Functional intravital imaging of tumor-associated macrophages in tumor microenvironment

• Project/Area Number: 26830070
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kansai Medical University (2016); Kyoto University (2014-2015)
• Principal Investigator: KAMIOKA Yuji 関西医科大学, 医学部, 講師 (50511424)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 生体蛍光イメージング / FRET / 癌微小環境 / 好中球 / マクロファージ / 生体イメージング / 蛍光

Outline of Final Research Achievements

Tumor microenvironment (TME) consists of complex interactions between tumor cells and stroma cells. In this project, cellular behaviors and activity of ERK in TME of tumor-bearing mice were investigated by intravital Fluorescence Resonance Energy Transfer (FRET) imaging with two-photon excitation microscope. Initially, we focused on tumor associated macrophages (TAM) in TEM, however, neutrophils in TME showed more important relationship with tumor cells than TAM in our model. Our results showed that osteopontin secreted from 4T1 mouse breast tumor cell induced cell aggregation followed by ERK activation in neutrophils and neutrophil-specific cell death NETosis. In agreement with previous reports, NETosis inhibitor DNase I inhibited lung metastasis of 4T1 cells. These observations suggest that osteopontin promotes metastasis of 4T1 cells by activating neutrophils and inducing NETosis.

Research Products

• [Journal Article] Intravital Forster resonance energy transfer imaging reveals osteopontin‐mediated polymorphonuclear leukocyte activation by tumor cell emboli (2017)
  • Author(s): Yuji Kamioka, Kanako Takakura, Kenta Sumiyama, Michiyuki Matsuda
  • Journal Title: Cancer Science Volume: 108(2) Issue: 2 Pages: 226-235
  • DOI: 10.1111/cas.13132
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Live imaging of TAK1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyI:C. (2016)
  • Author(s): Takaoka S, Kamioka Y, Takakura K, Baba A, Shime H, Seya T, Matsuda M
  • Journal Title: Cancer Science Volume: Epub ahead of print Issue: 5 Pages: 644-652
  • DOI: 10.1111/cas.12923
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Circuit-dependent striatal PKA and ERK signaling underlies rapid behavioral shift in mating reaction of male mice. (2015)
  • Author(s): Goto A, Nakahara I, Yamaguchi T, Kamioka Y, Sumiyama K, Matsuda M, Nakanishi S, Funabiki K
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: １１２ Issue: 21 Pages: 6718-6723
  • DOI: 10.1073/pnas.1507121112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intercellular propagation of extracellular signal-regulated kinase activation revealed by in vivo imaging of mouse skin. (2015)
  • Author(s): Hiratsuka T, Fujita Y, Naoki H, Aoki K, Kamioka Y, Matsuda M
  • Journal Title: eLife Volume: - Pages: 1-18
  • DOI: 10.7554/elife.05178
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PKA modulation of Rac in neuronal cells. (2014)
  • Author(s): Goto, A., Kamioka, Y., and Matsuda, M.
  • Journal Title: Frontiers in cellular neuroscience Volume: 8 Pages: 321-321
  • DOI: 10.3389/fncel.2014.00321
  • NAID: 120005512243
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines. (2014)
  • Author(s): Mizuno, R., Kamioka, Y., Kabashima, K., Imajo, M., Sumiyama, K., Nakasho, E., Ito, T., Hamazaki, Y., Okuchi, Y., Sakai, Y., Kiyokawa, E., and Matsuda, M.
  • Journal Title: J Exp Med Volume: 211 Issue: 6 Pages: 1123-36
  • DOI: 10.1084/jem.20132112
  • NAID: 120005439165
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Intravital FRET imaging of tumor metastasis and neovascularization 癌転移と血管新生の生体FRET イメージング (2014)
  • Author(s): Yuji Kamioka, Fumio Yamauchi, Michiyuki Matsuda
  • Organizer: 第73回日本癌学会学術総会 The 73rd Annual meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Book] がんの分子イメージング (2015)
  • Author(s): 浦野泰照 編
  • Total Pages: 269
  • Publisher: 化学同人
• [Remarks] 京都大学大学院医学研究科 病態生物医学講座
  • URL: http://www.fret.lif.kyoto-u.ac.jp/publist.htm
• [Remarks] 蛍光生体イメージング室
  • URL: http://support-center.med.kyoto-u.ac.jp/SupportCenter/room04
• [Remarks] 京都大学大学院医学研究科病態生物医学講座
  • URL: http://support-center.med.kyoto-u.ac.jp/SupportCenter/room04