Elucidation of a novel evasive adaptation mechanism against antiangiogenic treatment in colorectal cancer cells

• Project/Area Number: 15H04931
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka Prefecture University (2016-2017); The University of Tokushima (2015)
• Principal Investigator: Kondo Shigetada 大阪府立大学, 総合リハビリテーション学研究科, 教授 (40304513)
• Co-Investigator(Kenkyū-buntansha): 増田 清士 徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (00457318) ; 二川 健 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (20263824)
• Research Collaborator: TOMIDA Chisato 徳島大学, 大学院医歯薬学研究部・栄養生命科学教育部 ; YANO Chisato 徳島大学, 大学院医歯薬学研究部・栄養生命科学教育部 ; AIBARA Kana 徳島大学, 大学院医歯薬学研究部・栄養生命科学教育部
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: VEGF / VEGF受容体 / 悪性進展 / VEGF分子標的薬 / 浸潤 / 悪性転換 / 腫瘍血管新生 / 悪性腫瘍化 / 分子標的薬抵抗性 / がん悪性化 / 浸潤転移 / VEGF-R / 分子標的薬 / がん細胞の悪性転換

Outline of Final Research Achievements

VEGF- and its receptor (VEGF-R)-targeted anti-angiogenic therapies are important treatments for colorectal cancer. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. How the cancer cells become resistant remains unclear. We elucidated that VEGF/VEGF-R blockers directly act on tumor cells independently of anti-angiogenic effects, resulting in induction of receptor switching to activate the evasive adaptation. We further found several agents that effectively blocked the evasive mechanism.

