Molecular mechanism of astrocyte-related cachexia and pain due to neural invasion of pancreatic cancer

• Project/Area Number: 24790669
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine (including Psychosomatic medicine)
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: MITSUNAGA Shuichi 独立行政法人国立がん研究センター, その他部局等, 研究員 (20466197)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 緩和医療 / 膵がん / 悪液質 / 神経浸潤 / RAGE / S100A4 / CCL7 / マウスモデル / アストロサイト / S100P / S100A9

Research Abstract

The reaction of the nervous system to neural invasion (N-inv) may lead to cachexia and pain in pancreatic cancer (PCa). The N-inv model was created by injecting Capan-1 cells into the left sciatic nerve of severe combined immunodeficiency mice. The N-inv model was compared to a sham operation group. Propentofylline (PPF), an inhibitor of astrocytic activation, was administered daily into the abdominal cavity. Pain and body weight (BW) were measured weekly. Mice were euthanized 6 weeks after surgery.
Pain and astrocytic activation were observed 2 weeks after the start of N-inv and maintained throughout the experiment. Loss of BW began at 4 weeks and was worse at 6 weeks. PPF treatment inhibited pain, astrocytic activation, and BW loss in the N-inv model. The reaction of the nervous system to N-inv leads to cachexia in PCa. The reaction of the nervous system to N-inv leads to cachexia in PCa.

