Morphological analysis of the mechanisms of organ-specific metastasis using intravital multiphoton microscopy

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659646
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Mie University
• Principal Investigator: MORIMOTO Yuhki 三重大学, 大学院・医学系研究科, リサーチアソシエイト (30586764)
• Co-Investigator(Kenkyū-buntansha): TANAKA Koji 三重大学, 医学部附属病院, 講師 (10345986) ; TOIYAMA Yuji 三重大学, 大学院・医学系研究科, 助教 (00422824) ; INOUE Yasuhiro 三重大学, 医学部附属病院, 講師 (20324535) ; MIZOGUCHI Akira 三重大学, 大学院・医学系研究科, 教授 (90181916) ; KUSUNOKI Masato 三重大学, 大学院・医学系研究科, 教授 (50192026)
• Project Period (FY): 2011 – 2012
• Keywords: 小腸大腸肛門外科学

Research Abstract

We visualized the interactions between cancer cells and stromal cells in tumor microenvironment with regard to ‘organ-specific metastasis, and in vivo real-time chemotherapy response for metastatic tumor xenografts using intravital TPLSM. Cancer cells were arrested within hepatic sinusoids after intrasplenic cancer cell injection. Platelet aggregation surrounding a cancer cell was observed, indicating a phenomenon of tumor-cell induced platelet aggregation (TCIPA). Cancer cells were extravasated from hepatic sinusoids to the space of Disse. Protrusions of Kupffer cells surrounding a cancer cell were observed, indicating that Kupffer cells appear to phagocytose cancer cells. After 5-fluorouracil (5-FU) or irinotecan chemotherapy, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed. The platelet aggregation and the relatively decreased blood flow in the tumor vessels of colorectal liver metastases were also observed. 5-FU administration prior to the intrasplenic injection of cancer cells didn’t influence the adhesion of cancer cells to endothelial cells of hepatic sinusoids. We didn’t establish a liver metastasis model in subcutaneous tumor bearing mice because of the faster growth of subcutaneous tumor than liver metastatic tumor.

