Analysis of hepatic stem and progenitor cells in the tumor microenvironment of liver metastasis: For cancer metastasis suppression

• Project/Area Number: 26460997
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: Suetsugu Atsushi 岐阜大学, 医学部附属病院, 助教 (30340079)
• Co-Investigator(Kenkyū-buntansha): 青木 仁美 岐阜大学, 大学院医学系研究科, 講師 (10550361)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝癌 / 幹細胞 / 癌微小環境

Outline of Final Research Achievements

Cancer cells form microenvironment in primary and metastatic tumor. The cancer-associated cells play an important role. Cancer-associated fibroblast cells and tumor-associated macrophages are important in the liver metastasis. Cancer cells shed exosomes and transfer exsomal molecules to fibroblast cells during tumor progression. We confirmed that cancer cells release exomes into the circulation of mice with liver metastasis. We collected blood of mice and ditected exosomes. Imaging of exosomes can contribute to understanding the role of intercellular communication in tumor progression. Tumor-drived exosomes have been viewed as a mediater to condition tissues and prepare niches for metastasis.

Research Products

• [Journal Article] Genetic recombination between stromal and cancer cells results in highly malignant cells identified by color-coded imaging in a mouse lymphoma model. (2017)
  • Author(s): Nakamura M, Suetsugu A, Hasegawa K, Matsumoto T, Aoki H, Kunisada T, Shimizu M, Saji S, Moriwaki H, Hoffman RM.
  • Journal Title: J Cell Biochem Volume: - Issue: 12 Pages: 4216-4221
  • DOI: 10.1002/jcb.26068
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Color-coded live imaging of heterokaryon formation and nuclear fusion of hybridizing cancer cells. (2016)
  • Author(s): Suetsugu A, Matsumoto T, Hasegawa K, Nakamura M, Kunisada T, Shimizu M, Saji S, Moriwaki H, Bouvet M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 36 Pages: 3827-3831
  • Peer Reviewed
• [Journal Article] Color-coded imaging of syngeneic orthotopic malignant lymphoma interacting with host stromal cells during metastasis. (2016)
  • Author(s): Matsumoto T, Suetsugu A, Hasegawa K, Nakamura M, Aoki H, Kunisada T, Tsurumi H, Shimizu M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 36 Pages: 1473-1478
  • Peer Reviewed
• [Journal Article] A mouse model of fluorescent protein-expressing disseminated peritoneal lymphoma for fluorescence-guided surgery. (2016)
  • Author(s): Matsumoto T, Suetsugu A, Hasegawa K, Nakamura M, Shibata Y, Aoki H, Kunisada T, Tsurumi H, Shimizu M, Bouvet M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 36 Pages: 4483-4487
  • Peer Reviewed
• [Journal Article] Imaging nuclear-cytoplasmic dynamics in primary and metastatic colon cancer in nude mice. (2016)
  • Author(s): Hasegawa K, Suetsugu A, Nakamura M, Matsumoto T, Aoki H, Kunisada T, Bouvet M, Shimizu M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 36 Pages: 2113-2117
  • Peer Reviewed
• [Journal Article] Color-coded imaging enables fluorescence-guided surgery to resect the tumor along with the tumor microenvironment in a syngeneic mouse model of EL-4 lymphoma. (2016)
  • Author(s): Hasegawa K, Suetsugu A, Nakamura M, Matsumoto T, Kunisada T, Shimizu M, Saji S, Moriwaki H, Bouvet M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 36 Pages: 4443-4448
  • Peer Reviewed
• [Journal Article] Angiotensin II type I receptor blocker, Losartan, inhibits fibrosis in liver by suppressing TGF-beta1 production. (2016)
  • Author(s): Ogata H, Noguchi H, Ohtsubo T, Liao J, Kohara H, Yamada K, Murahashi M, Hijikata Y, Suetsugu A, Hoffman RM, Tani K.