Research Products

• [Journal Article] Prognostic impact of M2 macrophages at neural invasion in patients with invasive ductal carcinoma of the pancreas (2014)
  • Author(s): Sugimoto M, Mitsunaga S, Yoshikawa K, Kato Y, Gotohda N, Takahashi S, Konishi M, Ikeda M, Kojima M, Ochiai A, Kaneko H
  • Journal Title: Eur J Cancer Volume: 50(11) Pages: 1900-8
• [Journal Article] Prognostic impact of M2 macrophages at neural invasion in patients with invasive ductal carcinoma of the pancreas. (2014)
  • Author(s): Sugimoto M, Mitsunaga S, Yoshikawa K, Kato Y, Gotohda N, Takahashi S, Konishi M, Ikeda M, Kojima M, Ochiai A, Kaneko H.
  • Journal Title: Eur J Cancer Volume: 50(11) Issue: 11 Pages: 1900-8
  • DOI: 10.1016/j.ejca.2014.04.010
  • Peer Reviewed
• [Journal Article] Associations of interleukin-6 with vegetative but not affective depressive symptoms in terminally ill cancer patients (2013)
  • Author(s): Inagaki M, Akechi T, Okuyama T, Sugawara Y, Kinoshita H, Shima Y, Terao K, Mitsunaga S, Ochiai A, Uchitomi Y
  • Volume: 21(8)
  • Pages: 2097-106
• [Journal Article] Serum levels of IL-6 and IL-1βcan predict the efficacy of gemcitabine in patients with advanced pancreatic cancer (2013)
  • Author(s): Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Furuse J, Inagaki M, Higashi S, Kato H, Terao K, Ochiai A
  • Journal Title: Br J Cancer Volume: 108(10) Pages: 2063-9
• [Journal Article] Serum levels of IL-6 and IL-1β can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. (2013)
  • Author(s): Mitsunaga S
  • Journal Title: Br J Cancer Volume: 108(10) Issue: 10 Pages: 2063-2069
  • DOI: 10.1038/bjc.2013.174
  • Peer Reviewed
• [Journal Article] Associations of interleukin-6 with vegetative but not affective depressive symptoms in terminally ill cancer patients. (2013)
  • Author(s): Inagaki M, Akechi T, Okuyama T, Sugawara Y, Kinoshita H, Shima Y, Terao K, Mitsunaga S, Ochiai A, Uchitomi Y.
  • Journal Title: Support Care Cancer. Volume: in press
  • Peer Reviewed
• [Journal Article] Remarkable tumor lysis in a hepatocellular carcinoma patient immediately following glypican-3-derived peptide vaccination: An autopsy case. (2013)
  • Author(s): Sawada Y, Yoshikawa T, Fujii S, Mitsunaga S, Nobuoka D, Mizuno S, Takahashi M, Yamauchi C, Endo I, Nakatsura T.
  • Journal Title: Hum Vaccin Immunother. Volume: 9(7)
  • Peer Reviewed
• [Journal Article] Neural invasion induces cachexia via astrocytic activation of neural route in pancreatic cancer (2012)
  • Author(s): Imoto A, Mitsunaga S, Inagaki M, Aoyagi K, Sasaki H, Ikeda M, Nakachi K, Higuchi K, Ochiai A
  • Journal Title: Int J Cancer Volume: 131(12) Pages: 2795-807
  • NAID: 40019958265
• [Journal Article] Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head (2012)
  • Author(s): Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N, Kato Y, Aizawa M, Ochiai A
  • Journal Title: Cancer Sci Volume: 103(11) Pages: 2012-20
• [Journal Article] Phase I/II study of gemcitabine as a fixed dose rate infusion and S-1 combination therapy (FGS) in gemcitabine-refractory pancreatic cancer patients. (2012)
  • Author(s): Morizane C, Okusaka T, Ueno H, Kondo S, Ikeda M, Furuse J, Shinichi O, Nakachi K, Mitsunaga S, Kojima Y, Suzuki E, Ueno M, Yamaguchi T.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 69(4) Issue: 4 Pages: 957-64
  • DOI: 10.1007/s00280-011-1786-6
  • Peer Reviewed
• [Journal Article] Neural invasion induces cachexia via astrocytic activation of neural route in pancreatic cancer (2012)
  • Author(s): Imoto A, Mitsunaga S
  • Journal Title: Int J Cancer Volume: 131(12) Issue: 12 Pages: 2795-807
  • DOI: 10.1002/ijc.27594
  • NAID: 40019958265
  • Peer Reviewed
• [Journal Article] Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. (2012)
  • Author(s): Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N, Kato Y, Aizawa M, Ochiai A.
  • Journal Title: Cancer Sci. Volume: 103(11) Pages: 2012-20
  • Peer Reviewed
• [Journal Article] Treatment outcome for systemic chemotherapy for recurrent pancreatic cancer after postoperative adjuvant chemotherapy. (2012)
  • Author(s): Taniyama TK, Morizane C, Nakachi K, Nara S, Ueno H, Kondo S, Kosuge T, Shimada K, Esaki M, Ikeda M, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Okusaka T.
  • Journal Title: Pancreatology Volume: 12(5) Issue: 5 Pages: 428-33
  • DOI: 10.1016/j.pan.2012.07.016
  • Peer Reviewed
• [Presentation] Severe neural invasion related to cachexia in advanced pancreatic cancer (2014)
  • Author(s): Ａｋｉｒａ Ｉｍｏｔｏ， Ｓｈｕｉｃｈｉ Ｍｉｔｓｕｎａｇａ
