Roles of tumor invasion marker laminin gamma2 chain in tumor progression and cancer stem cell functions

• Project/Area Number: 26430119
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanagawa Cancer Center Research Institute
• Principal Investigator: MIYAZAKI KAORU 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), その他部局等, その他 (70112068)
• Co-Investigator(Renkei-kenkyūsha): MIYAGI Yohei 神奈川県立病院機構, 神奈川県立がんセンター臨床研究所, 総括部長 (00254194) ; HIGASHI Shouichi 横浜市立大学, 大学院生命ナノシステム科学研究科, 教授 (10275076)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: がん微小環境 / 浸潤・転移 / がん幹細胞 / ラミニン / CD44 / 細胞接着 / 細胞外マトリックス / 免疫染色 / がん浸潤 / MMP / 病理診断 / モノクローナル抗体 / ラミニンγ2 / がんマーカー / 浸潤

Outline of Final Research Achievements

The present study investigated functions of the tumor invasion marker laminin gamma2 chain (Lmg2) in tumor progression. 1. The most N-terminal, domain V (dV) of Lmg2 promoted vascular permeability and tumor cell invasion into endothelial cell layer. 2. The dV protein stimulated migration of metastatic breast cancer cells by binding the cancer stem cell marker CD44. However, it was not clear whether dV supports the stem cell function. 3. Novel antibodies recognizing dV were prepared. Analyses with these antibodies revealed that small proteolytic fragments containing dV were highly produced in various cultured human cancer cell lines, cancer tissues and sera of cancer patients. Immunohistochemistry showed that one of dV antibodies detects invasive lung cancer cells at high sensitivity. These results suggest that dV fragments are produced in cancer tissues and contribute to tumor invasion. The dV antibodies seem useful for pathological analysis and diagnosis of human cancers.

Research Products

• [Journal Article] Highly sensitive detection of invasive lung cancer cells by novel antibody against amino-terminal domain of laminin gamma2 chain. (2016)
  • Author(s): Miyazaki, K., Oyanagi, J., Sugino, A., Sato, H., Yokose, T., Nakayama, H., Miyagi, Y.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 12 Pages: 1909-1918
  • DOI: 10.1111/cas.13089
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Amino-terminal fragments of laminin γ2 chain stimulate migration of metastatic breast cancer cells by interacting with CD44 (2015)
  • Author(s): Sato, H, Oyanagi, J., Komiya, E., Ogawa, T, Higashi, S., Miyazaki, K.
  • Journal Title: Clin. Exp. Metastasis Volume: 32 Issue: 5 Pages: 405-415
  • DOI: 10.1007/s10585-015-9705-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Amino-terminal fragments of laminin gamma2 chain retract vascular endothelial cells and increase vascular permeability. (2014)
  • Author(s): Sato, H, Oyanagi, J., Komiya, E., Ogawa, T, Higashi, S., Miyazaki, K.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 2 Pages: 168-175
  • DOI: 10.1111/cas.12323
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of matrix metalloproteinase-9 secretion from tumor-associated macrophage-like cells by proteolytically processed laminin-332 (laminin-5) (2014)
  • Author(s): Kamoshida, G., Ogawa, T., Oyanagi, J., Sato, H., Komiya, E., Higashi, S., Miyazaki, K., Tsuji, T.
  • Journal Title: Clin. Exp. Metastasis Volume: 31 Pages: 285-291
  • Peer Reviewed
• [Journal Article] Angiomodulin (AGM/IGFBP-rP1) is a molecular marker of vascular endothelial cells activated by VEGF in human breast cancers. (2014)
  • Author(s): Komiya, E, Sato, H., Ise, I., Watanabe, N., Higashi, H., Miyagi, Y., Miyazaki, K.
  • Journal Title: Cancer Med Volume: 印刷中 Issue: 3 Pages: 537-549
  • DOI: 10.1002/cam4.216
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of transforming growth factor-β signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. (2014)
  • Author(s): Oyanagi, J., Kojima, N., Sato, H., Higashi, S., Kikuchi, K., Sakai, K., Matsumoto, K., Miyazaki, K.
  • Journal Title: Exp Cell Res. Volume: 印刷中 Issue: 2 Pages: 267-279
  • DOI: 10.1016/j.yexcr.2014.04.009
  • Peer Reviewed / Open Access
• [Presentation] Tumor invasion marker laminin γ2 chain - highly sensitive detection of invasive lung cancer cells by novel antibody recognizing its N-terminal fragment. (2017)
  • Author(s): Miyazaki, K.
  • Organizer: BIT’s 10th Annual World Cancer Congress
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2017-05-19
  • Int'l Joint Research / Invited
• [Presentation] Production of N-terminal active fragments of laminin γ2 chain by cultured human cancer cells and in lung cancer tissues. (2016)
  • Author(s): Miyazaki, K., Oyanagi, J., Sato, H., Miyagi, Y.
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] N-terminal fragments of laminin γ2 chain stimulate migration of metastatic breast cancer cells by interacting with CD44 (2015)
  • Author(s): Miyazaki, K., Sato, H., Higashi, S.
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] CD69 induced in CCC cells cultured under serum starvation and hypoxia activates cel surface integrin (2015)
  • Author(s): Kanayama, T., Koizume, S., Miyagi, E., Hirahara, F., Miyazaki, K., Miyagi, Y.
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] がん微小環境における細胞外マトリックス分子の変動と意義 (2015)
  • Author(s): 宮崎香
  • Organizer: 第33回日本ヒト細胞学会8月22-23日
  • Place of Presentation: 宮崎
  • Year and Date: 2015-08-22 – 2015-08-23
  • Invited
• [Presentation] Three-dimensional collagen gel co-culture model as a tool to investigate tumor invasion: roles of HGF and TGF-beta (2014)
  • Author(s): Miyazaki, K., Jun Oyanagi, J., Shouichi Higashi, S., Kikuchi, K., Sakai, K., Matsumoto, K.
  • Organizer: 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Laminin gamma2 Chain Interacts with CD44 and Stimulates Migration of Metastatic Breast Cancer Cells (2014)
  • Author(s): Sato, H., Miyazaki, K
  • Organizer: 第23回日本がん転移学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2014-07-10 – 2014-07-11