Research Products

• [Journal Article] VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells (2018)
  • Author(s): Tomida Chisato、Yamagishi Naoko、Nagano Hikaru、Uchida Takayuki、Ohno Ayako、Hirasaka Katsuya、Nikawa Takeshi、Teshima-Kondo Shigetada
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 1350-1362
  • DOI: 10.3892/ijo.2018.4291
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive oxygen species up-regulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells. (2018)
  • Author(s): Yuushi Okumura et al.
  • Journal Title: Am J Physiol Cell Physiol. Volume: 印刷中 Issue: 6 Pages: C721-C731
  • DOI: 10.1152/ajpcell.00184.2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor (2017)
  • Author(s): Tomida Chisato、Nagano Hikaru、Yamagishi Naoko、Uchida Takayuki、Ohno Ayako、Hirasaka Katsuya、Nikawa Takeshi、Teshima-Kondo Shigetada
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 262-265
  • DOI: 10.2152/jmi.64.262
  • NAID: 130006105177
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antiangiogenic agent sunitinib induces epithelial to mesenchymal transition and accelerates motility of colorectal cancer cells (2017)
  • Author(s): Chisato Tomida, Naoko Yamagishi, Hikaru Nagano, Takayuki Uchida, Ayako Ohno, Katsuya Hirasaka, Takeshi Nikawa, Shigetada Teshima-Kondo
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 250-254
  • DOI: 10.2152/jmi.64.250
  • NAID: 130006105181
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Capric Acid Up-Regulates UCP3 Expression without PDK4 Induction in Mouse C2C12 Myotubes (2016)
  • Author(s): Abe T, Hirasaka K, Kohno S, Tomida C, Haruna M, Uchida T, Ohno A, Oarada M, Teshima-Kondo S, Okumura Y, Choi I, Aoyama T, Terao J, Nikawa T*.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 62 Issue: 1 Pages: 32-39
  • DOI: 10.3177/jnsv.62.32
  • NAID: 130005148603
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] UCP3 is associated with Hax-1 in mitochondria in the presence of calcium ion (2016)
  • Author(s): Hirasaka K, Mills EM, Haruna M, Bando A, Ikeda C, Abe T, Kohno S, Nowinski SM, Lago CU, Akagi K, Tochio H, Ohno A, Teshima-Kondo S, Okumura Y, Nikawa T
  • Journal Title: Biochem Biophys Res Commun Volume: 472 Issue: 1 Pages: 108-113
  • DOI: 10.1016/j.bbrc.2016.02.075
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin (2016)
  • Author(s): Ohno A, Ochi A, Maita N, Ueji T, Bando A, Nakao R, Hirasaka K, Abe T, Teshima-Kondo S, Nemoto H, Okumura Y, Higashibata A, Yano S, Tochio H, Nikawa T
  • Journal Title: Arch Biochem Biophys Volume: 594 Pages: 1-7
  • DOI: 10.1016/j.abb.2016.02.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prevention of skeletal muscle atrophy in vitro using anti-ubiquitination oligopeptide carried by atelocollagen (2015)
  • Author(s): Kawai N, Hirasaka K, Maeda T, Haruna M, Shiota C, Ochi A, Abe T, Kohno S, Ohno A, Teshima-Kondo S Mori H, Tanaka E, Nikawa T
  • Journal Title: Biochim Biophys Acta Molecular Cell Research Volume: 1853 Issue: 5 Pages: 873-880
  • DOI: 10.1016/j.bbamcr.2015.01.024
  • Peer Reviewed / Open Access
• [Journal Article] A novel myogenic function residing in the 5’ non-coding region of Insulin receptor substrate-1 (Irs-1) transcript. (2015)
  • Author(s): Nagano H, Yamagishi N, Tomida C, Yano C, Aibara K, Kohno S, Abe T, Ohno A, Hirasaka K, Okumura Y, Mills EM, Nikawa T, Teshima-Kondo S.
  • Journal Title: BMC Cell Biol Volume: in press Issue: 1 Pages: 1-10
  • DOI: 10.1186/s12860-015-0054-8
  • NAID: 120006859993
  • Peer Reviewed / Open Access
• [Journal Article] Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells (2015)
  • Author(s): Tomida C, Yamagishi N, Aibara K, Yano C, Uchida T, Abe T, Ohno A, Hirasaka K, Nikawa T, Teshima-Kondo S.
  • Journal Title: The Journal of Medical Investigation Volume: 62 Issue: 1.2 Pages: 75-79
  • DOI: 10.2152/jmi.62.75
  • NAID: 130005129700
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] The malignant progression effects of regorafenib in human colon cancer cells (2015)
