Identification of molecular mechanisms underlying lymphangiogenesis and angiogenesis in tumor progression and metastasis

• Project/Area Number: 17014078
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kumamoto University (2007-2009); Keio University (2005-2006)
• Principal Investigator: OIKE Yui chi Kumamoto University, 大学院・生命科学研究部, 教授 (90312321)
• Co-Investigator(Kenkyū-buntansha): MORISADA Tooru 慶応義塾大学, 医学部, 助教 (70317923)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥48,800,000 (Direct Cost: ¥48,800,000); Fiscal Year 2009: ¥10,100,000 (Direct Cost: ¥10,100,000); Fiscal Year 2008: ¥10,100,000 (Direct Cost: ¥10,100,000); Fiscal Year 2007: ¥10,100,000 (Direct Cost: ¥10,100,000); Fiscal Year 2006: ¥10,100,000 (Direct Cost: ¥10,100,000); Fiscal Year 2005: ¥8,400,000 (Direct Cost: ¥8,400,000)
• Keywords: リンパ管 / 血管新生 / がん / がん転移 / アンジオポエチン様因子 / 転移 / リンパ管新生 / アンジオポエチン / 抗体

Research Abstract

Despite intense effort, strategies designed to inhibit tumor cell metastasis have been unsuccessful because of lack of understanding of mechanisms underlying the process. Here we report that increases in expression and secretion of angiopoietin-like protein 2 (Angptl2) by primary tumors are highly correlated with the frequency of tumor metastasis both in patients and in tumor cell-implanted mouse models. Tumor cell-derived Angptl2 accelerates metastasis by activating tumor angiogenesis and lymphangiogenesis. Angptl2 expressed in tumor cells was induced by hypoxia and undernutrition, suggesting that the tumor microenvironment induces a tumor cell-derived Angptl2 signal that promotes metastasis. Conversely, targeted deletion of Angptl2 in tumor cells significantly decreased metastasis in tumor cell-implanted mouse models. Based on the present findings we propose that Angptl2 functions as a key regulator of tumor metastasis. These studies could form the basis of new treatment strategies to antagonize tumor metastasis.

Research Products

• [Journal Article] Endogenous angiogenesis inhibitor vasohibin1 exhibits broad-spectrum antilymphangiogenicactivity and suppresses lymph node metastasis. (2010)
  • Author(s): Heishi T., HosakaT., Suzuki Y., Miyashita H., Oike Y., Takahashi T., Nakamura T., Arioka S, Mitsuda Y., Takakura T., Hojo K., Matsumoto M., Yamauchi C., Ohta H., Sonoda H., Sato Y.
  • Journal Title: Am J Pathol 176 Pages: 1950-1958
  • Peer Reviewed
• [Journal Article] Synoviocyte-derived Angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis. (2010)
  • Author(s): Okada T., Tsukano H., Endo M., Tabata M., Miyata K., Kadomatsu T., Miyashita K., Semba K., Nakamura E., Tsukano M., Mizuta H., Oike Y. *
  • Journal Title: Am J Pathol 176 Pages: 2309-2319
  • Peer Reviewed
• [Journal Article] Endogenous angiogenesis inhibitor vasohibinl exhibits broad-spectrum antilymphangiogenicactivity and suppresses lymph node metastasis. (2010)
  • Author(s): Heishi T., et al
  • Journal Title: Am J Pathol 176 Pages: 1950-1958
  • Peer Reviewed
• [Journal Article] Synoviocyte-derived Angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis. (2010)
  • Author(s): Okada T., et al
  • Journal Title: Am J Pathol (in press)
  • Peer Reviewed
• [Journal Article] Angiopoietin-like proteins: potential therapeutic targets for metabolic syndrome and cardiovascular disease. (2009)
  • Author(s): Oike Y., Tabata M.
  • Journal Title: Circ J 73 Pages: 2192-2197
  • NAID: 10025937894
  • Peer Reviewed
• [Journal Article] Humanized anto-Interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. (2009)
  • Author(s): Shinriki S., Jono H., Ota K., Ueda M., Kudo M., Ota T., Oike Y., Endo M., Ibusuki M., Hiraki A., NakayamaH., YoshitakeY., Shinohara M., AndoY.
