Can the control of vascular and lymphatic homeostasis be a method to inhibit cancer metastasis?

• Project/Area Number: 20K21569
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Shinshu University
• Principal Investigator: Shindo Takayuki 信州大学, 学術研究院医学系, 教授 (90345215)
• Co-Investigator(Kenkyū-buntansha): 神吉 昭子 信州大学, 学術研究院医学系, 助教 (10397309) ; 桜井 敬之 信州大学, 学術研究院医学系, 准教授 (80317825)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌 / 転移 / 血管 / アドレノメデュリン / RAMP2 / リンパ管

Outline of Research at the Start

現在、癌の転移を確実に抑制する方法は存在しない。我々は、従来の治療法の様に癌細胞だけに注目するのではなく、原発巣と転移巣、それをつなぐ血管、リンパ管を一つのシステムとして捉える新しいコンセプトが、革新的な癌の転移抑制法に繋がると考えた。我々は、生理活性ペプチド：アドレノメデュリン(AM)と、AMの受容体活性調節タンパク：RAMP2から構成される、血管・リンパ管の恒常性制御システム=「AM-RAMP2システム」を同定し、癌転移制御の新たな治療標的として着目した。
本研究では、AM-RAMP2システムによる血管・リンパ管制御機構を解明し、癌転移を抑制する治療法として応用展開をはかる。

Outline of Final Research Achievements

We have focused on the mechanism of vascular homeostasis by adrenomedullin (AM) and RAMP2, a protein that regulates AM receptor activity. AM and RAMP2 are also expressed in a variety of cancers. In this study, we examined the significance of the AM-RAMP2 system in tumor growth and metastasis.
We found that induction of RAMP2 deficiency in vascular endothelial cells promotes cancer metastasis by inducing chronic inflammation in the vasculature of target organs and destabilizing vascular structure through endothelial-mesenchymal transition (EndMT). Focusing on the mechanism of vascular homeostasis by the AM-RAMP2 system is expected to lead to the development of therapies that inhibit cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

現在、癌の転移を確実に抑制する方法は存在しない。我々は、従来の治療法の様に癌細胞だけに注目するのではなく、原発巣と転移巣、そしてそれをつなぐ脈管系を一つの生体システムとして捉えるコンセプトが、癌の転移抑制法につながると考えた。中でも血管の恒常性の破綻や異常増殖は癌の病態に密接に関与していることから、我々は、血管の恒常性制御の観点から、癌転移を抑制する新しいアプローチを考えた。
本研究では、血管内皮細胞のRAMP2欠損誘導により、遠隔臓器への癌転移が亢進することが示された。AM-RAMP2系による血管恒常性維持機構に着目することで、癌転移を抑制する新しい治療法への展開が期待される。