  • Organizer: Digestive Disease Week 2014
  • Place of Presentation: Chicago 米国
• [Presentation] ゲムシタビン耐性進行膵癌に対するS-1療法の3週レジメンの有効性と安全性―6週レジメンとの比較― (2013)
  • Author(s): 田中弘人、光永修一、小林美沙樹、船崎秀樹、高橋秀明、大野泉、清水怜、和泉啓司郎、池田公史
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台市
  • Year and Date: 2013-08-30
• [Presentation] 進行膵がんにおける塩酸ゲムシタビン療法の有害事象と炎症性サイトカイン・タンパクの関連 (2013)
  • Author(s): 奥山浩之、光永修一、桑原明子、高橋秀明、大野泉、清水怜、池田公史
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台市
  • Year and Date: 2013-08-29
• [Presentation] Characterization of patient with high serum level of IL-6 in advanced panceratic cancer (2013)
  • Author(s): 三浦智史、光永修一、清水怜、大野泉、高橋秀明、奥山浩之、桑原明子、池田公史
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台市
  • Year and Date: 2013-08-29
• [Presentation] 胆道がんの患者背景と治療成績の変遷―国立がん研究センター東病院1031例の検討― (2013)
  • Author(s): 4.光永修一、池田公史、清水怜、大野泉、高橋秀明、奥山浩之、桑原明子、加藤祐一郎、落合敦志、小西大
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台市
  • Year and Date: 2013-08-29
• [Presentation] 進行肝細胞癌患者におけるSorafenib療法-C型肝炎とB型肝炎の背景肝の違いによる有効性と安全性の検討― (2013)
  • Author(s): 篠原旭、奥山浩之、高橋秀明、小林美沙樹、船崎秀樹、桑原明子、大野泉、清水怜、光永修一、池田公史、市田泰彦、和泉啓司郎
  • Organizer: 第7回日本肝がん分子標的治療研究会
  • Place of Presentation: 岐阜市
  • Year and Date: 2013-01-19
• [Presentation] 血小板低値の肝細胞癌患者に対するSorafenib (2013)
  • Author(s): 清水怜、桑原明子、奥山浩之、高橋秀明、大野泉、光永修一、篠原旭、小林美沙樹、船崎秀樹、近藤俊輔、森実千種、上野秀樹、奥坂拓志、池田公史
  • Organizer: 第7回日本肝がん分子標的治療研究会
  • Place of Presentation: 岐阜市
  • Year and Date: 2013-01-19
• [Presentation] 肝動脈化学塞栓術に不応の肝細胞癌に対するソラフェニブの有効性-肝動注化学療法との比較- (2013)
  • Author(s): 桑原明子、池田公史、光永修一、清水怜、大野泉、高橋秀明、奥山浩之、近藤俊輔、森実千種、上野秀樹、佐竹光夫、荒井保明、奥坂拓志
  • Organizer: 第7回日本肝がん分子標的治療研究会
  • Place of Presentation: 岐阜市
  • Year and Date: 2013-01-19
• [Presentation] Phase I/II study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC) : Phase I results (2013)
  • Author(s): Shuichi Mitsunaga, Masafumi Ikeda, Hideki Ueno, Kohei Nakachi, Chigusa Morizane, Shunsuke Kondo, Satoshi Shimizu, Yasushi Kojima, Takuya Suzuki, Toshiyuki Tamai, James P. O'Brien, Takuji Okusaka
  • Organizer: ASCO-GI2013 Gastrointestinal Cancers Symposium
  • Place of Presentation: San Francisco
• [Presentation] Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma (2013)
  • Author(s): Masafumi Ikeda, Shuichiro Shiina, Kohei Nakachi, Shuichi Mitsunaga, Satoshi Shimizu, Yasushi Kojima, Hideki Ueno, Chigusa Morizane, Shunsuke Kondo, Yasunari Sakamoto, Ryosuke Tateishi, Yoshinari Asaoka, Kazuhiko Koike, Hitoshi Arioka, Takuji Okusaka
  • Organizer: ASCO-GI2013 Gastrointestinal Cancers Symposium
  • Place of Presentation: San Francisco
• [Presentation] Phase I/II study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results. (2013)
  • Author(s): Shuichi Mitsunaga, Masafumi Ikeda, Hideki Ueno, Kohei Nakachi, Chigusa Morizane, Shunsuke Kondo, Satoshi Shimizu, Yasushi Kojima, Takuya Suzuki, Toshiyuki Tamai,et al.
  • Organizer: ASCO-GI2013 Gastrointestinal Cancers Symposium
  • Place of Presentation: San Francisco, America
• [Presentation] 80歳以上の高齢者の切除不能膵癌症例に対するゲムシタビン療法の有効性と忍容性 (2012)
  • Author(s): 小林美沙樹、奥山浩之、船崎秀樹、桑原明子、高橋秀明、大野泉、清水怜、光永修一、池田公史、市田泰彦、和泉啓司郎
  • Organizer: 第50回日本癌治療学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2012-10-25
• [Presentation] 肝転移を有する膵腺房細胞癌に対しゲムシタビン塩酸塩とS-1併用療法を行った2例. (2012)
  • Author(s): 桑原明子、光永修一、清水怜、大野泉、高橋秀明、奥山浩之、池田公史.
  • Organizer: 第320回 日本消化器病学会 関東支部例会
  • Place of Presentation: 東京
• [Presentation] 進行膵がんにおける腹腔動脈および上腸間膜動脈周囲浸潤の臨床的意義． (2012)
  • Author(s): 光永修一、池田公史、大野泉、清水怜、高橋秀明、奥山浩之、桑原明子、奥坂拓志、上野秀樹、森実千種、近藤俊輔、落合淳志．
  • Organizer: 第10回日本臨床腫瘍学会学術集会.
  • Place of Presentation: 大阪市
• [Presentation] 膵がん化学療法において治療前デスアシルグレリン値は消化器症状の予測因子である． (2012)
  • Author(s): 三浦智史、光永修一、松元信弘、中里雅光、大野泉、清水怜、高橋秀明、奥山浩之、桑原明子、池田公史．
  • Organizer: 第10回日本臨床腫瘍学会学術集会.
  • Place of Presentation: 大阪市
• [Presentation] 膵癌化学療法において腫瘍制御予測因子となりうる症状変動の検討． (2012)
  • Author(s): 桑原明子、光永修一、池田公史、大野泉、清水怜、高橋秀明、奥山浩之、奥坂拓志、上野秀樹、森実千種、近藤俊輔．
  • Organizer: 第10回日本臨床腫瘍学会学術集会.
  • Place of Presentation: 大阪市
• [Presentation] 進行膵がん患者に対する2次化学療法としてのS-1療法の早期中止に関わる因子解析． (2012)
  • Author(s): 田中弘人、光永修一、小林美沙樹、船崎秀樹、市田泰彦、高橋秀明、大野泉、清水怜、池田公史、和泉啓司郎．
  • Organizer: 第10回日本臨床腫瘍学会学術集会.
  • Place of Presentation: 大阪市
• [Presentation] IL-6/STAT3経路は、膵癌の腫瘍浸潤と疼痛に関与する
  • Author(s): 光永修一
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] 膵がん神経浸潤モデルによる悪液質解明
  • Author(s): 光永修一
  • Organizer: 第7回In vivo実験医学シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] Nervous system reaction to neural invasion leads to cachexia in pancreatic cancer
  • Author(s): Shuichi Mitsunaga
  • Organizer: 7th cachexia conference（国際悪液質会議）
  • Place of Presentation: 神戸市