Research Products

• [Journal Article] Leucine-rich repeat-containing G protein-coupled receptor 5 expression in ductular reactions after chemotherapy for metastatic colorectal cancer (2013)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Uchida K, Inoue Y, Mohri Y, Kusunoki M
  • Journal Title: Hepatol Res Volume: 43 Pages: 84-90
  • Peer Reviewed
• [Journal Article] Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer (2013)
  • Author(s): Okugawa Y, Tanaka K, Inoue Y, Kawamura M, Kawamoto A, Hiro J, Saigusa S, Toiyama Y, Ohi M, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Br J Cancer Volume: 108 Pages: 121-30
  • Peer Reviewed
• [Journal Article] Smad interacting protein 1 (SIP1) is associated with peritoneal carcinomatosis in intestinal type gastric cancer (2013)
  • Author(s): Okugawa Y, Inoue Y, Tanaka K, Kawamura M, Saigusa S, Toiyama Y, Ohi M, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Clin Exp Metastasis Volume: 30 Pages: 417-29
  • Peer Reviewed
• [Journal Article] Macrophage inflammatory protein-3 alpha (MIP-3a) is a novel serum prognostic marker in patients with colorectal cancer (2013)
  • Author(s): Iwata T, Tanaka K, Inoue Y, Toiyama Y, Hiro J, Fujikawa H, Okugawa Y, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: J Surg Oncol Volume: 107 Pages: 160-6
  • Peer Reviewed
• [Journal Article] Intravital imaging of gastrointestinal diseases in preclinical models using two-photon laser scanning microscopy (2013)
  • Author(s): Tanaka K, Toiyama Y, Inoue Y, Uchida K, Araki T, Mohri Y, Mizoguchi A, Kusunoki M
  • Journal Title: Surg Today Volume: 43 Pages: 123-9
  • Peer Reviewed
• [Journal Article] Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy (2012)
  • Author(s): Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Hiro J, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Int J Oncol Volume: 41 Pages: 1643-52
  • Peer Reviewed
• [Journal Article] In vivo real-time imaging of chemotherapy response on the liver metastatic tumor microenvironment using multiphoton microscopy (2012)
  • Author(s): Tanaka K, Okigami M, Toiyama Y, Morimoto Y, Matsushita K, Kawamura M, Hashimoto K, Saigusa S, Okugawa Y, Inoue Y, Uchida K, Araki T, Mohri Y,Mizoguchi A, Kusunoki M
  • Journal Title: Oncol Rep Volume: 28 Pages: 1822-30
  • Peer Reviewed
• [Journal Article] Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy (2012)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Hiro J, Inoue Y, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Oncol Rep Volume: 28 Pages: 855-61
  • Peer Reviewed
• [Journal Article] High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells (2012)
  • Author(s): Fujikawa H, Tanaka K, Toiyama Y, Saigusa S, Inoue Y, Uchida K, Kusunoki M
  • Journal Title: J Gastroenterol Volume: 47 Pages: 775-84
  • Peer Reviewed
• [Journal Article] Okugawa Y, Toiyama Y, Inoue Y, Iwata T, Fujikawa H, Saigusa S, Konishi N, Tanaka K, Uchida K, Kusunoki M (2012)
  • Author(s): Okugawa Y, Toiyama Y, Inoue Y, Iwata T, Fujikawa H, Saigusa S, Konishi N, Tanaka K, Uchida K, Kusunoki M
  • Journal Title: J Surg Res Volume: 175 Pages: e67-73
  • Peer Reviewed
• [Journal Article] CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer (2012)
  • Author(s): Kawamura M, Toiyama Y, Tanaka K, Saigusa S, Okugawa Y, Hiro J, Uchida K, Mohri Y, Inoue Y, Kusunoki M
  • Journal Title: Eur J Cancer Volume: 48 Pages: 2244-51
  • Peer Reviewed
• [Journal Article] In vivo time-course imaging of tumor angiogenesis in colorectal liver metastases in the same living mice using two-photon laser scanning microscopy (2012)
  • Author(s): Tanaka K, Morimoto Y, Toiyama Y, Matsushita K, Kawamura M, Koike Y, Okugawa Y, Inoue Y, Uchida K, Araki T, Mizoguchi A, Kusunoki M
  • Journal Title: J Oncol Volume: 2012 Pages: 265487
  • Peer Reviewed
• [Journal Article] Evaluation of CXCL10 as a novel serum marker for predicting liver metastasis and prognosis in colorectal cancer (2012)
  • Author(s): Toiyama Y, Fujikawa H, Kawamura M, Matsushita K, Saigusa S, Tanaka K, Inoue Y, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Int J Oncol Volume: 40 Pages: 560-6
  • Peer Reviewed
• [Journal Article] TS and DPD mRNA levels on formalin-fixed paraffin-embedded specimens as predictors for distant recurrence of rectal cancer treated with preoperative chemoradiotherapy (2012)
  • Author(s): Tanaka K, Saigusa S, Toiyama Y, Koike Y, Okugawa Y, Yokoe T, Inoue Y, Kobayashi M, Miki C, Kusunoki M
  • Journal Title: J Surg Oncol Volume: 105 Pages: 529-34
  • Peer Reviewed
• [Journal Article] Radiation induces epithelial-mesenchymal transition in colorectal cancer cells (2012)
  • Author(s): Kawamoto A, Yokoe T, Tanaka K, Saigusa S, Toiyama Y, Yasuda H, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Oncol Rep Volume: 27 Pages: 51-7
  • Peer Reviewed
• [Journal Article] Inhibition of HGF/cMET expression prevents distant recurrence of rectal cancer after preoperative chemoradiotherapy (2012)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Yokoe T, Fujikawa H, Matsushita K, Okugawa Y, Inoue Y, Uchida K, Mohri Y, Kusunoki M
  • Journal Title: Int J Oncol Volume: 40 Pages: 583-91
  • Peer Reviewed
• [Journal Article] Soluble CXCL16 in preoperative serum is a novel prognostic marker and predicts recurrence of liver metastases in colorectal cancer patients (2012)