  • Journal Title: Clin Cancer Res 15 Pages: 5426-5434
  • Peer Reviewed
• [Journal Article] Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation formation and obesity-related systemic insulin resistance. (2009)
  • Author(s): Tabata M., Kadomatsu T., Fukuhara S., Miyata K., Ito Y., Endo M., Urano T., Zhu HJ., Tsukano H., Tazume H., Kaikita K., Miyashita K., Iwawaki T., Shimabukuro M., Sakaguchi K., Ito T., Ando Y., Ogawa H., Mochizuki N., Itoh H., Suda T., Oike Y.
  • Journal Title: Cell Metab 10 Pages: 178-188
  • Peer Reviewed
• [Journal Article] Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of Hoxd8 in lymphangiogenesis. (2009)
  • Author(s): Harada K., Yamazaki T., Iwata C., Yoshimatsu Y., Sasea H., Mishima K., Morishita Y., Hirashima M., Oike Y., Suda T., Miura N., Watabe T., Miyazono K.
  • Journal Title: J Cell Sci 122 Pages: 3293-3230
  • Peer Reviewed
• [Journal Article] Humanized anto-Interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. (2009)
  • Author(s): Shinriki S., et al
  • Journal Title: Clin Cancer Res 15 Pages: 5426-5434
  • Peer Reviewed
• [Journal Article] Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation formation and obesitv-related systemic insulin resistance. (2009)
  • Author(s): Tabata M., et al
  • Journal Title: Cell Metab 10 Pages: 178-188
  • Peer Reviewed
• [Journal Article] Angiopoietin-like proteins : potential therapeutic targets for metabolic syndrome and cardiovascular disease. (2009)
  • Author(s): Oike Y., Tabata M.
  • Journal Title: Circ J 73 Pages: 2192-2197
  • NAID: 10025937894
  • Peer Reviewed
• [Journal Article] Angiopoietins contribute to lung development by regulating pulmonary vascular network formation. (2009)
  • Author(s): Hato T., et.al.
  • Journal Title: Biochem Biophys Res Commun 381 Pages: 218-223
  • Peer Reviewed
• [Journal Article] The role of angiopoietin-like proteins (Angptls) in angiogenesis and metabolism. (2008)
  • Author(s): Hato T., Tabata M., Oike Y. *
  • Journal Title: Trends Cardiovasc Med 18 Pages: 6-14
  • Peer Reviewed
• [Journal Article] Angiopoietin-related growth factor enhances blood flow via activation of the ERK1/2-eNOS-NO pathway in a mouse hind-limb ischemia model. (2008)
  • Author(s): Urano T., Ito Y., Akao M., Sawa T., Miyata K., Tabata M., Morisada T., Hato T., Kadomatsu T., Yano T., Yasunaga K., Shibata R., Murohara T., Akaike T., Tanihara H., Suda T., Oike Y.
  • Journal Title: Arterioscler Thromb Vasc Biol 28 Pages: 827-834
• [Journal Article] Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. (2008)
  • Author(s): Matsuoka S., Oike Y., Onoyama I., Iwama A., Arai F., Takubo K., Mashimo Y., Oguro H., Nitta E., Ito K., Miyamoto K., Yoshiwara H., Hosokawa K., Nakamura Y., Gomei Y., Iwasaki H., Hayashi Y., Matsuzaki Y., Nakayama K., Ikeda Y., Hata A., Chiba S., Nakayama KI., Suda T.
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical fail-safe against premature loss of he matonoietic stem cells and development of T-ALL (2008)
  • Author(s): Matsuoka S., et.al.
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] The role of angiopoietin-like proteins (Angptls) in angiogenesis and metabolism (2008)
  • Author(s): Hato T., et.al.
  • Journal Title: Trends Cardiovasc Med 18 Pages: 6-14
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. (2008)
  • Author(s): Matsuoka S., et. al.
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] The role of angiopoietin-like proteins(Angptls)in angiogenesis and metabolism. (2008)
  • Author(s): Hato T., et. al.
