腎細胞癌における上皮間葉転換に着目した新規標的分子の探索

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24390374
• Research Institution: Keio University
• Principal Investigator: 大家 基嗣 慶應義塾大学, 医学部, 教授 (00213885)
• Co-Investigator(Kenkyū-buntansha): 三上 修治 慶應義塾大学, 医学部, 講師 (20338180) ; 菊地 栄次 慶應義塾大学, 医学部, 講師 (10286552) ; 中川 健 東京歯科大学, 歯学部, 教授 (50227740) ; 水野 隆一 慶應義塾大学, 医学部, 講師 (60383824) ; 浅沼 宏 慶應義塾大学, 医学部, 講師 (70245570) ; 宮嶋 哲 慶應義塾大学, 医学部, 准教授 (90245572) ; 長田 浩彦 慶應義塾大学, 医学部, 研究員 (90265900)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 腎細胞癌 / 分子標的治療 / 薬剤耐性 / CD44

Outline of Annual Research Achievements

腎細胞癌を特徴付ける強い転移能と血管新生能に着目して、腎細胞癌の浸潤・転移機構の解析とともに分子標的治療抵抗性の分子病理学的解析を中心に研究した。
タバコをはじめとした外因性物質誘導性発癌に関わる転写因子aryl hydrocarbon receptor (AhR) の発現が、腎細胞癌の浸潤・転移に関与することを見出した。120名の腎細胞癌患者の病理組織を免疫組織学的に検討し、AhRの活性化が予後不良因子であることを示した。細胞株を使用したin vitroの実験で、AhRを活性化するTCDDを投与すると浸潤能が亢進した。siRNAによってAhRの発現を減弱化すると浸潤能は低下した。AhRは腎細胞癌の治療標的分子となりうる可能性を示した。
腎細胞癌における予後不良因子である紡錘細胞癌成分に関しては、上皮―間葉転換(EMT)に関わるSnailが紡錘細胞癌への移行に中心的な役割を果たし、MMP-2と MMP-9の発現亢進により浸潤・転移を促進することを示した。
淡明細胞型腎細胞癌ではVHL遺伝子の不活化によるHIF-VEGF分子経路が血管新生と癌細胞増殖に関与しており、転移性淡明細胞型腎細胞癌では同経路を阻害するスニチニブなどのtyrosine kinase inhibitor (TKI)による分子標的治療が第一選択となっている。TKI治療後残存癌組織では微小血管密度は低下を示すも、残存癌細胞の多くは癌幹細胞マーカーでもあるCD44とADAM17が陽性であり、これらがTKI治療抵抗性に関わる可能性を示した。腎癌細胞株を用いた研究では低酸素刺激によりCD44の発現が誘導されることを示した。TKIによる血管新生阻害によって低酸素環境が細胞内の代謝経路を変化させ、CD44をはじめとするがん幹細胞性分子を誘導し、治療抵抗性獲得に関与していることが示唆された。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Causes of Carryover