  • Author(s): Matsushita K, Toiyama Y, Tanaka K, Saigusa S, Hiro J, Uchida K, Inoue Y, Kusunoki M
  • Journal Title: Ann Surg Oncol Volume: 19 Pages: S518-27
  • Peer Reviewed
• [Journal Article] Intravital dual-colored visualization of colorectal liver metastasis in living mice using two photon laser scanning microscopy (2012)
  • Author(s): Tanaka K, Morimoto Y, Toiyama Y, Okugawa Y, Inoue Y, Uchida K, Kimura K, Mizoguchi A, Kusunoki M
  • Journal Title: Microsc Res Tech Volume: 75 Pages: 307-15
  • Peer Reviewed
• [Journal Article] Clinical significance of radiation-induced CD133 expression in residual rectal cancer cells after chemoradiotherapy (2012)
  • Author(s): Kawamoto A, Tanaka K, Saigusa S, Toiyama Y, Morimoto Y, Fujikawa H, Iwata T, Matsushita K, Yokoe T, Yasuda H, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Exp Ther Med Volume: 3(3) Pages: 403-409
  • Peer Reviewed
• [Journal Article] Intravital three-dimensional dynamic pathology of experimental colitis in living mice using two-photon laser scanning microscopy (2011)
  • Author(s): Morimoto Y, Tanaka K, Toiyama Y, Inoue Y, Araki T, Uchida K, Kimura K, Mizoguchi A, Kusunoki M
  • Journal Title: J Gastrointest Surg Volume: 15 Pages: 1842-50
  • Peer Reviewed
• [Journal Article] In vivo real-time two-photon microscopic imaging of platelet aggregation induced by selective laser irradiation to the endothelium created in the beta-actin-green fluorescent protein transgenic mice (2011)
  • Author(s): Koike Y, Tanaka K, Okugawa Y, Morimoto Y, Toiyama Y, Uchida K, Miki C, Mizoguchi A, Kusunoki M
  • Journal Title: J Thromb Thrombolysis Volume: 32 Pages: 138-45
  • Peer Reviewed
• [Journal Article] Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy (2011)
  • Author(s): Saigusa S, Toiyama Y, Tanaka K, Yokoe T, Okugawa Y, Fujikawa H, Matsusita K, Kawamura M, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Int J Oncol Volume: 38 Pages: 655-63
  • Peer Reviewed
• [Journal Article] Evaluation of an inflammation-based prognostic score for the identification of patients requiring postoperative adjuvant chemotherapy for stage II colorectal cancer (2011)
  • Author(s): Toiyama Y, Miki C, Inoue Y, Tanaka K, Mohri Y, Kusunoki M
  • Journal Title: Exp Ther Med Volume: 2 Pages: 95-101
  • Peer Reviewed
• [Journal Article] Clinical significance of CD133 and hypoxia inducible factor-1α gene expression in rectal cancer after preoperative chemoradiotherapy (2011)
  • Author(s): Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Koike Y, Fujikawa H, Inoue Y, Miki C, Kusunoki M
  • Journal Title: Clin Oncol (R Coll Radiol) Volume: 23 Pages: 323-32
  • Peer Reviewed
• [Presentation] In vivo real-time imaging of tumor microcirculatory alterations in colorectal liver metastatic xenografts by chemotherapy using multiphoton microscopy. J Clin Oncol 30, 2012 (suppl; abstr e21053) (2012)
  • Author(s): Koji Tanaka, Masato Okigami, Yuji Toiyama, Yuhki Morimoto, Kohei Matsushita, Mikio Kawamura, Kiyoshi Hashimoto, Susumu Saigusa, Yoshinaga Okugawa, Junichiro Hiro, Yasuhiro Inoue, Keiichi Uchida, Toshimitsu Araki, Yasuhiko Mohri, Akira Mizoguchi, Masato Kusunoki
  • Organizer: 2012 ASCO Annual Meeting
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 20120601-05
• [Presentation] Time-series assessment of 5-fluorouracil efficacy on murine colorectal liver metastasis model using intravital multiphoton microscopy (2432) (2012)
  • Author(s): Koji Tanaka, Masato Okigami, Yuhki Morimoto, Kohei Matsushita, Mikio Kawamura, Kiyoshi Hashimoto, Yuji Toiyama, Susumu Saigusa, Yoshinaga Okugawa, Yuhki Koike, Yasuhiro Inoue, Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Akira Mizoguchi, Masato Kusunoki.
  • Organizer: AACR 103rdAnnual Meeting
  • Place of Presentation: Chicago Illinois
  • Year and Date: 20120331-0404
• [Presentation] Intravital assessment of infliximab efficacy in murine ulcerative colitis model using two photon laser scanning microscopy (P-76) (2012)
  • Author(s): Kohei Matsushita, Koji Tanaka, Yuhki Morimoto, Masato Okigami, Mikio Kawamura, Kiyosi Hashimoto, Susumu Saigusa, Yuji Toiyama, Yuuki Koike, Yoshinaga Okugawa, Yasuhiro Inoue, Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Akira Mizoguchi, and Masato Kusunoki
  • Organizer: The 6th Korea-Japan IBD Symposium
  • Place of Presentation: Keio Plaza Hotel Tokyo
  • Year and Date: 2012-01-28
• [Presentation] Intravital evaluation of time-course efficacy of anticancer drugs on colorectal liver metastases in the same living mice using two-photon laser scanning microscopy. J Clin Oncol 29: 2011 (suppl; abstr 10621) (2011)
  • Author(s): K. Tanaka, Y. Morimoto, Y. Toiyama, S. Saigusa, Y. Okugawa, Y. Inoue, K. Uchida, K. Matsushita, M. Kawamura, A. Mizoguchi, M. Kusunoki
  • Organizer: 2011 ASCO Annual Meeting
  • Place of Presentation: Chicago, Illinois
  • Year and Date: 20110601-05
• [Presentation] Intravital dual-colored visualization of colorectal liver metastasis formation in the living mice using two photon laser scanning microscopy (5278) (2011)
  • Author(s): Koji Tanaka, Yuhki Morimoto, Kohei Matsushita, Mikio Kawamura, Yuji Toiyama, Susumu Saigusa, Yoshinaga Okugawa, Yuhki Koike, Yasuhiro Inoue, Chikao Miki, Akira Mizoguchi, Masato Kusunoki.
  • Organizer: AACR 102ndAnnual Meeting 2011
  • Place of Presentation: Orlando, Florida
  • Year and Date: 20110402-06