Color-coded intravital imaging demonstrates a transforming growth factor B antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model

• Project/Area Number: 26830081
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Yokohama City University
• Principal Investigator: HIROSHIMA Yukihiko 横浜市立大学, 医学研究科, 客員研究員 (60718021)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 膵癌 / 微小環境 / マウスモデル / 蛍光イメージング / SMAD4 / TGFーβ / 間質 / TGFβ / プロテオーム解析 / realtime imaging / PDX

Outline of Final Research Achievements

The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-β inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The PDOX, which has a high TGF-β expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-β receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells was significantly decreased in the TGF-β-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in Fluorescent-PDOX mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-β inhibitor.

Research Products

• [Journal Article] Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model. (2017)
  • Author(s): Murakami T, Hiroshima Y, Miyake K, Hwang HK, Kiyuna T, DeLong JC, Lwin TM, Matsuyama R, Mori R, Kumamoto T, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: Cell Cycle Volume: 25 Issue: 10 Pages: 1-7
  • DOI: 10.1080/15384101.2017.1315489
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. (2017)
  • Author(s): Murakami T, Li S, Han Q, Tan Y, Kiyuna T, Igarashi K, Kawaguchi K, Hwang HK, Miyake K, Singh AS, Nelson SD, Dry SM, Li Y, Hiroshima Y, Lwin TM, DeLong JC, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM.
  • Journal Title: Oncotarget Volume: Epub ahead of print Issue: 22 Pages: 35630-35638
  • DOI: 10.18632/oncotarget.15823
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy. (2016)
  • Author(s): Hiroshima Y, Maawy A, Zhang Y, Zhang N, Murakami T, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: Oncotarget Volume: 7 Pages: 71696-71702
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effective fluorescence-guided surgery of liver metastasis using a fluorescent anti-CEA antibody. (2016)
  • Author(s): Hiroshima Y, Lwin TM, Murakami T, Mawy AA, Kuniya T, Chishima T, Endo I, Clary BM, Hoffman RM, Bouvet M.
  • Journal Title: J Surg Oncol. Volume: 114 Issue: 8 Pages: 951-958
  • DOI: 10.1002/jso.24462
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Patient-derived orthotopic xenograft (PDOX) nude mouse model of soft-tissue sarcoma more closely mimics the patient behavior in contrast to the subcutaneous ectopic model. (2015)
  • Author(s): Hiroshima Y, Zhang Y, Zhang N, Uehara F, Maawy A, Murakami T, Mii S, 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: Anticancer Res. Volume: 35 Pages: 697-701
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of a patient-derived orthotopic Xenograft (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern. (2015)
  • Author(s): Hiroshima Y, Zhang Y, Zhang N, Maawy A, Mii S, Yamamoto M, Uehara F, Miwa S, Yano S, Murakami T, Momiyama M, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Murata T, Endo I, Hoffman RM.
  • Journal Title: PLoS One. Volume: 10 Issue: 2 Pages: e0117417-e0117417
  • DOI: 10.1371/journal.pone.0117417
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Fluorescence-guided surgery, but not bright-light surgery, prevents local recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) model resistant to neoadjuvant chemotherapy (NAC). (2015)
  • Author(s): Hiroshima Y, Maawy A, Zhang Y, Murakami T, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Endo I, Hoffman RM, Bouvet M.
  • Journal Title: Pancreatology Volume: 15 Issue: 3 Pages: 295-301
  • DOI: 10.1016/j.pan.2015.02.008
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Photoimmunotherapy Inhibits Tumor Recurrence After Surgical Resection on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model. (2015)