  • Journal Title: Trends Cardiovasc Med. 18 Pages: 6-14
  • Peer Reviewed
• [Journal Article] Angiogenic role of LYVE-1-positive macrophages in adipose tissue. (2007)
  • Author(s): Cho CH., Jun Koh Y., Han J., Sung HK., Jong Lee H., Morisada T., Schwendener RA., Brekken RA., Kang G., Oike Y., Choi TS., Suda T., Yoo OJ., Koh GY.
  • Journal Title: Circ Res 100
  • Peer Reviewed
• [Journal Article] Prox1 induces lymphatic endothelial differentiation via integrin a9 and other signaling cascades. (2007)
  • Author(s): Mishima K., Watabe T., Saito A., Yoshimatsu Y., Imaizumi N., Masui S., Hirashima M., Morisada T., Oike Y., Araie M., Niwa H., Kubo H., Suda T., Miyazono K.
  • Journal Title: Mol Biol Cell 18 Pages: 1421-1429
  • Peer Reviewed
• [Journal Article] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor-3 signaling. (2007)
  • Author(s): Taniguchi K., Kohno R., Ayada T., Kato R., Morisada T., Oike Y., Yonemitsu Y., Maehara Y., Yoshimura, A.
  • Journal Title: Mol Cell Biol 27 Pages: 4541-4550
  • Peer Reviewed
• [Journal Article] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor-3 signaling. (2007)
  • Author(s): Taniguchi, K., et. al.
  • Journal Title: Mol Cell Biol 27 Pages: 4541-4550
  • Peer Reviewed
• [Journal Article] Prox1 Induces Lymphatic Endothelial Differentiation via Integrin ag and Other Signaling Cascades. (2007)
  • Author(s): Mishima K., et. al.
  • Journal Title: Mol Biol Cell 18 Pages: 1421-1429
  • Peer Reviewed
• [Journal Article] Angiogenic Role of LYVE-1-positive Macrophages in Adipose Tissue. (2007)
  • Author(s): Cho CH, et. al.
  • Journal Title: Circ Res 100 Pages: 47-57
  • Peer Reviewed
• [Journal Article] Proxl Induces Lympatic Endothelial Differentiation via Integrin a9 and Other Signaling Cascades. (2007)
  • Author(s): Mishima K. et al.
  • Journal Title: Mol Biol Cell (印刷中)
• [Journal Article] Angiopoietins and Angiopoietin-like proteins in angiogenesis. (2006)
  • Author(s): Morisada T., Kubota Y., Urano T., Suda T., Oike Y. *
  • Journal Title: Endothelium 13 Pages: 71-79
  • Peer Reviewed
• [Journal Article] Loss of Tie2 receptor compromises embryonic stem cell-derived endothelial but not hematopoietic cell survival. (2006)
  • Author(s): Hamaguchi I., Morisada T., Azuma M., Murakami K., Kuramitsu M., Mizukami T., Ohbo K., Yamaguchi K., Oike Y., Dumont DJ., Suda T.
  • Journal Title: Blood 107 Pages: 1207-1213
  • Peer Reviewed
• [Journal Article] Distribution of lymphatic vessels in mouse thymus: immunofluorescence analysis. (2006)
  • Author(s): Odaka C., Morisada T., Oike Y., Suda T.
  • Journal Title: Cell Tissue Res 325 Pages: 13-22
  • Peer Reviewed
• [Journal Article] Genetic marking of hematopoietic stem and endothelial cells: identification of the Tmtsp gene encoding a novel cell-surface protein with the thrombospondin-1 domain. (2006)
  • Author(s): Takayanagi S., Hiroyama T., Yamazaki S., Nakajima T., Morita Y., Usui J., Eto K., Motohashi T., Shiomi K., Keino-Masu K., Oike Y., Mori S., Yoshida N., Iwama A., Nakakuchi H.
  • Journal Title: Blood 107 Pages: 4317-4325
  • Peer Reviewed
• [Journal Article] Intestinal and peri-tumoral lymphatic endothelial cells are resistant to radiation-induced apoptosis. (2006)
  • Author(s): Sung HK., Morisada T., Cho CH., Oike Y., Lee J., Sung EK., Chung JH., Suda T., Koh GY.
  • Journal Title: Biochem Biophys Res Commun 345 Pages: 545-551
  • Peer Reviewed
• [Journal Article] Angiopoietins and Angiopoietin-like proteins in angiogenesis (2006)
  • Author(s): Morisada, T. et al.
