Fragmented hyaluronan is an autocrine factor potentiating cancer cell invasion supported by HAS2 -CD44/hyaluronidase-2 system on the plasma membrane

• Project/Area Number: 22390074
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Chiba University
• Principal Investigator: HARIGAYA Kenichi 千葉大学, 大学院・医学研究院, 教授 (40101894)
• Co-Investigator(Kenkyū-buntansha): KITAGAWA Motoo 千葉大学, 大学院・医学研究院, 准教授 (40262026)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2012: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
• Keywords: 癌浸潤・転移、CD44 / 上皮-間葉転換(EMT) / ヒアルロン酸、がん治療 / CD44 / ヒアルロン酸 / RanBPM / hMena / EMT / CD44核内移行 / 癌幹細胞 / がん治療 / 腫瘍浸潤・転移 / RTK / EGFR

Research Abstract

Here we show that fragmented 23 kDa HA elicits enhanced cell motility and changes the shape of epithelial cells. Our study also indicates that hyaluronidase-2-mediated catabolism could play a significant role in the generation of LMWHA (about 20 kDa) with the association of CD44 in epithelial cells. This indicates the possibility that fragmented HA acts as a mediator in the autocrine/paracrine mechanism. Our study showed that signals initiated by LMWHA-CD44 interactions induce the phenotypes of cancer cells undergoing epithelial-mesenchymal transition (EMT), expanding our understanding of the functions of HA in cancer cell biology.

