Strategic analysis for the development of new anticancer treatments targeting tumor-associated macrophages
Project/Area Number |
17H04060
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Human pathology
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Research Institution | Kumamoto Health Science University (2019) Kumamoto University (2017-2018) |
Principal Investigator |
Takeya Motohiro 熊本保健科学大学, 保健科学部, 教授 (90155052)
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Co-Investigator(Kenkyū-buntansha) |
藤原 章雄 熊本大学, 大学院生命科学研究部(医), 講師 (70452886)
大西 紘二 熊本大学, 大学院生命科学研究部(医), 特任准教授 (40613378)
哈 斯塔 熊本大学, 大学院生命科学研究部(医), 研究員 (00644840)
西東 洋一 熊本大学, 大学院生命科学研究部(医), 研究員 (20783567)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2017: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
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Keywords | 腫瘍随伴マクロファージ / 腫瘍微小環境 / トリプルネガティブ乳癌 / 未分化多形肉腫 / CD163 / CD163欠損マウス / 新規がん治療法 / 天然化合物 / リンパ節洞マクロファージ / 浸潤性膀胱癌 / CD169 / α1-酸性糖蛋白 / イカリソウ / 担癌モデルマウス / 癌治療法開発 / IL-6 / がん関連線維芽細胞 / がん治療法開発 / CD204 / 乳癌 |
Outline of Final Research Achievements |
In triple-negative breast cancer, density of M2-type tumor-associated macrophages (TAM) correlated with proliferative capacity of tumor cells. In undifferentiated pleomorphic sarcoma, density of CD163-positive M2-type TAM showed positive correlation with poor prognosis of the patients. In co-culture of macrophages (Mφ) and sarcoma cells, CD163-deficient Mφ suppressed tumor proliferation in comparison with wild-type Mφ. Growth of transplanted tumors in CD163-deficient mice was significantly suppressed compared to wild-type. CD163-mediated production of IL-6 by Mφ enhanced tumor cell proliferation. Through the screening of natural compounds that suppress CD163 expression, we found epimedokoreanin B derived from Epimedii Herb suppressed stat3 activation both in Mφ and tumor cells and suppressed growth of tumors transplanted in mice.
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Academic Significance and Societal Importance of the Research Achievements |
癌微小環境は癌治療の新たな標的となっており、中でも腫瘍随伴マクロファージ(TAM)は多様な機序に基づいて、多くのヒト腫瘍の増殖進展を促進することから、新規癌治療の標的として注目される。私どもはM2型TAMがヒト癌の増殖を促進することを示し、M2型TAMのマーカー分子であるCD163が直接的に腫瘍増殖に関与することを明らかにした。更に、CD163の発現を抑制する天然化合物を同定し、マウスの移植腫瘍の増殖を抑制することを示した。本研究は、天然化合物によるM2型TAMの抑制が腫瘍抑制に有用であることを示しており、TAMを標的とするヒト癌治療への応用が期待される。
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Report
(4 results)
Research Products
(110 results)
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[Journal Article] Clinical impact of TROP2 in non-small lung cancers and its correlation with abnormal p53 nuclear accumulation.2020
Author(s)
Mito R, Matsubara E, Komohara Y, Shinchi Y, Sato K, Yoshii D, Ohnishi K, Fujiwara Y, Tomita Y, Ikeda K, Sakagami T, Suzuki M.
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Journal Title
Pathol Int
Volume: in press
Issue: 5
Pages: 287-294
DOI
Related Report
Peer Reviewed
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[Journal Article] Phlenumdines D and E, new Lycopodium alkaloids from Phlegmariurus nummulariifolius, and their regulatory effects on macrophage differentiation during tumor development.2019
Author(s)
Nakayama W, Fujiwara Y, Kosuge Y, Monthakantirat O, Fujikawa K, Watthana S, Kitanaka S, Makino T, Ishiuchi K.
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Journal Title
Phytochem Lett
Volume: 29
Pages: 98-103
Related Report
Peer Reviewed
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[Journal Article] Nω -(Carboxymethyl)arginine Is One of the Dominant Advanced Glycation End Products in Glycated Collagens and Mouse Tissues.2019
Author(s)
Kinoshita S, Mera K, Ichikawa H, Shimasaki S, Nagai M, Taga Y, Iijima K, Hattori S, Fujiwara Y, Shirakawa JI, Nagai R.
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Journal Title
Oxid Med Cell Longev
Volume: 2019
Pages: 9073451-9073451
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Elevation of Pulmonary CD163 + and CD204 + Macrophages Is Associated With the Clinical Course of Idiopathic Pulmonary Fibrosis Patients2019
Author(s)
Nouno T, Okamoto M, Ohnishi K, Kaieda S, Tominaga M, Zaizen Y, Ichiki M, Momosaki S, Nakamura M, Fujimoto K, Fukuoka J, Shimizu S, Komohara Y, Hoshino T.
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Journal Title
Journal of Thoracic Disease
Volume: 11
Issue: 9
Pages: 4005-4017
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] CD163 is required for protumoral activation of macrophages in human and murine sarcoma.2018
Author(s)
Shiraishi D, Fujiwara Y, Horlad H, Saito Y, Iriki T, Tsuboki J, Cheng P, Nakagata N, Mizuta H, Bekki H, Nakashima Y, Oda Y, Takeya M, Komohara Y.
