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Development of Novel Therapies for Pancreatic Cancer by Regulating the Cancer Microenvironment Using Hyaluronan as a Target

Research Project

Project/Area Number 16K10587
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Digestive surgery
Research InstitutionHirosaki University

Principal Investigator

Hakamada Kenichi  弘前大学, 医学研究科, 教授 (30271802)

Co-Investigator(Kenkyū-buntansha) 石戸 圭之輔  弘前大学, 医学研究科, 准教授 (00436023)
工藤 大輔  弘前大学, 医学研究科, 客員研究員 (00587024)
三浦 卓也  弘前大学, 医学部附属病院, 講師 (30722136)
脇屋 太一  弘前大学, 医学部附属病院, 講師 (50571246)
木村 憲央  弘前大学, 医学研究科, 講師 (60436029)
Project Period (FY) 2016-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords膵癌 / 間質 / ヒアルロン酸 / 4メチルウンベリフェロン / 癌幹細胞 / 4-methylumbelliferone / ヒアルロン酸合成抑制 / 抗癌剤細胞内移行 / CD44 / γδT細胞 / γδT cell / 免疫担当細胞 / 4メチルウンベリフェロン / 4-Methylumbelliferone / pancreatic cancer / extracellular matrix / hyaluronan / 細胞外マトリックス / 膵癌間質 / 膵癌治療
Outline of Final Research Achievements

In this study, we investigated the effects of 4-methylumberlliferone (MU), an inhibitor of hyaluronan synthesis, on pancreatic cancer growth and progression, enhancement of anticancer drug effects, and immune function in order to develop novel therapies targeting hyaluronan, a major component of the stroma involved in the regulation of pancreatic cancer growth and the acquisition of resistance to treatment.
We confirmed 1) the suppression of hyaluronan synthesis by MU in various pancreatic cancer cell lines, 2) the suppression of hyaluronan synthesis by MU at the tissue level, 3) the increased intracellular transfer of the anticancer drug 5-FU into pancreatic cancer cells under MU administration, and 4) the intratumoral transfer of cytotoxic lymphocytes during hyaluronan depletion, and these results clarified the tumor suppressive effect and mechanism. Targeting hyaluronic acid, which forms a microenvironment, is expected to be a novel therapeutic method for pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

膵癌の難治性の機序として、癌細胞自体の悪性度に加えて、強固に形成された間質を特徴とする微小環境が、抗癌剤の分布・拡散と免疫細胞の到達を阻害していることが示唆されている。本研究は、膵癌間質の多くを占め、細胞機能に重要な役割をもつヒアルロン酸を標的として、ヒアルロン酸合成阻害剤である4-methylumberlliferone(MU)による新規治療の可能性を検証した点で学術的意義が高い。
得られた結果は、MUによる直接的な膵癌に対する抗腫瘍作用に加え、微小環境変化による抗癌剤や細胞障害性免疫担当細胞の腫瘍内への移行促進効果を明らかにし、新規機序による膵癌治療の可能性を示した点で社会的意義が大きい。

Report

(6 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (31 results)

All 2021 2020 2019 2018 2017 2016

All Journal Article (18 results) (of which Peer Reviewed: 18 results,  Open Access: 17 results,  Acknowledgement Compliant: 3 results) Presentation (13 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] Time density curve of dynamic contrast enhanced computed tomography correlates with histological characteristics of pancreatic cancer2021

    • Author(s)
      Shintaro Goto, Hiroko Seino, Tadashi Yoshizawa, Satoko Morohashi, Keinosuke Ishido, Kenichi Hakamada, Hiroshi Kijima.
    • Journal Title

      Oncology Letters

      Volume: 21 Issue: 4 Pages: 276-276

    • DOI

      10.3892/ol.2021.12537

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Widespread anorectal lymphovascular networks and tissue drainage: analyses from submucosal India ink injection and indocyanine green fluorescence imaging2021