  • Journal Title: Endothelium 13・2 Pages: 71-79
• [Journal Article] Loss of Tie2 receptor compromises embryonic stem cell-derived endothelial but not hematopoietic cell survival (2006)
  • Author(s): Hamaguchi, I. et al.
  • Journal Title: Blood 107・3 Pages: 1207-1213
• [Journal Article] Distribution of lymphatic vessels in mouse thymus : immunofluorescence analysis (2006)
  • Author(s): Odaka, C. et al.
  • Journal Title: Cell Tissue Res 325・1 Pages: 13-22
• [Journal Article] Genetic marking of hematopoietic stem and endothelial cells : Identification of the Tmtsp gene encoding a novel cell-surface protein with the thrombospondin-1 domain. (2006)
  • Author(s): Takayanagi, S. et al.
  • Journal Title: Blood 107・11 Pages: 4317-4325
• [Journal Article] Intestinal and peri-tumoral lymphatic endothelial cells are resistant to radiation-induced apoptosis (2006)
  • Author(s): Sung, HK. et al.
  • Journal Title: Biochem Biophys Res Commun 345・2 Pages: 545-551
• [Journal Article] Loss of Tie2 receptor compromises embryonic stem cell-derived endothelial but not hematopoietic cell survival (2006)
  • Author(s): Hamaguchi I. et al.
  • Journal Title: Blood 107・3 Pages: 1207-1213
• [Journal Article] Distribution of lymphatic vessels in mouse thymus : immunofluorescence analysis. (2006)
  • Author(s): Okada C. et al.
  • Journal Title: Cell Tissue Res (印刷中)
• [Journal Article] Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. (2005)
  • Author(s): Morisada T., Oike Y. *, Yamada Y., Urano T., Akao M., Kubota Y., Maekawa H., Kimura Y., Ohmura M., Miyamoto T., Nozawa S., Koh GY., Alitalo K., Suda T.
  • Journal Title: Blood 105 Pages: 4649-4656
  • NAID: 120001129412
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. (2005)
  • Author(s): Tammela T., SaaristoA., Lohela M., Morisada T., Tornberg J., Norrmen C., Oike Y., Pajusola K., Thurston G., Suda T., Yla-Herttuala S., Alitalo K.
  • Journal Title: Blood 105 Pages: 4642-4648
  • Peer Reviewed
• [Journal Article] Oncogenic transcription factor Evi-1 regulates hematopoietic stem cell proliferation through GATA-2 expression. (2005)
  • Author(s): Yuasa H. #, Oike Y. # *, Iwama A., Nishikata I., Sugiyama D., Perkins A., Mucenski ML., Suda T., Morishita K. (# equally contributed)
  • Journal Title: EMBO J 24 Pages: 1976-1987
  • Peer Reviewed
• [Journal Article] Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development. (2005)
  • Author(s): Kubota Y., Oike Y. *, Satoh S., Tabata Y., Niikura Y., Morisada T., Akao M., Urano T., Ito Y., Miyamoto T., Nagai N., Koh GY., Watanabe S., Suda T.
  • Journal Title: Proc Natl Acad Sci USA 102 Pages: 13502-13507
  • Peer Reviewed
• [Journal Article] Isolation and expression patterns of genes for three angiopoietin-like proteins, Angptl1, 2 and 6 in zebrafish. (2005)
  • Author(s): Kubota Y., Oike Y, Satoh S., Tabata Y., Niikura Y., Morisada T., Akao M., Urano T., Ito Y., Miyamoto T., Watanabe S., Suda T.
  • Journal Title: Gene Expr Patterns 5 Pages: 679-685
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation (2005)
  • Author(s): Morisada T. et al.
  • Journal Title: Blood 105・12 Pages: 4649-4656
  • NAID: 120001129412
• [Journal Article] Angiopoietin-1 promotes lymphatic sprouting and hyperplasia (2005)
  • Author(s): Tammela T. et al.
  • Journal Title: Blood 105・12 Pages: 4642-4648
• [Journal Article] Oncogenic transcription factor Evi-1 regulates hematopoietic stem cell proliferation through GATA-2 expression (2005)
  • Author(s): Yuasa H. et al.
