Reprogramming the tumor microenvironment to establish novel strategies and approaches for cancer therapy

• Project/Area Number: 18K08717
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Kitahara Shuji 東京女子医科大学, 医学部, 特任准教授 (40510235)
• Co-Investigator(Kenkyū-buntansha): 鈴木 康弘 東北大学, 未来科学技術共同研究センター, 助教 (60332277)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腫瘍血管 / 腫瘍微小環境 / 免疫環境 / 併用療法 / 消化器癌 / 免疫環 / 腫瘍免疫 / VASH2 / 免疫細胞 / 慢性炎症 / 免疫療法

Outline of Final Research Achievements

The objective of this study was to understand the characteristics of tumors by following alterations in the tumor microenvironment (TME), which plays a key role in the growth and metastasis of tumor cells. We used tumor model mice and human pathological specimens and analyzed them from both morphological and functional perspectives. By reprogramming the environment, we aimed to develop new anti-vascular therapies to limit tumor growth, and improve the efficacy of combination therapies including immunotherapy as well as of chemopreventive drugs.

Academic Significance and Societal Importance of the Research Achievements

血管新生因子であるVasohibin2をコントロールすることで、用いた主要モデルマウスの血管正常化、免疫細胞の侵入が見られ、腫瘍微小環境の正常化が見られた。今後、Vasohibin2を始め、微小循環系を制御することで、微小免疫環境が改善され、腫瘍増殖を抑制し、今後の併用療法の可能性の拡大を示唆できた。また、病理検体より、微小環境の変化によって分類することで、より個別の分子標的治療薬の選定が可能になることが示唆された。