    • Author(s)
      Sato Kentaro、Shimoda Hiroshi、Miura Takuya、Sakamoto Yoshiyuki、Morohashi Hajime、Watanabe Seiji、Narita Hirokazu、Mitsuhashi Yuto、Umemura Kotaro、Hakamada Kenichi
    • Journal Title

      Colorectal Disease

      Volume: - Issue: 6 Pages: 1-12

    • DOI

      10.1111/codi.15582

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effective dissection for rectal cancer with lateral lymph node metastasis based on prognostic factors and recurrence type2021

    • Author(s)
      Morohashi Hajime、Sakamoto Yoshiyuki、Miura Takuya、Ichinohe Daichi、Umemura Kotaro、Akaishi Takanobu、Sato Kentaro、Kuwata Daisuke、Yamazaki Keisuke、Wakiya Taiichi、Hakamada Kenichi
    • Journal Title

      International Journal of Colorectal Disease

      Volume: - Issue: 6 Pages: 1-11

    • DOI

      10.1007/s00384-021-03870-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Essential updates 2018/2019: Current topics in the surgical treatment of pancreatic ductal adenocarcinoma2020

    • Author(s)
      Ishido K, Hakamada K, Kimura N, Miura T, Wakiya T.
    • Journal Title

      Ann Gastroenterol Surg

      Volume: 5 Issue: 1 Pages: 7-23

    • DOI

      10.1002/ags3.12379

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lipopolysaccharide-binding protein is a distinctive biomarker of abnormal pain threshold in the general Japanese population.2020

    • Author(s)
      Kudoh K, Mizukami H, Itabashi C, Fuke N, Osonoi S, Takeuchi Y, Wada K, Igawa A, Ogasawara S, Ishibashi Y, Hakamada K, Yagihashi S, Nakaji S.
    • Journal Title

      BMJ Open Diabetes Res Care

      Volume: 8 Issue: 1 Pages: e001739-e001739

    • DOI

      10.1136/bmjdrc-2020-001739

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diabetes, an independent poor prognostic factor of non-B non-C hepatocellular carcinoma, correlates with dihydropyrimidinase-like 3 promoter methylation.2020

    • Author(s)
      Umetsu S, Mizukami H, Saito T, Uchida C, Igawa A, Kudo K, Itabashi C, Osonoi S, Danyang G, Sasaki T, Yagihashi S, Hakamada K.
    • Journal Title

      Sci Rep

      Volume: 10 Issue: 1 Pages: 1156-1156

    • DOI

      10.1038/s41598-020-57883-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Organ/space infection is a common cause of high output stoma and outlet obstruction in diverting ileostomy.2020

    • Author(s)
      Hara Y, Miura T, Sakamoto Y, Morohashi H, Nagase H, Hakamada K.
    • Journal Title

      BMC Surg.

      Volume: 20 Issue: 1 Pages: 83-83

    • DOI

      10.1186/s12893-020-00734-7

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Investigating the association between radiological images and the pathology of rectal cancer treated with neoadjuvant chemotherapy.2019

    • Author(s)
      Morohashi S, Morohashi H, Seino H, Yoshizawa T, Haga T, Goto S, Wu Y, Sakamoto Y, Hakamada K, Kijima H
    • Journal Title

      Mol Clin Oncol.

      Volume: 11 Pages: 573-579

    • DOI

      10.3892/mco.2019.1931

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Delay in hepatocyte proliferation and prostaglandin D2 synthase expression for cholestasis due to endotoxin during partial hepatectomy in rats.2019

    • Author(s)
      Wakasa Y, Kimura N, Yamada T, Shimizu T, Hakamada K, Tsuchida S.
    • Journal Title

      Mol Med Rep

      Volume: 20 Pages: 4367-4375

    • DOI

      10.3892/mmr.2019.10681

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A double-blind randomized comparative clinical trial to evaluate the safety and efficacy of dendritic cell vaccine loaded with WT1 peptides (TLP0-001) in combination with S-1 in patients with advanced pancreatic cancer refractory to standard chemotherapy.2019