  • Author(s): Hiroshima Y, Maawy A, Zhang Y, Guzman MG, Heim R, Makings L, Luiken GA, Kobayashi H, Tanaka K, Endo I, Hoffman RM, Bouvet M.
  • Journal Title: Ann Surg Oncol. Volume: 22 Issue: S3 Pages: 1469-1474
  • DOI: 10.1245/s10434-015-4553-9
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models. (2015)
  • Author(s): Hiroshima Y, Zhang Y, Zhao M, Zhang N, Murakami T, Maawy A, 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 Issue: 6 Pages: e0120358-e0120358
  • DOI: 10.1371/journal.pone.0120358
  • Peer Reviewed / Open Access / 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 Issue: 8 Pages: e0134324-e0134324
  • DOI: 10.1371/journal.pone.0134324
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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 Issue: 39 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 Issue: 10 Pages: e0138752-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 Issue: 31 Pages: 31368-31377
  • DOI: 10.18632/oncotarget.5187
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Improved disease-free survival and overall survival after fluorescence-guided surgery of liver metastasis in an orthotopic nude mouse model. (2015)
  • Author(s): Murakami T, Hiroshima Y, Zhang Y, Bouvet M, Chishima T, Tanaka K, Endo I, Hoffman RM.
  • Journal Title: J Surg Oncol. Volume: 112 Issue: 2 Pages: 119-124
  • DOI: 10.1002/jso.23986
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer. (2015)
  • Author(s): Hiroshima Y, Maawy AA, Katz MH, Fleming JB, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: J Surg Oncol. Volume: 111(3) Issue: 3 Pages: 311-5
  • DOI: 10.1002/jso.23816
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metastatic Recurrence in a Pancreatic Cancer Patient Derived Orthotopic Xenograft (PDOX) Nude Mouse Model Is Inhibited by Neoadjuvant Chemotherapy in Combination with Fluorescence-Guided Surgery with an Anti-CA 19-9-Conjugated Fluorophore. (2014)
  • Author(s): Hiroshima Y, Maawy A, Zhang Y, Murakami T, Momiyama M, Mori R, Matsuyama R, Katz MH, Fleming JB, Chishima T, Tanaka K, Ichikawa Y, Endo I, Hoffman RM, Bouvet M.
  • Journal Title: PLoS One. Volume: 2;9(12) Issue: 12 Pages: e114310-e114310
  • DOI: 10.1371/journal.pone.0114310
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX) and cell line mouse models. (2014)
  • Author(s): Hiroshima Y, Zhang Y, Murakami T, Maawy A, Miwa S, Yamamoto M, Yano S, Sato S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Zhao M, Hoffman RM.
  • Journal Title: Oncotarget. Volume: 15;5(23) Pages: 12346-57
  • Peer Reviewed / Acknowledgement Compliant
• [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] The tumor-educated-macrophage increase of malignancy of human pancreatic cancer is prevented by zoledronic acid. (2014)
  • Author(s): Hiroshima Y, Maawy A, Hassanein MK, Menen R, Momiyama M, Murakami T, Miwa S, Yamamoto M, Uehara F, Yano S, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: PLoS One. Volume: 12;9(8) Issue: 8 Pages: e103382-e103382
  • DOI: 10.1371/journal.pone.0103382
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fluorescence-guided surgery in combination with UVC irradiation cures metastatic human pancreatic cancer in orthotopic mouse models. (2014)
  • Author(s): Hiroshima Y, Maawy A, Zhang Y, Sato S, Murakami T, Yamamoto M, Uehara F, Miwa S, Yano S, Momiyama M, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM.
  • Journal Title: PLoS One. Volume: 12;9(6) Issue: 6 Pages: e99977-e99977
  • DOI: 10.1371/journal.pone.0099977
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Transforming growth factor-beta (TGF-β) inhibitor modulates cancer stroma in a pancreatic cancer orthotopic mouse model (2017)
