Y, Mikami S, Niwa N, Otsuka Y, Minamishima YA, Mizuno R, Kikuchi E, Miyajima A, Sabe H, Okada Y, Uhlen P, Suematsu M, Oya M.
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Journal Title
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] 転移性腎細胞癌に対するニボルマブの効果予測因子の検討2018
Author(s)
高松 公晴, 水野 隆一, 田中 伸之, 武田 利和, 森田 伸也, 松本 一宏, 小坂 威雄, 篠島 利明, 菊地 栄次, 浅沼 宏, 三上 修治, 大家 基嗣
Organizer
第56回日本癌治療学会学術集会
Related Report
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[Presentation] 分子標的薬1次治療が短期間で中止された進行性腎癌症例の検討2018
Author(s)
伊藤 敬一, 升永 綾子, 田中 伸之, 城武 卓, 水野 隆一, 安水 洋太, 伊藤 祐二郎, 宮崎 保匡, 萩原 正幸, 金尾 健人, 三上 修治, 門間 哲雄, 中川 健, 増田 毅, 小山 政史, 浅野 友彦, 大家 基嗣
Organizer
第106回日本泌尿器科学会総会
Related Report
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