Research Products

• [Journal Article] Receptor activity modifying protein RAMP sub-isoforms and their functional differentiation, which regulates functional diversity of adrenomedullin (2022)
  • Author(s): Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Sakurai T
  • Journal Title: Biology(Basel) Volume: 11(5) Issue: 5 Pages: 788-788
  • DOI: 10.3390/biology11050788
  • Peer Reviewed / Open Access
• [Journal Article] Production of single- and multiple-gene-modified mice via maternal SpCas9-based gene editing (2021)
  • Author(s): Sakurai Takayuki、Shindo Takayuki
  • Journal Title: STAR Protocols Volume: 2 Issue: 2 Pages: 100509-100509
  • DOI: 10.1016/j.xpro.2021.100509
  • Peer Reviewed / Open Access
• [Journal Article] Adrenomedullin ameliorates pulmonary fibrosis by regulating TGF-b-Smads signaling and myofibroblast differentiation (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T
  • Journal Title: Endocrinology Volume: 162(8) Issue: 8 Pages: 1-22
  • DOI: 10.1210/endocr/bqab090
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shindo T
  • Journal Title: Endocrinology Volume: 162(3) Issue: 3 Pages: 0-0
  • DOI: 10.1210/endocr/bqab001
  • Peer Reviewed
• [Journal Article] Adrenomedullin-receptor activity-modifying protein 2 system ameliorates subretinal fibrosis by suppressing epithelial-mesenchymal transition in age-related macular degeneration (2021)
  • Author(s): Tanaka M, Kakihara S, Hirabayashi K, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Aruga K, Yamauchi A, Murata T, Shindo T
  • Journal Title: Am J Pathol Volume: 191(4) Issue: 4 Pages: 652-668
  • DOI: 10.1016/j.ajpath.2020.12.012
  • Peer Reviewed
• [Journal Article] Mid-regional pro-adrenomedullin is a novel biomarker for arterial stiffness as the criterion for vascular failure in a cross-sectional study. (2021)
  • Author(s): Koyama T, Kuriyama N, Suzuki Y, Saito S, Tanaka R, Iwao M, Tanaka M, Maki T, Itoh H, Ihara M, Shindo T, Uehara R.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 305-305
  • DOI: 10.1038/s41598-021-96984-3
  • Peer Reviewed / Open Access
• [Journal Article] アドレノメデュリンの機能の多様性を制御する受容体活性調節タンパクRAMPサブアイソフォームとその機能分化 (2021)
  • Author(s): 新藤隆行
  • Journal Title: 血管 Volume: 44 Pages: 1-7
• [Journal Article] Adrenomedullin-RAMP2 system ameliorates pulmonary fibrosis by regulating TGF-β-Smads pathway and differentiation of myofibroblasts. (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui1 N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T.
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shind T.
  • Journal Title: Endocrinology. Volume: in press
• [Journal Article] Placental extract ameliorates liver fibrosis in a methionine- and choline-deficient diet-induced mouse model of non-alcoholic steatohepatitis (2020)
  • Author(s): Yamauchi A. Tone T, Tokedo A, Igarashi K, Sugimoto K, Miyai H, Deng D, Nakamura J, Lim HS, Kaku T, Hirano E, Shindo T.
  • Journal Title: Biomedical Research Volume: 41 Issue: 1 Pages: 1-12
  • DOI: 10.2220/biomedres.41.1
  • NAID: 130007801485
  • ISSN: 0388-6107, 1880-313X
  • Year and Date: 2020-02-01
  • Peer Reviewed
• [Journal Article] Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts (2020)
  • Author(s): Dai K, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Matsui S, Shindo T
  • Journal Title: Oncogene Volume: 39(9) Issue: 9 Pages: 1914-1930
  • DOI: 10.1038/s41388-019-1112-z
  • Peer Reviewed
• [Journal Article] Investigation of the therapeutic mechanism of subthreshold micropulse laser irradiation in retina (2020)
  • Author(s): Kazutaka Hirabayashi, Shinji Kakihara, Masaaki Tanaka, Takayuki Shindo, Toshinori Murata
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: 258 Issue: 5 Pages: 1039-1047
  • DOI: 10.1007/s00417-020-04638-3
  • Peer Reviewed
• [Presentation] アドレノメデュリン-RAMP2系による、高内皮細静脈を介したリンパ節転移の制御 (2023)
  • Author(s): 田中愛、桜井敬之、神吉昭子、市川優佳、河手久香、柿原伸次、Zhao Yunlu、松田順繁、Zhang Yan、Guo Qianqian、Li Peixuan、大西菜穂、笠原智貴、新藤隆行
  • Organizer: 第52回日本心脈管作動物質学会
• [Presentation] 癌細胞のRAMP3欠損は、Meflin 陽性の良性癌関連線維芽細胞を誘導し、腫瘍増殖を抑制する (2023)
  • Author(s): 甲斐健佑、田中愛、桜井敬之、神吉昭子、市川優佳、河手久香、柿原伸次、Zhao Yunlu、松田順繁、Zhang Yan、Guo Qianqian、Li Peixuan、大西菜穂、笠原智貴、新藤隆行
  • Organizer: 第52回日本心脈管作動物質学会
• [Presentation] Vascular homeostatic function of the AM-RAMP2 system and its application to the regulation of lymph node metastasis. (2023)
  • Author(s): Tanaka M, Sakurai T, Kamiyoshi K, Ichikawa-Shindo Y, Kawate H, Kakihara S, Zhao Y, Matsuda Y, Zhang Y, Guo Q, Li P, Onishi N, Kasahara T, Shindo T.
  • Organizer: 第87回日本循環器学会
• [Presentation] AM-RAMP2系の血管恒常性制御を介したリンパ節転移抑制作用 (2022)
  • Author(s): 田中愛、桜井敬之、神吉昭子、市川優佳、河手久香、Guo Qianqia、Li Peixua、大西菜穂、笠原智貴、新藤隆行
  • Organizer: 第26回日本心血管内分泌代謝学会
• [Presentation] Homeostatic Regulation of High Endothelial Venules and Suppression of Lymphatic Metastasis by Adrenomedullin-RAMP2 System (2022)
  • Author(s): Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Hisaka K, Kakihara S, Zhao Y, Matsuda Y, Aruga K, Kasahara T, Shindo T
  • Organizer: 第86回日本循環器学会
• [Presentation] アドレノメデュリンとその受容体活性調節システムによる生体内恒常性制御 (2021)
  • Author(s): 新藤隆行
  • Organizer: 第50回日本心脈管作動物質学会
  • Invited
• [Presentation] AM-RAMP2系の血管恒常性制御による血行性、リンパ行性転移抑制機構の解明 (2021)
  • Author(s): 田中愛、桜井敬之、神吉昭子、新藤優佳、河手久香、崔南奇、田中正明、Wei Yangxuan、柿原伸次、Zhao Yunlu、笠原智貴、有賀公亮、新藤隆行
  • Organizer: 第50回日本心脈管作動物質学会
• [Presentation] AM-RAMP2系による高内皮細静脈の機能制御とリンパ行性転移抑制作用 (2021)
  • Author(s): 田中愛、桜井敬之、神吉昭子、市川優佳、河手久香、柿原伸次、Zhao Yunlu、松田順繁、有賀公亮、新藤隆行
  • Organizer: 第25回日本心血管内分泌代謝学会
• [Presentation] Adrenomedullin-RAMP2 system regulates vascular endothelial homeostasis, which suppresses hematogenous and lymphogenous metastasis. (2021)
  • Author(s): Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 system ameliorates age-related macular degeneration by suppressing choroidal neovascularization and subretinal fibrosis. (2021)
  • Author(s): Tanaka M, Kakihara S, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Remarks] 信州大学医学部 循環病態学教室
  • URL: http://www7a.biglobe.ne.jp/~shindo/
• [Remarks] 信州大学医学部 循環病態学教室
  • URL: http://www7a.biglobe.ne.jp/~shindo/