  • Author(s): Takashi Murakami, Yukihiko Hiroshima, Kentaro Miyake, Tasuku Kiyuna, Ho Kyoung Hwang, Kei Kawaguchi, Jonathan C. DeLong, Thinzer M. Lwin, Kentaro Igarashi, Ryusei Matsuyama, Ryutaro Mori, Takafumi Kumamoto, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: Washington, D.C., USA
  • Year and Date: 2017-04-01
  • Int'l Joint Research
• [Presentation] Tumor-targeting Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in pancreatic cancer in an orthotopic syngeneic mouse model (2016)
  • Author(s): Takashi Murakami, Yukihiko Hiroshima, Yong Zhang, Ming Zhao, Tasuku Kiyuna, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • 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): Imaging formation of the tumor microenvironment in orthotopic liver tumors in red fluorescent protein (RFP) transgenic nude mice
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Tumor-targeting Salmonella typhimurium A1-R efficacy on colon cancer liver metastasis alone and in combination with fluorescence-guided surgery (2016)
  • Author(s): Takashi Murakami, Yukihiko Hiroshima, Yong Zhang, Ming Zhao, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, MIchael Bouvet, Itaru Endo, Robert M. Hoffman.
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • 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
  • Int'l Joint Research
• [Presentation] Efficacy of photo-immunotherapy in combination with surgical resection on a pancreatic cancer patient derived orthotopic xenograft (PDOX) (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
  • Int'l Joint Research
• [Presentation] Fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore in combination with neoadjuvant chemotherapy inhibits metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model (2015)
  • Author(s): Yukihiko Hiroshima1, Ali Maawy2, Yong Zhang3, Takashi Murakami4, Masashi Momiyama4, Ryutaro Mori4, Ryusei Matsuyama4, Matthew H. Katz5, Jason B. Fleming5, Takashi Chishima4, Kuniya Tanaka4, Yasushi ichikawa4, Itaru Endo4, Robert M. Hoffman6, Michael Bouvet
  • Organizer: 米国癌学会（AACR annual meeting 2015）
  • Place of Presentation: Philadelphia、米国
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Efficacy of photo-immunotherapy in combination with surgical resection on a pancreatic cancer patient derived orthotopic xenograft (PDOX) (2015)
  • Author(s): Yukihiko Hiroshima1, Ali Maawy2, Takashi Murakami1, Nzola De Magalhães2, Daisuke Kawaguchi3, Kenichi Matsuo3, Kuniya Tanaka3, Michael Bouvet2, Robert M. Hoffman2, Itaru Endo1.
  • Organizer: 米国癌学会（AACR annual meeting 2015）
  • Place of Presentation: Philadelphia、米国
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] The correlation between the change of future remnant liver 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): Daisuke Kawaguchi1, Yukihiko Hiroshima1, Takashi Murakami1, Kenichi Matsuo1, Chihiro Kosugi1, Kiyohiko Syuto1, Akimitsu Yamada2, Itaru Endo2, Keiji Koda1, Kuniya Tanaka
  • Organizer: 米国癌学会（AACR annual meeting 2015）
  • Place of Presentation: Philadelphia、米国
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models (2015)
  • Author(s): Yukihiko Hiroshima1, Ali Maawy2, Yong Zhang1, Sho Sato3, Takashi Murakami1, Mako Yamamoto1, Fuminari Uehara1, Shinji Miwa1, Shuya Yano1, Masashi Momiyama3, Takashi Chishima3, Kuniya Tanaka3, Michael Bouvet2, Itaru Endo3, Robert M. Hoffman
  • Organizer: 米国癌学会（AACR annual meeting 2015）
  • Place of Presentation: Philadelphia、米国
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] luorescence-guided surgery of liver metastasis in orthotopic nude-mouse models (2015)
  • Author(s): Takashi Murakami1, Yukihiko Hiroshima1, Shinji Miwa1, Yano Shuya1, Makoto Toneri1, Mako Yamamoto1, Masashi Momiyama2, Takashi Chishima2, Kuniya Tanaka2, Michael Bouvet1, Satoshi Hasegawa2, Itaru Endo2, Robert M. Hoffman
  • Organizer: 米国癌学会（AACR annual meeting 2015）
  • Place of Presentation: Philadelphia、米国
  • Year and Date: 2015-04-18 – 2015-04-22