Research Products

• [Int'l Joint Research] マサチューセッツ総合病院(米国)
• [Int'l Joint Research] ハーバード大学/マサチューセッツ総合病院(米国)
• [Int'l Joint Research] Harvard Medical School/MGH(米国)
• [Int'l Joint Research] 西南医科大学(中国)
• [Int'l Joint Research] Harvard Medical School/Massachusetts General Hospital,(米国)
• [Journal Article] Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma (2022)
  • Author(s): Aoki S, Inoue K, Klein S, Halvorsen S, Chen J, Matsui A, Nikmaneshi MR, Kitahara S, et al
  • Journal Title: Gut Volume: 1 Issue: 1 Pages: 185-193
  • DOI: 10.1136/gutjnl-2020-322493
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 癌治療の鍵となる腫瘍内微小環境のリプログラミング (2021)
  • Author(s): 松居彩、北原秀治
  • Journal Title: Medical Science Digest Volume: 10 Pages: 495-498
• [Journal Article] Potential Circulating Biomarkers of Recurrence after Hepatic Resection or Liver Transplantation in Hepatocellular Carcinoma Patients (2020)
  • Author(s): Duda Dan G.、Dima Simona O.、Cucu Dana、Sorop Andrei、Klein Sebastian、Ancukiewicz Marek、Kitahara Shuji、et al.
  • Journal Title: Cancers Volume: 12 Issue: 5 Pages: 1275-1275
  • DOI: 10.3390/cancers12051275
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma (2020)
  • Author(s): Shigeta Kohei、Matsui Aya、Kikuchi Hiroto、Klein Sebastian、Mamessier Emilie、Chen Ivy X、Aoki Shuichi、Kitahara Shuji、et al.
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 8 Issue: 2 Pages: e001435-e001435
  • DOI: 10.1136/jitc-2020-001435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ultrastructural changes in the choriocapillaris of N-methyl-N -nitrosourea- induced retinal degeneration in C57BL/6 mice. (2020)
  • Author(s): Hayakawa R, Komoike K, Kawakami H, Morishima M, Shimizu K, Kitahara S, Fujieda H, Ezaki T.
  • Journal Title: Med Mol Morphol Volume: - Issue: 4 Pages: 198-209
  • DOI: 10.1007/s00795-020-00246-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma (2019)
  • Author(s): Shigeta Kohei、Datta Meenal、Hato Tai、Kitahara Shuji、Chen Ivy X.、Matsui Aya、Kikuchi Hiroto、Mamessier Emilie、Aoki Shuichi、Ramjiawan Rakesh R.、Ochiai Hiroki、Bardeesy Nabeel、Huang Peigen、Cobbold Mark、Zhu Andrew X.、Jain Rakesh K.、Duda Dan G.
  • Journal Title: Hepatology Volume: 71 Issue: 4 Pages: 1247-1261
  • DOI: 10.1002/hep.30889
  • Peer Reviewed / Open Access
• [Journal Article] IMP dehydrogenase-2 Drives Aberrant Nucleolar Activity and Promotes Tumorigenesis in Glioblastoma (2019)
  • Author(s): Kofuji S, Hirayama A, Eberhardt AO, Kawaguchi R, Sakamoto N, Kitahara S, Wolfe K, Lange L, Onishi N, Uematsu M, Saya H, Soga T, Grummt I, Bierhoff H, Sasaki AT.
  • Journal Title: Nat Cell Biol Volume: 21 Issue: 8 Pages: 1003-1014
  • DOI: 10.1038/s41556-019-0363-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Basic and Clinical Perspective on the Future of Perioperative Therapy for Gastric Cancer (2019)
  • Author(s): Chen Jiang、G. Duda Dan、Matsui Aya、Kikuchi Hiroto、Kawakubo Kazumichi、Kitahara Shuji
  • Journal Title: Surgery, Gastroenterology and Oncology Volume: 24 Issue: 6 Pages: 273-273
  • DOI: 10.21614/sgo-24-6-273
  • Peer Reviewed / Open Access
• [Journal Article] Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice (2018)
  • Author(s): Pereira Ethel R.、Kedrin Dmitriy、Seano Giorgio、Gautier Olivia、Meijer Eelco F. J.、Jones Dennis、Chin Shan-Min、Kitahara Shuji、Bouta Echoe M.、Chang Jonathan、Beech Elizabeth、Jeong Han-Sin、Carroll Michael C.、Taghian Alphonse G.、Padera Timothy P.
  • Journal Title: Science Volume: 359 Issue: 6382 Pages: 1403-1407
  • DOI: 10.1126/science.aal3622
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Morphological characterization of pulmonary microvascular disease in bronchopulmonary dysplasia caused by hyperoxia in newborn mice (2018)
  • Author(s): Nakanishi Hidehiko、Morikawa Shunichi、Kitahara Shuji、Yoshii Asuka、Uchiyama Atsushi、Kusuda Satoshi、Ezaki Taichi
  • Journal Title: Medical Molecular Morphology Volume: 51 Issue: 3 Pages: 1-10
  • DOI: 10.1007/s00795-018-0182-2
  • Peer Reviewed
• [Journal Article] How immunotherapy and targeted therapy are changing gastrointestinal cancer treatment (2018)
  • Author(s): Shuji Kitahara, Yasuhiro Suzuki, Taichi Ezaki
  • Journal Title: Medical Research Archives Volume: 6 Pages: 1-14
  • Peer Reviewed / Open Access
• [Journal Article] Combined Angiotensin Receptor Blocker Losartan and the CXCR4 Inhibitor AMD3100 Increases the Efficacy of Radiotherapy in a Metastatic Osteosarcoma Mouse Model (2018)
  • Author(s): Li Sen、Li Wende、Leung Chi-Ho、Kitahara Shuji、Liu Yujiao、Klein Sebastian、Fukumura Dai、Gerweck Leo E、Loeffler Jay S、Jain Rakesh K、Duda Dan G、Huang Peigen
  • Journal Title: Journal of Cancer Science & Therapy Volume: 10 Issue: 12 Pages: 358-365
  • DOI: 10.4172/1948-5956.1000570
  • Peer Reviewed / Open Access
• [Presentation] VASH２とがん微小環境 (2020)
  • Author(s): 北原秀治
  • Organizer: 第43会日本分子生物医学会年会フォーラム
  • Invited
• [Presentation] これからのアカデミア学術集会 (2020)
  • Author(s): 北原秀治
  • Organizer: 第4回デジタルヘルス学会シンポジウム
  • Invited
• [Presentation] がん微小環境選択的な分子標的治療戦略 (2020)
  • Author(s): 北原秀治
  • Organizer: 第109回日本病理学会総会シンポジウム
  • Invited
• [Presentation] がん微小環境選択的な分子標的治療戦略 (2019)
  • Author(s): 北原秀治
  • Organizer: 東北大学加齢研セミナー
  • Invited
• [Presentation] Novel approaches to pancreatic cancer (2019)
  • Author(s): Shuji Kitahara
  • Organizer: IASGO/Post Graduate Course2019
  • Int'l Joint Research / Invited
• [Presentation] 胃癌における新しい診断と治療戦略の開発 (2019)
  • Author(s): 北原秀治
  • Organizer: 日本血管生物医学会学術集会
• [Presentation] 腫瘍内微小環境リプログラミングによる新規治療法の開発 (2019)
  • Author(s): 北原秀治
  • Organizer: 消化器がんプロジェクト会議
  • Invited
• [Presentation] がん微小環境における血管の役割（骨肉腫モデルを用いて） (2018)
  • Author(s): 北原秀治
  • Organizer: 第124回日本解剖学会総会シンポジウム
  • Invited