  • Journal Title: Integr Mol Med Volume: 3 Pages: 520-523
  • Peer Reviewed
• [Journal Article] Rapid skeletal muscle wasting predicts worse survival in patients with liver cirrhosis. (2015)
  • Author(s): Hanai T, Shiraki M, Ohnishi S, Miyazaki T, Ideta T, Kochi T, Imai K, Suetsugu A, Takai K, Moriwaki H, Shimizu M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 8 Pages: 743-751
  • DOI: 10.1111/hepr.12616
  • Peer Reviewed
• [Journal Article] Recruitment of Cancer-Associated Fibroblasts and Blood Vessels by Orthotopic Liver Tumors Imaged in Red Fluorescent Protein (RFP) Transgenic Nude Mice. (2015)
  • Author(s): Suetsugu A, Hiroshima Y, Matsumoto T, Hasagawa K, Nakamura M, Shimizu M, Saji S, Moriwaki H, Bouvet M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 35 Pages: 5821-5825
  • Peer Reviewed
• [Journal Article] Impact of serum glycosylated Wisteria floribunda agglutinin positive Mac-2 binding protein levels on liver functional reserves and mortality in patients with liver cirrhosis. (2015)
  • Author(s): Hanai T, Shiraki M, Ohnishi S, Miyazaki T, Ideta T, Kochi T, Imai K, Suetsugu A, Takai K, Shimizu M, Moriwaki H.
  • Journal Title: Hepatol Res Volume: 45 Issue: 11 Pages: 1083-1090
  • DOI: 10.1111/hepr.12473
  • Peer Reviewed
• [Journal Article] Skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma treated with sorafenib. (2015)
  • Author(s): Imai K, Takai K, Hanai T, Ideta T, Miyazaki T, Kochi T, Suetsugu A, Shiraki M, Shimizu M.
  • Journal Title: Int J Mol Sci Volume: 16 Issue: 5 Pages: 9612-9624
  • DOI: 10.3390/ijms16059612
  • Peer Reviewed
• [Journal Article] A Color-coded Imageable Syngeneic Mouse Model of Stromal-cell Recruitment by Metastatic Lymphoma. (2015)
  • Author(s): Matsumoto T, Suetsugu A, Shibata Y, Nakamura N, Aoki H, Kunisada T, Tsurumi H, Shimizu M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 35 Pages: 4647-54
  • Peer Reviewed
• [Journal Article] Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery. (2015)
  • Author(s): Yano S, Hiroshima Y, Maawy A, Kishimoto H, Suetsugu A, Miwa S, Toneri M, Yamamoto M, Katz MH, Fleming JB, Urata Y, Tazawa H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM.
  • Journal Title: Cancer Gene Ther Volume: 22 Issue: 7 Pages: 344-50
  • DOI: 10.1038/cgt.2015.26
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Imaging the Different Mechanisms of Prostate Cancer Cell-killing by Tumor-targeting Salmonella typhimurium A1-R. (2015)
  • Author(s): Uchugonova A, Zhang Y, Salz R, Liu F, Suetsugu A, Zhang L, Koenig K, Hoffman RM, Zhao M.
  • Journal Title: Anticancer Res Volume: 35 Pages: 5225-9
  • Peer Reviewed
• [Journal Article] Color-Coded Imaging of Breast Cancer-Metastatic Niche Formation in Nude Mice. (2015)
  • Author(s): Suetsugu A, Momiyama M, Hiroshima Y, Shimizu M, Saji S, Moriwaki H, Bouvet M, Hoffman RM.
  • Journal Title: J Cell Biochem Volume: 116 Issue: 12 Pages: 2730-4
  • DOI: 10.1002/jcb.25227
  • Peer Reviewed
• [Journal Article] The Use of Living Cancer Cells Expressing Green Fluorescent Protein in the Nucleus and Red Fluorescence Protein in the Cytoplasm for Real-time Confocal Imaging of Chromosome and Cytoplasmic Dynamics During Mitosis. (2015)
  • Author(s): Suetsugu A, Jiang P, Yang M, Yamamoto N, Moriwaki H, Saji S, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 35 Pages: 2553-2557
  • Peer Reviewed
• [Journal Article] Imaging the Interaction of Pancreatic Cancer and Stellate Cells in the Tumor Microenvironment during Metastasis. (2015)
  • Author(s): Suetsugu A, Snyder CS, Moriwaki H, Saji S, Bouvet M, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 35 Pages: 2545-2551
  • Peer Reviewed
• [Journal Article] 新規肝線維化マーカー「Mac-2 binding protein 糖鎖修飾異性体（M2BPGi）」のＣ型肝炎に対するペグインターフェロン・リバビリン併用療法による変化 (2015)
  • Author(s): 石田秀和、末次 淳、中村真大、田内里奈、中山純里、片野由里子、古田伸行、白上洋平、伊藤弘康、清島 満
  • Journal Title: 臨床病理 Volume: 63 Pages: 901-906
  • NAID: 40020594726
  • Peer Reviewed
• [Journal Article] Sarcopenia impairs prognosis of patients with liver cirrhosis. (2015)
  • Author(s): Hanai T, Shiraki M, Nishimura K, Ohnishi S, Imai K, Suetsugu A, Takai K, Shimizu M, Moriwaki H.