26年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Invasion and metastasis of renal cell carcinoma. (2014)
  • Author(s): Mikami S, Oya M, Mizuno R, Kosaka T, Katsube KI, Okada Y
  • Journal Title: Med Mol Morphol Volume: 47(2) Pages: 63-7
  • DOI: 10.1007/s00795-013-0064-6
  • Peer Reviewed
• [Journal Article] The Predictive Value of C-reactive Protein for Prognosis in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Multi-institutional Study. (2014)
  • Author(s): Tanaka N, Kikuchi E, Shirotake S, Kanao K, Matsumoto K, Kobayashi H, Miyazaki Y, Ide H, Obata J, Hoshino K, Hayakawa N, Ito Y, Kosaka T, Kodaira K, Oyama M, Miyajima A, Momma T, Nakagawa K, Ueno M, Oya M
  • Journal Title: Eur Urol Volume: 65(1) Pages: 227-34
  • DOI: 10.1016/j.eururo.2012.11.050
  • Peer Reviewed
• [Journal Article] Independent Predictors for Bladder Outcomes after Treatment of Intravesical Recurrence following Radical Nephroureterectomy in Patients with Primary Upper Tract Urothelial Carcinoma. (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Kobayashi H, Miyazaki Y, Ide H, Obata J, Hoshino K, Hayakawa N, Hagiwara M, Kosaka T, Oyama M, Miyajima A, Momma T, Nakagawa K, Jinzaki M, Hasegawa S, Nakajima Y, Oya M
  • Journal Title: Ann Surg Oncol Volume: 21(9) Pages: 3151-8
  • DOI: 10.1245/s10434-014-3657-y
  • Peer Reviewed
• [Journal Article] Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy: association with primary tumor location. (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Kobayashi H, Ide H, Miyazaki Y, Obata J, Hoshino K, Shirotake S, Akita H, Kosaka T, Miyajima A, Momma T, Nakagawa K, Hasegawa S, Nakajima Y, Jinzaki M, Oya M
  • Journal Title: Ann Surg Oncol Volume: 21(3) Pages: 1038-45
  • DOI: 10.1245/s10434-013-3349-z
  • Peer Reviewed
• [Journal Article] The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma: a multi-institutional study. (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Kobayashi H, Miyazaki Y, Ide H, Obata J, Hoshino K, Hayakawa N, Kosaka T, Oyama M, Miyajima A, Momma T, Nakagawa K, Jinzaki M, Nakajima Y, Oya M
  • Journal Title: Urol Oncol Volume: 32(1) Pages: e19-26
  • DOI: 10.1016/j.urolonc.2013.07.003
  • Peer Reviewed
• [Journal Article] Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas. (2014)
  • Author(s): Mikami S, Mizuno R, Kosaka T, Saya H, Oya M, Okada Y
  • Journal Title: Int J Cancer Volume: 136(7) Pages: 1504-1514
  • DOI: 10.1002/ijc.29137
  • Peer Reviewed
• [Journal Article] A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio for Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy. (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Miyazaki Y, Kobayashi H, Kaneko G, Hagiwara M, Ide H, Obata J, Hoshino K, Hayakawa N, Kosaka T, Hara S, Oyama M, Momma T, Nakajima Y, Jinzaki M, Oya M
  • Journal Title: Ann Surg Oncol Volume: 21(12) Pages: 4041-8
  • DOI: 10.1245/s10434-014-3830-3
  • Peer Reviewed
• [Journal Article] Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma. (2014)
  • Author(s): Kaneko G, Miyajima A, Yuge K, Yazawa S, Mizuno R, Kikuchi E, Jinzaki M, Oya M
  • Journal Title: Jpn J Clin Oncol Volume: 45(2) Pages: 210-6
  • DOI: 10.1093/jjco/hyu193
  • Peer Reviewed
• [Journal Article] Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib. (2014)
  • Author(s): Kondo T, Nakazawa H, Oya M, Kimura G, Fujii Y, Hatano T, Kawata N, Kume H, Morita M, Nakajima K, Ohno Y, Okegawa T, Takahashi S, Wakumoto Y, Horie S
  • Journal Title: Jpn J Clin Oncol Volume: 45(3) Pages: 274-80
  • DOI: 10.1093/jjco/hyu200
  • Peer Reviewed
• [Journal Article] Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high-risk patients with upper tract urothelial carcinoma: A Japanese multi-institution experience. (2014)
  • Author(s): Shirotake S, Kikuchi E, Tanaka N, Matsumoto K, Miyazaki Y, Kobayashi H, Ide H, Obata J, Hoshino K, Kaneko G, Hagiwara M, Kosaka T, Kanao K, Kodaira K, Hara S, Oyama M, Momma T, Miyajima A, Nakagawa K, Hasegawa S, Nakajima Y, Oya M
  • Journal Title: J Urol Volume: 193(4) Pages: 1122-8
  • DOI: 10.1016/j.juro.2014.10.022
  • Peer Reviewed
• [Journal Article] Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. (2014)
  • Author(s): Ishida M, Mikami S, Shinojima T, Kosaka T, Mizuno R, Kikuchi E, Miyajima A, Okada Y, Oya M
  • Journal Title: Int J Cancer Volume: Epub ahead of print Pages: Epub
  • DOI: 10.1002/ijc.29398
  • Peer Reviewed
• [Presentation] Efficacy of axitinib in patients with metastatic renal cell carcinoma previously treated with both VEGFR-TKI and mTORI. (2014)
  • Author(s): Mizuno R , Kosaka T, Mikami S, Oya M
  • Organizer: 2014 ASCO Annual Meeting
  • Place of Presentation: Chicago, The United States of America
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Dose adjustment of axitinib based on AUC monitoring in sunitinib-refractory advanced renal cell carcinoma. (2014)
  • Author(s): Miura Y, Chiyo K, Imamura, Uchino K, Kishida T, Matsubara N, Shinojima T, Oya M, Nakaigawa N, Yoshimura K, Takano T, Tanigawara Y
  • Organizer: 2014 ASCO Annual Meeting
  • Place of Presentation: Chicago, The United States of America
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Increased expression of aryl hydrocarbon receptor in clear cell renal cell carcinoma and infiltrating lymphocytes: Implications for cancer invasion, prognosis and tumor immunity. (2014)
  • Author(s): Ishida M, Mikami S, Kosaka T, Mizuno R, Kikuchi E, Miyajima A, Nakagawa K, Okada Y, Oya M
  • Organizer: AUA2014 Annual Meeting
  • Place of Presentation: Orlando,The United States of America
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Prognostic significance of TNF-α and CD44 expression in crear cell renal cell carcinomas: implication of cancer invasion, metastasis, and resistance to sunitinib treatment. (2014)
  • Author(s): Mikami S, Mizuno R, Kosaka T, Saya H, Oya M, Okada Y
  • Organizer: AUA2014 Annual Meeting
  • Place of Presentation: Orlando, The United States of America
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Visceral obesity is a useful predictor of better recurrence-free survival after curative surgeries for Japanese patients with localized clear cell renal cell carcinoma. (2014)
  • Author(s): Kaneko G, Miyajima A, Hasegawa R, Mizuno R, Uchida Y, Hara S, Kikuchi E, Nakagawa K, Jinzaki M, Oya M
  • Organizer: 29th Annual EAU Congress
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-04-11 – 2014-04-15