Research Products

• [Journal Article] Charac- terization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma (2012)
  • Author(s): Jujo T, Sakao S, Kantake M, Maruoka M, Tanabe N, Kasahara Y, Kurosu K, Masuda M, Harigaya K, Tatsumi K
  • Journal Title: Int J Oncol Volume: 41(2) Pages: 701-11
  • Peer Reviewed
• [Journal Article] Interleukin 6 mediates production of interleukin 10 in metastatic melanoma (2012)
  • Author(s): Terai M, Eto M, Young GD, Berd D, Mastrangelo MJ, Tamura Y, Harigaya K, Sato T
  • Journal Title: Cancer Immunol Immunother Volume: 61 Pages: 145-55
  • Peer Reviewed
• [Journal Article] Characterization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma. (2012)
  • Author(s): Jujo T, Sakao S, Kantake M, Maruoka M, Tanabe N, Kasahara Y, Kurosu K, Masuda M, Harieava K, Tatsumi K
  • Journal Title: Int J Oncol. Volume: 41 Issue: 2 Pages: 701-711
  • DOI: 10.3892/ijo.2012.1493
  • Peer Reviewed
• [Journal Article] Interleukin 6 mediates production of interleukin 10 in metastatic melanoma. (2012)
  • Author(s): Terai M, Eto M, Young GD, Berd D, Mastrangelo MJ, Tamura Y, Harieava K, Sato T
  • Journal Title: Cancer Immunol Immunother Volume: 61 Issue: 2 Pages: 145-155
  • DOI: 10.1007/s00262-011-1084-5
  • Peer Reviewed
• [Journal Article] Interleukin 6 mediates production of interleukin 10 in metastatic melanoma (2012)
  • Author(s): Terai M, Harigaya K
  • Journal Title: Cancer Immunol Immunother Volume: 61(2) Pages: 145-55
  • Peer Reviewed
• [Journal Article] Fragmented hyaluronan is an autocrine chemokinetic motility factor supported by theHAS2-HYAL2/CD44 system on the plasma membrane (2011)
  • Author(s): Saito T, Kawana H, Azuma K,Toyoda,A,Fujita H, Kitagawa M, Harigaya K
  • Journal Title: Int J Oncol Volume: 39(5) Pages: 1311-20
  • Peer Reviewed
• [Journal Article] Overexpression of human ortholog of mammalian enabled (hMena) is associated with the expression of mutant p53 protein in human breast cancers (2011)
  • Author(s): Toyoda A, Yokota A, Saito T, Kawana H, Higashi M, Suzuki Y, Tanaka T, Kitagawa M, Harigaya K
  • Journal Title: Int J Oncol Volume: 38(1) Pages: 89-96
  • Peer Reviewed
• [Journal Article] Mastermind-like 1 (MamL1) andmastermind-like 3 (MamL3) are essential forNotch signaling in vivo (2011)
  • Author(s): Oyama T, Harigaya K, Sasaki N, Okamura Y, Kokubo H, Saga Y, Hozumi K, Suganami A, Tamura Y, Nagase T, Koga H, Nishimura M, Sakamoto R, Sato M, Yoshida N, Kitagawa M
  • Journal Title: Development Volume: 138 Pages: 5235-46
  • Peer Reviewed
• [Journal Article] Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo (2011)
  • Author(s): Oyama T, Harigaya K
  • Journal Title: Development Volume: 138(23) Pages: 5235-46
  • Peer Reviewed
• [Journal Article] Fragmented hyaluronan is an autocrine chemokinetic motility factor supported by the HAS2-HYAL2/CD44 system on the plasma membrane (2011)
  • Author(s): Saito T, Harigaya K
  • Journal Title: Int J Oncol Volume: 39(5) Pages: 1311-20
  • Peer Reviewed
• [Journal Article] Overexpression of human ortho log of mammalian enabled (hMena) is associated with the expression of mutant p53 protein in human breast cancers. (2011)
  • Author(s): Toyoda A, Harigaya K
  • Journal Title: Int J Oncol. Volume: 38(1) Pages: 89-96
  • Peer Reviewed
• [Journal Article] Visualization of the Activity of Rac1Small GTPase in a Cell (2010)
  • Author(s): Higashi M, Yu J, Tsuchiya H, Saito T, Oyama T, Kawana H, Kitagawa M, Tamaru J, Harigaya K
  • Journal Title: Acta Histochem Cytochem Volume: 43(6) Pages: 163-8
  • Peer Reviewed
• [Journal Article] Fibroblasts associated with cancer cells keep enhanced migration activity after separation from cancer cells: a novel character of tumor educated fibroblasts (2010)
  • Author(s): Ishii G, Hashimoto H, Asada K, Ito T, Hoshino A, Fujii S, Kojima M, Kuwata T, Harigaya K, Nagai K, Ushijima T, Ochiai A
  • Journal Title: Int J Oncol Volume: 37(2) Pages: 317-25
  • Peer Reviewed
• [Journal Article] Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells (2010)
  • Author(s): Watarai H, Fujii S, Yamada D, Rybouchkin A, Sakata S, Nagata Y, Iida-Kobayashi M, Sekine-Kondo E, Shimizu K, Shozaki Y,Sharif J, Matsuda M, Mochiduki S, Hasegawa T, Kitahara G, Endo TA, Toyoda T, Ohara O, Harigaya K, Koseki H, Taniguchi M
  • Journal Title: J Clin Invest Volume: 120(7) Pages: 2610-8
  • Peer Reviewed
• [Journal Article] Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex (2010)
  • Author(s): Ishitani T, Hirao T, Suzuki M, Isoda M, Ishitani S, Harigaya K, Kitagawa M, Matsumoto K, Itoh M
  • Journal Title: Nat Cell Biol Volume: 12(3) Pages: 278-85
  • NAID: 120005293254
  • Peer Reviewed
• [Journal Article] Visualization of the Activity of Racl Small GTPase in a Cell. (2010)
  • Author(s): Higashi M, Harigaya K
  • Journal Title: Acta Histochem Cytochem. Volume: 43(6) Pages: 163-168
  • Peer Reviewed