  • Journal Title: Nutrition Volume: 31 Issue: 1 Pages: 193-199
  • DOI: 10.1016/j.nut.2014.07.005
  • Peer Reviewed
• [Journal Article] Skeletal muscle depletion is an independent prognostic factor for hepatocellular carcinoma. (2015)
  • Author(s): Iritani S, Imai K, Takai K, Hanai T, Ideta T, Miyazaki T, Suetsugu A, Shiraki M, Shimizu M, Moriwaki H.
  • Journal Title: J Gastroenterol Volume: 50 Issue: 3 Pages: 323-332
  • DOI: 10.1007/s00535-014-0964-9
  • Peer Reviewed
• [Journal Article] Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness. (2014)
  • Author(s): Yano S, et al.
  • Journal Title: Cell Cycle Volume: 13 Issue: 13 Pages: 2110-2119
  • DOI: 10.4161/cc.29156
  • Peer Reviewed
• [Journal Article] Efficacy of Salmonella typhimurium A1-R Versus Chemotherapy on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX). (2014)
  • Author(s): Hiroshima Y, Zhao M, Maawy A, Zhang Y, Katz MH, Fleming JB, Uehara F, Miwa S, Yano S, Momiyama M, Suetsugu A, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: J Cell Biochem Volume: 115(7) Issue: 7 Pages: 1254-61
  • DOI: 10.1002/jcb.24769
  • Peer Reviewed
• [Journal Article] Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids. (2014)
  • Author(s): Shimizu M, Shirakami Y, Hanai T, Imai K, Suetsugu A, Takai K, Shiraki M, Moriwaki H.
  • Journal Title: Mol Nutr Food Res. Volume: 58 Issue: 1 Pages: 124-135
  • DOI: 10.1002/mnfr.201300538
  • Peer Reviewed
• [Journal Article] 劇症肝炎におけるTNF-αを介したNF-κB活性調節の細胞死および細胞生存シグナルへの影響 (2014)
  • Author(s): 末次 淳, 森脇久隆
  • Journal Title: 肝胆膵 Volume: 68 Pages: 513-518
• [Journal Article] Free fatty acid as a marker of energy malnutrition in liver cirrhosis. (2013)
  • Author(s): Hanai T, Shiraki M, Nishimura K, Imai K, Suetsugu A, Takai K, Shimizu M, Naiki T, Moriwaki H.
  • Journal Title: Hepatol Res. Volume: 44 Issue: 2 Pages: 218-228
  • DOI: 10.1111/hepr.12112
  • Peer Reviewed
• [Presentation] Imaging of colon cancer-cell mitosis within liver metastasis in nude mice. (2016)
  • Author(s): Hasegawa K, Suetsugu A, Nakamura M, Matsumoto T, Aoki H, Kunisada T, Shimizu M, Hoffman RM.
  • Organizer: 107th American Association for Cancer Research (AACR) Annual Meeting
  • Place of Presentation: New Orleans
  • Int'l Joint Research
• [Presentation] Color-coded imaging of the tumor microenvironment of malignant lymphoma in a syngeneic mouse model (2016)
  • Author(s): Matsumoto T, Suetsugu A, Hasegawa K, Nakamura M, Aoki H, Kunisada T, Tsurumi H, Shimizu M, Hoffman RM.