  • Author(s): Tomida C, Aibara K, Yamagishi N, Yano C, Nagano H, Abe T, Ohno A, Hirasaka K, Nikawa T, Teshima-Kondo S
  • Journal Title: The Journal of Medical Investigation Volume: 62 Issue: 3.4 Pages: 195-198
  • DOI: 10.2152/jmi.62.195
  • NAID: 130005099146
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] VEGF受容体阻害薬のヒト大腸がん細胞に対する直接的影響 (2017)
  • Author(s): 冨田知里、近藤茂忠
  • Organizer: 第7６回日本癌学会学術総会
• [Presentation] 坐骨神経切除による筋萎縮におけるホエイペプチドと大豆タンパク質の阻害効果 (2017)
  • Author(s): 二宮みゆき、木森有希、髙木麻理奈、井田くるみ、岸本ひかる、高津絵梨香、石田祐子、加藤健、越智ありさ、内田貴之、真板綾子、安倍知紀、近藤茂忠、中尾玲子、平坂勝也、二川健
  • Organizer: 第71回日本栄養・食糧学会大会
• [Presentation] 高病原性インフルエンザ感染に関わる宿主酵素MSPLと阻害ペプチドとの複合体構造 (2017)
  • Author(s): 真板綾子、真板宣夫、奥村裕司、永野ひかる、有田恭平、平坂勝也、安倍知紀、近藤茂忠、二川健
  • Organizer: 第71回日本栄養・食糧学会大会
• [Presentation] Mfn2ノックダウンの筋肉における影響の検討 (2017)
  • Author(s): 木森有希、二宮みゆき、相原知佳、坂下禎宏、内田貴之、安倍知紀、中尾玲子、真板綾子、近藤茂忠、二川健
  • Organizer: 第71回日本栄養・食糧学会大会
• [Presentation] 廃用性筋萎縮を防ぐ高機能米の開発 (2017)
  • Author(s): 二宮みゆき、岸本ひかる、井田くるみ、越智ありさ、北畑香菜子、髙木麻理奈、真板綾子、近藤茂忠、安倍知紀、赤間一仁、二川健
  • Organizer: 第50回日本栄養・食糧学会 中国・四国支部大会
• [Presentation] アピゲニンによる大腸癌細胞悪性化の抑制とその分子機構の解明 (2016)
  • Author(s): 矢野千晶
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-11-30
• [Presentation] VEGF受容体阻害剤による大腸がん細胞悪性化の分子機構の解明 (2016)
  • Author(s): 冨田知里
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-11-30
• [Presentation] 血管新生阻害薬によるがん細胞の悪性化機構の解明 (2016)
  • Author(s): 相原可奈
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Ⅱ型膜貫通型セリンプロテアーゼMSPLとペプチド性阻害剤との複合体結晶楮解析 (2016)
  • Author(s): 真板綾子
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Elucidation of molecular mechanism by which VEGF-R inhibitors promote malignant phenotype of colon cancer cells (2016)
  • Author(s): 冨田知里
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Calcium-Dependent Interactive between UCP3 and Hax-1 (2016)
  • Author(s): Ohno Ayako
  • Organizer: The 27th International Conference on Msgnetic Resonance in Biological Systems
  • Place of Presentation: 国立京都国際会館（京都市）
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] アピゲニンにがん細胞悪性化の抑制とその分子メカニズムの解明 (2016)
  • Author(s): 矢野千晶
  • Organizer: 第70回日本栄養・食糧学会大会
  • Place of Presentation: 武庫川女子大学中央キャンパス（兵庫県西宮市）
  • Year and Date: 2016-05-13
• [Presentation] 無重力による筋細胞内シグナル・トランスダクション (2016)
  • Author(s): 内田貴之
  • Organizer: 第70回日本栄養・食糧学会大会
  • Place of Presentation: 武庫川女子大学中央キャンパス（兵庫県西宮市）
  • Year and Date: 2016-05-13
• [Presentation] VEGF阻害薬による大腸がん細胞の悪性化とその分子機構の解明 (2015)
  • Author(s): 冨田知里, 相原可奈, 矢野千晶, 山岸直子, 安倍知紀、真板（大野）綾子, 二川健, 近藤茂忠
  • Organizer: 第38回日本分子生物学会大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] VEGF受容体阻害薬によるがん細胞の悪性進展機構の解明 (2015)
  • Author(s): 相原可奈, 冨田知里, 矢野千晶, 山岸直子, 安倍知紀、真板（大野）綾子, 二川健, 近藤茂忠
  • Organizer: 第38回日本分子生物学会大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Chemopreventive effects of polyphenols on malignant phenotypes induced by chronic inhibition on VEGF in colorectal cancer cells (2015)
  • Author(s): Shigetada Teshima-Kondo, Yano Chiaki, Yamagishi Naoko, Tomida Chisato, Aibara Kana, Abe Tomoki, Ohno Ayako, Nikawa Takeshi
  • Organizer: 第12回アジア栄養学会議
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-05-14
  • Int'l Joint Research
• [Presentation] N-Myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoide-induced atrophy in mouse skeletal muscle (2015)
  • Author(s): Marina Takagi, Arisa Ochi, Kanako Kitahata, Hikaru Kishimoto, Reiko Nakao, Ayako Maita, Shigetada Kondo, Tomoki Abe, Hisao Nemoto, Takeshi Nikawa
  • Organizer: 第12回アジア栄養学会議
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-05-14
  • Int'l Joint Research
• [Presentation] Cbl-b is a Critical Regulator of macrophage Activation With Obesity-Induced insulin Resistance in Mice (2015)
  • Author(s): Tomoki Abe, Katsuya Hirasaka, Takayuki Uchida, Marina Takagi, Ayako Ohno, Shigetada Kondo, Takeshi Nikawa
  • Organizer: 第12回アジア栄養学会議
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-05-14
  • Int'l Joint Research