• [Journal Article] Fibroblasts associated with cancer cells keep enhanced migration activity after separation from cancer cells : a novel character of tumor edu Gated fibroblasts. (2010)
  • Author(s): Ishii G, Harigaya K
  • Journal Title: Int J Oncol. Volume: 37(2) Pages: 317-325
  • Peer Reviewed
• [Journal Article] Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells. (2010)
  • Author(s): watarai H, Harigaya K
  • Journal Title: J Clin Invest. Volume: 120(7) Pages: 2610-2618
  • Peer Reviewed
• [Presentation] Switching of CD44 and hMena mRNA splice variants between the intramucosal lesion and invasive front of early stage human colorectal carcinoma (pT1) : and their relationship to the expression of cancer stem cell markers and clinicopathological features. (2013)
  • Author(s): Hiroshi Yoshida^<1,2>, Akihiro Toyoda^<1>, Wataru Masuda^<1>, Noriyuki Tanaka^<1,2>, Motoo Kitagawa^<1>, Yoshio Suzuki^<2>, Kenichi Harigaya^<1>
  • Organizer: AACR 2013
  • Place of Presentation: Washington, DC、USA
  • Year and Date: 2013-04-07
• [Presentation] Switching of CD44 and hMena mRNA splice variants between the intramucosal lesion and invasive front of early stage human colorectal carcinoma (pT1), and their relationship to the expression of cancer stem cell markers and clinico- pathological features (2013)
  • Author(s): Yoshida H, Toyoda A, Tanaka N, Masuda W,Kitagawa M, Suzuki Y, Harigaya K
  • Organizer: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 280
• [Presentation] Functions of Mastermind in Notch-dependent and Notch-independent transcriptional activation (2011)
  • Author(s): Motoo Kitagawa, Kenichi Harigaya
  • Organizer: 第6回Notch研究会
  • Place of Presentation: 千葉県野田市
  • Year and Date: 2011-11-15
• [Presentation] CD44-EGFR interaction regulates motility of cancer cells associates with the EMT (2011)
  • Author(s): Kenichi Harigaya
  • Organizer: 第20回日本癌病態治療研究会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2011-06-18
• [Presentation] ヒト大腸癌および腫瘍浸潤部におけるhMenaの発現についての解析 (2011)
  • Author(s): 豊田亮彦、張ヶ谷健一
  • Organizer: 第20回日本癌病態治療研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-18
• [Presentation] HAS2-HYAL2/CD44が産生した低分子ヒアルロン酸はautocrine chemokinetic motility factorである (2011)
  • Author(s): 斉藤光芳、張ヶ谷健一
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-04-30
• [Presentation] ヒト大腸癌および腫瘍浸潤部におけるhMenaの発現についての解析 (2011)
  • Author(s): 豊田亮彦、張ヶ谷健一
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-04-30
• [Presentation] 心筋炎の合併が考えられた新型インフルエンザ感染症の剖検例 (2011)
  • Author(s): 小豆畑康児、張ヶ谷健一
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-04-30
• [Presentation] HAS2-Hyal2/CD44 system supports spontaneous random cell movement of human cancer cells in an autocrine mechanism (2011)
  • Author(s): Saito T, Kawana H, Azuma K, Toyoda A, Fujita H, Kitagawa M, HarigayaK
  • Organizer: Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2011-01-23
• [Presentation] HAS2-HYAL2/CD44 system supports spontaneous random cell movement of human cancer cells in an anticrine mechanism. (2011)
  • Author(s): Harigaya K
  • Organizer: Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2011-01-23
• [Presentation] CD44 has dual functions to enhance the hyaluronan-induced chemokinesis in cancer cells as an associated molecule of hyaluronidase2-mediated HA catabolism and a hyaluronan receptor for RhoGTPase activation (2011)
  • Author(s): Kenichi Harigaya
  • Organizer: AACR 102^<nd> Annual Meeting 2011
  • Place of Presentation: Orlando, Florida
• [Presentation] Fragmented hyalu- ronan is an autocrine chemokinetic motility factor supported by HAS2 -CD44/hyaluronidase-2 system on the plasma membrane (2010)
  • Author(s): Harigaya K
  • Organizer: 15th World Congress on Advances in Oncology
  • Place of Presentation: Loutaraki, Greece. (Invited Speaker)
  • Year and Date: 2010-10-08
• [Presentation] Fragmented hyaluronan is an autocrine chemokinetic motility factor supported by HAS2-CD44/hyaluronidase-2system on the plasma membrane. (2010)
  • Author(s): Harigaya K
  • Organizer: 15^<th>world Congress on Advances on Oncology
  • Place of Presentation: Loutraki, Greece(招待講演)
  • Year and Date: 2010-10-08
• [Presentation] CD44 suppresses Toll-like receptor signaling (2010)
  • Author(s): Harigaya K
  • Organizer: 8th International Conference on Hyaluronan Science
  • Place of Presentation: Kyoto (Invited Speaker)
  • Year and Date: 2010-06-10
• [Presentation] CD44 suppresses the toll-like receptor signaling. (2010)
  • Author(s): Harigaya K
  • Organizer: The 8^<th> International Conference on Hyaluronan Sciences
  • Place of Presentation: Kyoto(招待講演)
  • Year and Date: 2010-06-10
• [Book] 第2部病理診断医になじみのある疾患関連分子解説編CD44(病理と臨床臨時増刊号vol.29 (2011)
  • Author(s): 豊田亮彦、斉藤光芳、張ヶ谷健一
  • Publisher: 分光堂
• [Book] 第2部病理診断医になじみのある疾患関連分子診断編CD44(病理と臨床臨時増刊号vol.29 (2011)
  • Author(s): 豊田亮彦、斉藤光芳、張ヶ谷健一
  • Publisher: 分光堂
• [Remarks]
  • URL: http://www.m.chiba-u.jp/class/patholl/
• [Remarks]
  • URL: http://www.m.chiba-u.jp/class/patholl/