  • Organizer: 107th American Association for Cancer Research (AACR) Annual Meeting
  • Place of Presentation: New Orleans
  • Int'l Joint Research
• [Presentation] Imaging formation of the tumor microenvironment in orthotopic liver tumors in red fluorescent protein (RFP) transgenic nude mice. (2016)
  • Author(s): Suetsugu A, Hiroshima Y, Matsumoto T, Hasegawa K, Nakamura M, Shimizu M, Saji S, Moriwaki H, Bouvet M, Hoffman RM.
  • Organizer: 107th American Association for Cancer Research (AACR) Annual Meeting
  • Place of Presentation: New Orleans
  • Int'l Joint Research
• [Presentation] Ｃ型肝炎ウイルス治療前後の肝線維化マーカー“ELF Score”の検討 (2016)
  • Author(s): 末次 淳, 長谷川恒輔, 華井竜徳, 今井健二, 白木 亮, 高井光治, 石田秀和, 清島 満, 清水雅仁
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] 当院におけるB型肝炎再活性化対策の実態 (2015)
  • Author(s): 今井健二、末次 淳、清水雅仁
  • Organizer: 第41回日本急性肝不全研究会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-20
• [Presentation] Development of a syngeneic metastatic mouse model of malignant lymphoma (2015)
  • Author(s): Takuro Matsumoto, Atsushi Suetsugu, Yuhei Shibata, Nobuhiko Nakamura, Hitomi Aoki ,Takahiro Kunisada, Masahito Shimizu, Hisashi Tsurumi, Robert M. Hoffman
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-21
  • Int'l Joint Research
• [Presentation] Hepatitis B virus reactivation in lymphoma patients with rituximab therapy (2015)
  • Author(s): uetsugu A, Tsurumi H, Shibata Y, Matsumoto T, Nakamura N, Shimizu M, Moriwaki H.
  • Organizer: APASL
  • Place of Presentation: Istanbul
  • Year and Date: 2015-03-13
• [Presentation] Imaging exosome transfer from colon cancer cells to stroma at liver metastatic sites (2014)
  • Author(s): Suetsugu A, Homma K, Saji S, Moriwaki H, Osawa Y, Ochiya T, Robert M. Hoffman
  • Organizer: APDW
  • Place of Presentation: bali
  • Year and Date: 2014-11-24
• [Presentation] Color-coded chemotherapy: S/G2-phase-trapping by methioninase pre-treatment, indicated by FUCCI imaging, enables highly effective cancer chemotherapy. (2014)
  • Author(s): Yano S, Tome Y, Michelle Digman, Momiyama M, Suetsugu A, Enrico Gratton, Robert Hoffman.
  • Organizer: Experimental Biology 2014 FASEB J
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-26
• [Presentation] Real-time FUCCI imaging of cell cycle phase in tumors demonstrates why cancer chemotherapy is not effective in solid cancers (2014)
  • Author(s): Yano S, Tome Y, Yong Zhang, Hiroshima Y, Miwa S, Uehara F, Suetsugu A, Kishimoto H, Tazawa H, Ming Zhao, Fujiwara T, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-09
• [Presentation] elomerase-specific GFP-expressing adenovirus enables fluorescence-guided surgery (FGS) for patient-derived orthotopic xenograft (PDOX) in nude mice (2014)
  • Author(s): Yano S, Hiroshima Y, Ali Maawy, Matthew H.G. Katz, Jason B. Fleming, Kishimoto H, Suetsugu A, Uehara F, Miwa S, Tazawa H, Michael Bouvet, Fujiwara T, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-07
• [Presentation] Real-time imaging of exosomes dynamic of cross-talking and cell trafficking in 3D Gelfoam® histoculture. (2014)
  • Author(s): Yamamoto M, Miwa S, Hiroshima Y, Yano S, Uehara F, Matsumoto Y, Suetsugu A, Kimi Homma, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-07
• [Presentation] Imaging of stromal cells during hepatocellular metastasis formation in the RFP-MUP-uPA mouse. (2014)
  • Author(s): Suetsugu A, Ogata H, Hiroshima Y, Momiyama M, Osawa Y, Moriwaki H, Saji S, Michael Karin, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-06
• [Book] 消化器病診療第2版 (2014)
  • Author(s): 末次 淳，森脇久隆．
  • Total Pages: 528
  • Publisher: 医学書院