大腸癌肝転移巣における癌幹細胞

2015 Fiscal Year Annual Research Report

• Project/Area Number: 24592009
• Research Institution: Yokohama City University
• Principal Investigator: 田中 邦哉 横浜市立大学, 医学(系)研究科(研究院), 客員教授 (10295503)
• Co-Investigator(Kenkyū-buntansha): 平野 久 横浜市立大学, 生命科学研究, 特任教授 (00275075) ; 廣島 幸彦 横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (60718021)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: 転移性肝癌 / 癌幹細胞 / CD133 / CD44 / 大腸癌

Outline of Annual Research Achievements

目的：大腸肝転移巣検体を用いて、１）原発巣と転移巣で癌幹細胞マーカー発現が同一であるか、２）転移巣での癌幹細胞マーカー発現は予後規定因子になり得るか検討を行った。対象と方法：1998年～2008年までに当科で切除術を施行した大腸癌肝転移症例103例を対象とし、CD44、CD133の発現を免疫染色を用いて検討した。また、浸潤能、増殖能、抗癌剤耐性能を評価するためMIB-1,E-cadherin,ABC-G2の発現も検討した。103例中44例は原発巣での評価も行った。結果：CD44の発現率は原発巣で41.4％、転移巣で58.7％であった。原発巣と転移巣で発現にmarginalな相関を認めた（r=0.250, p=0.071）。CD133の発現は原発巣で53.6％、転移巣で44.6％で相関を認めなかった（r=0.219, p=0.135）。肝転移巣におけるCD133の発現は独立予後規定因子であった（HR 0.320,p=0.0016）。肝転移巣CD133陰性群は有意にMIB-1indexが高く（p＝0.003）、E-cadherinの発現が低かった（p=0.001）。
以上の結果から肝転移巣のCD133陰性は予後不良因子であり、癌細胞の増殖、浸潤に関連している可能性が示唆されため、肝転移巣におけるCD133の役割を解明するため、CD133陽性群と陰性群に発現している蛋白をプロテオーム解析により網羅的に解析した。
プロテオーム解析の結果、1160の蛋白質が同定され、これらの候補蛋白群をネットワーク解析し、有力なシグナル経路の同定に成功した（Hypoxia関連pathway）。

Research Products

• [Journal Article] ALPPS: Short-term Outcome and Functional Changes in the Future Liver Remnant. (2015)
  • Author(s): Tanaka K, Endo I.
  • Journal Title: Ann Surg. Volume: 262 Pages: e88-89
  • DOI: 10.1097/SLA.0000000000000665.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Low infiltration of peritumoral regulatory T cells predicts worse outcome following resection of colorectal liver metastases. (2015)
  • Author(s): Nakagawa K, Tanaka K, Homma Y, Nojiri K, Kumamoto T, Takeda K, Endo I.
  • Journal Title: Low infiltration of peritumoral regulatory T cells predicts worse outcome following resection of colorectal liver metastases. Volume: 22 Pages: 180-186
  • DOI: 10.1245/s10434-014-3974-1.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adjuvant treatment with tumor-targeting Salmonella typhimurium A1-R reduces recurrence and increases survival after liver metastasis resection in an orthotopic nude mouse model. (2015)
  • Author(s): Murakami T, Hiroshima Y, Zhao M, Zhang Y, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: Oncotarget Volume: 6 Pages: 41856-41862
  • DOI: 10.18632/oncotarget.6170.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Fluorescence-Guided Surgery of Liver Metastasis in Orthotopic Nude-Mouse Models. (2015)
  • Author(s): Murakami T, Hiroshima Y, Zhang Y, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: PLoS One. Volume: 10 Pages: e0138752
  • DOI: 10.1371/journal.pone.0138752.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Therapeutic efficacy of tumor-targeting Salmonella typhimurium A1-R on human colorectal cancer liver metastasis in orthotopic nude-mouse models. (2015)
  • Author(s): Murakami T, Hiroshima Y, Zhao M, Zhang Y, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: Oncotarget Volume: 6 Pages: 119-124
  • DOI: 10.18632/oncotarget.5187.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice. (2015)
  • Author(s): Hiroshima Y, Zhao M, Zhang Y, Zhang N, Maawy A, Murakami T, Mii S, Uehara F, Yamamoto M, Miwa S, Yano S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: PLoS One Volume: 10 Pages: e0134324
  • DOI: 10.1371/journal.pone.0134324.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] The correlation between the change of future liver remnant volume and functional capacity in ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), and establishment of ALPPS model in rats (2015)
  • Author(s): Kawaguchi Daisuke, Yukihiko Hiroshima, Takashi Murakami, Kenichi Matsuo, Chihiro Kosugi, Kiyohiko Syuto, Masashi Momiyama, Itaru Endo, Keiji Koda, Kuniya Tanaka
  • Organizer: AACR
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-20 – 2015-04-22
  • Int'l Joint Research
• [Presentation] Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models (2015)
  • Author(s): Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman
  • Organizer: AACR
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-20 – 2015-04-22
  • Int'l Joint Research