    • Author(s)
      Katsuda M, Miyazawa M, Ojima T, Katanuma A, Hakamada K, Sudo K, Asahara S, Endo I, Ueno M, Hara K, Yamada S, Fujii T, Satoi S, Ioka T, Ohira M, Akahori T, Kitano M, Nagano H, Furukawa M, Adachi T, Yamaue H.
    • Journal Title

      Trials

      Volume: 20 Issue: 1 Pages: 242-242

    • DOI

      10.1186/s13063-019-3332-5

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cancer stroma-targeting therapy: A new tool for fighting pancreatic cancer?2019

    • Author(s)
      Hakamada K
    • Journal Title

      Ann Gastroenterol Surg

      Volume: 1 Pages: 120-121

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increase of Tumor Infiltrating γδ T-cells in Pancreatic Ductal Adenocarcinoma Through Remodeling of the Extracellular Matrix by a Hyaluronan Synthesis Suppressor, 4-Methylumbelliferone.2019

    • Author(s)
      Suto A, Kudo D, Yoshida E, Nagase H, Suto S, Mimura J, Itoh K, Hakamada K.
    • Journal Title

      Pancreas.

      Volume: 48 Issue: 2 Pages: 292-298

    • DOI

      10.1097/mpa.0000000000001211

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 4-Methylumbelliferone Decreases the Hyaluronan-rich Extracellular Matrix and Increases the Effectiveness of 5-Fluorouracil2018

    • Author(s)
      Yoshida E, Kudo D, Nagase H, Suto A, Shimoda H, Suto S, Kakizaki I, Endo M, Hakamada K.
    • Journal Title

      Anticancer Res

      Volume: 38 Issue: 10 Pages: 5799-5804

    • DOI

      10.21873/anticanres.12919

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.2017

    • Author(s)
      Saito T, Mizukami H, Umetsu S, Uchida C, Inaba W, Abe M, Takahashi K, Kudo K, Itabashi C, Yagihashi S, Hakamada K.
    • Journal Title

      Sci Rep

      Volume: 7 Issue: 1 Pages: 18056-18067

    • DOI

      10.1038/s41598-017-18438-z

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Combination therapy with gemcitabine and nab-paclitaxel for locally advanced unresectable pancreatic cancer2017

    • Author(s)
      Saito Takeshi、Ishido Keinosuke、Kudo Daisuke、Kimura Norihisa、Wakiya Taiichi、Nakayama Yoshihito、Hakamada Kenichi
    • Journal Title

      Mol Clin Oncol

      Volume: 6 Issue: 6 Pages: 963-967

    • DOI

      10.3892/mco.2017.1251

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma.2017

    • Author(s)
      Kudo D, Suto A, Hakamada K.
    • Journal Title

      Int J Mol Sci

      Volume: 18 Issue: 3 Pages: 600-600

    • DOI

      10.3390/ijms18030600

    • NAID

      120006576911

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 4-Methylumbelliferone Suppresses Hyaluronan Synthesis and Tumor Progression in SCID Mice Intra-abdominally Inoculated With Pancreatic Cancer Cells.2017

    • Author(s)
      Nagase H, Kudo D, Suto A, Yoshida E, Suto S, Negishi M, Kakizaki I, Hakamada K
    • Journal Title

      Pancreas.

      Volume: 46 Issue: 2 Pages: 190-197

    • DOI

      10.1097/mpa.0000000000000741

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Antitumor effects of the hyaluronan inhibitor 4-methylumbelliferone on pancreatic cancer.2016

    • Author(s)
      Yoshida E, Kudo D, Nagase H, Shimoda H, Suto S, Negishi M, Kakizaki I, Endo M, Hakamada K.
    • Journal Title

      Oncol Lett.