  • Journal Title: EMBO J 24・11 Pages: 1976-1987
• [Journal Article] Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development (2005)
  • Author(s): Kubota Y. et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA 102・38 Pages: 13502-13507
• [Presentation] がん浸潤・転移におけるアンジオポエチン様因子の機能解析 (2010)
  • Author(s): 尾池雄一シンポジウム
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Roles of ANGPTL2 in chronic infl ammation and life-style related diseases("慢性炎症"の鍵因子ANGPTL2と生活習慣病・癌の病態生理) (2009)
  • Author(s): 尾池雄一
  • Organizer: 第32回日本分子生物学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市
  • Year and Date: 2009-12-09
• [Presentation] がん浸潤・転移におけるアンジオポエチン様因子の機能解析 (2009)
  • Author(s): 尾池雄一
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2009-10-01
• [Presentation] ワークショップRoles of ANGPTL2 in chronic infl ammation and life-style related diseases("慢性炎症"の鍵因子ANGPTL2と生活習慣病・癌の病態生理) (2009)
  • Author(s): 尾池雄一
  • Organizer: 第32回日本分子生物学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 血管新生因子ANGPTLファミリー研究の最前線 (2009)
  • Author(s): 尾池雄一シンポジウム
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] アンジオポエチン様因子(ANGPTL)と血管・リンパ管 (2008)
  • Author(s): 尾池雄一シンポジウム
  • Organizer: 第29回日本炎症・再生医学会
  • Place of Presentation: 東京都・都市センターホテル
• [Presentation] ワークショップRoles of Angiopoietins and Angiopoietin-like proteins (Angptls) in angiogenesis and Lymphangiogenesis (2008)
  • Author(s): 尾池雄一
  • Organizer: THE U.S. -JAPAN COOPERATIVE CANCER RESEARCH
  • Place of Presentation: 京都
• [Presentation] アンジオポエチンファミリーとリンパ管・血管;リンパ管・血管標的抗がん療法を目指して (シンポジウム) (2007)
  • Author(s): 尾池 雄一
  • Organizer: 第15回日本血管生物医学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2007-11-30
• [Presentation] アンジオポエチンファミリーとリンパ管・血管-リンパ管・血管標的抗がん療法を目指して- (2007)
  • Author(s): 尾池雄一シンポジウム
  • Organizer: 第15回日本血管生物医学会学術大会
  • Place of Presentation: 九州大学
• [Presentation] Pleiotropic effects of angiopoietin-like proteins (Angptls) (2006)
  • Author(s): Symposium
  • Organizer: 4th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Tokyo, Japan
• [Presentation] アンジオポエチンファミリーと血管・リンパ管-血管・リンパ管標的療法を目指して- (2006)
  • Author(s): 尾池雄一、森定徹、羽藤泰
  • Organizer: 第65回日本癌学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Roles of Angiopoietin-like proteins (Angptls) in angiogenesis (2006)
  • Author(s): Symposium Yuichi Oike
  • Organizer: XIVth International Vascular Biology meeting
  • Place of Presentation: Noordwijkerhout, Netherlands
• [Presentation] リンパ管形成の分子基盤解明 (2005)
  • Author(s): 尾池雄一、森定徹、須田年生
  • Organizer: 第28回日本分子生物学会
  • Place of Presentation: 福岡・国立病院機構九州医療センター
• [Book] アンジオポエチン様因子と病態(癌と血管新生の分子生物学分担)(渋谷正史 編) (2006)
  • Author(s): 羽藤泰, 森定徹, 尾池雄一
  • Total Pages: 190
  • Publisher: 南山堂
• [Book] 癌と血管新生の分子生物学 分担:アンジオポエチン様因子と病態 (2006)
  • Author(s): 羽藤泰, 森定徹, 尾池雄一
  • Publisher: 南山堂(印刷中)
• [Remarks]
  • URL: http://molegene.kumamoto-u.ac.jp/
• [Patent(Industrial Property Rights)] 癌治療剤 (2009)
  • Inventor(s): 尾池雄一, 他1名
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2009-09-30
• [Patent(Industrial Property Rights)] 生活習慣病及び/又は癌の診断剤 (2008)
  • Inventor(s): 尾池雄一, 他6名
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2008-11-06