      Volume: 12 Pages: 2337-2344

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Stage I膵癌切除症例の長期成績と臨床的特徴2020

    • Author(s)
      長瀬勇人、石戸圭之輔、木村憲央、脇屋太一、小田切理、久保田隼介、袴田健一
    • Organizer
      第120回日本外科学会定期学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] BRおよびUR膵癌の成績と集学的治療戦略の再考2020

    • Author(s)
      石戸圭之輔、木村憲央、脇屋太一、長瀬勇人、小田切理、袴田健一
    • Organizer
      第120回日本外科学会定期学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] BRおよびUR膵癌に対するConversion surgeryの適応2020

    • Author(s)
      石戸圭之輔、木村憲央、脇屋太一、長瀬勇人、小田切理、袴田健一
    • Organizer
      第18回日本消化器外科学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] AGEs-RAGE signalを介したPSCの活性化によりIL-6の分泌能が亢進する2020

    • Author(s)
      原裕太郎、水上浩哉、遅野井祥、井川明子、工藤和洋、袴田健一
    • Organizer
      第18回日本消化器外科学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Impact of chemotherapy with gemcitabine and nab-paclitaxel in conversion surgery for UR-LA pancreatic cancer2019

    • Author(s)
      Ishido K, Kimura N, Wakiya T, Nagase H, Hakamada K
    • Organizer
      第31回日本肝胆膵外科学会・学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Pathological Impact on the Stroma After Preoperative Chemotherapy With nab-Paclitaxel and Gemcitabine for Pancreatic Cancer.2019

    • Author(s)
      Ishido K, Kimura N, Wakiya T, Goto S, Yoshizawa T, Kijima H, Hakamada K
    • Organizer
      The 7th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association
    • Related Report
      2019 Research-status Report
  • [Presentation] The rationale of conversion surgery for far-advanced pancreatic adenocarcinoma2019

    • Author(s)
      Hakamada K
    • Organizer
      The 31st World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Clinical Experience of Nab-paclitaxel Plus Gemcitabine Treatment in Recurrent Cases with Pancreatic Cancer in our Institution2019

    • Author(s)
      Wakasa Y, Kimura N, Ishido K, Kudo D, Nagase N, Hakamada K.
    • Organizer
      International Hepato-Pancreatic-Biliary Association
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膵癌間質中ヒアルロン酸を標的とした新規治療法の可能性2017

    • Author(s)
      須藤亜希子、工藤 大輔、吉田 枝里、長瀬 勇人、三橋 佑人、脇屋 太一、木村 憲央、石戸圭之輔、袴田 健一
    • Organizer
      第117回日本外科学会定期学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵癌間質中ヒアルロン酸を標的とした新規治療2017

    • Author(s)
      須藤亜希子、工藤 大輔、吉田 枝里、長瀬 勇人、三橋 佑人、脇屋 太一、木村 憲央、石戸圭之輔、袴田 健一
    • Organizer
      第72回日本消化器外科学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] A novel tactics for the treatment of pancreatic adenocarinoma by targeting extracellular matrix2016

    • Author(s)
      Suto A, Kudo D, Toyoki Y, Ishido K, Wakiya T, Nagase H, Yoshida T, Hakamada K
    • Organizer
      20th meeting of the International Association of Pancreatology
    • Place of Presentation
      仙台国際センター(宮城県、仙台市)
    • Year and Date
      2016-08-04
    • Related Report
      2016 Research-status Report
  • [Presentation] ヒアルロン酸合成阻害剤4-メチルウンベリフェロンの膵癌に対する抗腫瘍効果2016

    • Author(s)
      長瀬 勇人、工藤 大輔、須藤亜希子、吉田 枝里、豊木 嘉一、袴田 健一
    • Organizer
      第71回日本消化器外科学会総会
    • Place of Presentation
      あわぎんホール(徳島県、徳島市)
    • Year and Date
      2016-07-14
    • Related Report
      2016 Research-status Report
  • [Presentation] ヒアルロン酸合成抑制剤を用いた間質制御による新たな膵癌治療法開発2016

    • Author(s)
      吉田 枝里、工藤 大輔、長瀬 勇人、須藤亜希子、脇屋 太一、石戸圭之輔、豊木 嘉一、袴田 健一
    • Organizer
      第116回日本外科学会定期学術集会
    • Place of Presentation
      大阪国際会議場(大阪府、大阪市)
    • Year and Date
      2016-04-14
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2022-01-27  

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