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Journal Title
Cancer Res
Volume: in press
Issue: 12
Pages: 3255-3266
DOI
Related Report
Peer Reviewed
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[Journal Article] High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer.2018
Author(s)
Takeya H, Shiota T, Yagi T, Ohnishi K, Baba Y, Miyasato Y, Kiyozumi Y, Yoshida N, Takeya M, Baba H, Komohara Y.
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Journal Title
Pathology international
Volume: 68
Issue: 12
Pages: 685-693
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Differential roles of Rad18 and Chk2 in genome maintenance and skin carcinogenesis following UV exposure.2018
Author(s)
Tanoue, Y., Toyoda, T., Sun, J, Mustofa, M.K., Tateishi, C., Endo, S., Motoyama, N., Araki, K., Wu, D., Okuno, Y., Tsukamoto, T., Takeya, M., Ihn, H., Vaziri, C., Tateishi, S.
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Journal Title
J. Invest. Dermatol.
Volume: 138
Issue: 12
Pages: 2550-2557
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Genetic Fusion of Type-I Interferon to a Recombinant Albumin Mutant with polymannosylated N-linked oligosaccharide attached is a Novel and Superior Kupffer Cell Targeting Agent for the Treatment of Hepatitis.2018
Author(s)
Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T.
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Journal Title
Drug Delivery
Volume: 25
Issue: 1
Pages: 1067-1077
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis.2018
Author(s)
Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
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Journal Title
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume: 印刷中
Issue: 5
Pages: 994-1006
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling.2018
Author(s)
Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
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Journal Title
Oncogene.
Volume: 37
Issue: 9
Pages: 1205-1219
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Atypical Cyclic Sulfides, Garlicnins G, I, and J, Extracted from <i>Allium sativum</i>2017
Author(s)
Ono M, Fujiwara Y, Ikeda T, Pan C, El-Aasr M, Lee JH, Nakano D, Kinjo J, Nohara T.
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Journal Title
Chemical and Pharmaceutical Bulletin
Volume: 65
Issue: 1
Pages: 102-106
DOI
NAID
ISSN
0009-2363, 1347-5223
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] PD-L1 expression in papillary renal cell carcinoma2017
Author(s)
Takanobu Motoshima, Yoshihiro KomoharaEmail author, Chaoya Ma, Arni Kusuma Dewi, Hirotsugu Noguchi, Sohsuke Yamada, Toshiyuki Nakayama, Shohei Kitada, Yoshiaki Kawano, Wataru Takahashi, Masaaki Sugimoto, Motohiro Takeya, Naohiro Fujimoto, Yoshinao Oda and Masatoshi Eto
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Journal Title
BMC Urology
Volume: 17
Issue: 1
Pages: 8-8
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Antitumor <i>Allium</i> Sulfides2017
Author(s)
Nohara T, Fujiwara Y, El-Aasr M, Ikeda T, Ono M, Nakano D, Kinjo J.
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Journal Title
Chemical and Pharmaceutical Bulletin
Volume: 65
Issue: 3
Pages: 209-217
DOI
NAID
ISSN
0009-2363, 1347-5223
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Cell adhesion molecule-1 (CADM1) expressed on adult T-cell leukemia/lymphoma cells is not involved in the interaction with macrophages.2017
Author(s)
Komohara Y, Ma C, Yano H, Pan C, Horlad H, Saito Y, Ohnishi K, Fujiwara Y, Okuno Y, Nosaka K, Shimosaki S, Morishita K, Matsuoka M, Wakayama T, Takeya M
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Journal Title
Journal of Clinical and Experimental Hematopathology
Volume: 57
Issue: 1
Pages: 15-20
DOI
NAID
ISSN
1346-4280, 1880-9952
Related Report
Peer Reviewed / Open Access
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[Journal Article] Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines2017
Author(s)
Ma C, Horlad H, Pan C, Yano H, Ohnishi K, Fujiwara Y, Matsuoka M, Lee A, Niidome T, Yamanaka R, Takeya M, Komohara Y
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Journal Title
Journal of Clinical and Experimental Hematopathology
Volume: 57
Issue: 1
Pages: 21-25
DOI
NAID
ISSN
1346-4280, 1880-9952
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] High density of CD204-positive macrophages predicts worse clinical prognosis in patients with breast cancer2017
Author(s)
Miyasato Y, Shiota T, Ohnishi K, Pan C, Yano H, Horlad H, Yamamoto Y, Yamamoto-Ibusuki M, Iwase H, Takeya M, Komohara Y.
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Journal Title
Cancer Science
Volume: 108
Issue: 8
Pages: 1693-1700
DOI
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Peer Reviewed / Open Access
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[Journal Article] The significance of TIMD4 expression in clear cell renal cell carcinoma2017
Author(s)
Yano H, Motoshima T, Ma C, Pan C, Yamada S, Nakayama T, Kitada S, Fujimoto N, Kamba T, Takeya M, Komohara Y.
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Journal Title
Medical Molecular Morphology
Volume: 50
Issue: 4
Pages: 220-226
DOI
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Peer Reviewed
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[Presentation] IL-34 induces cell migration, and its ectopic expression correlates with macrophage infiltration and prognosis of DLBCL.2018
Author(s)
Yoshihiro Komohara, Osamu Noyori, Chaoya Ma, Cheng Pan, Joaquim Carreras, Naoya Nakamura, Ai Sato, Kiyoshi Ando, Yutaka Okuno, Kisato Nosaka, Masao Matsuoka, Motohiro Takeya, and Shinya Suzu.
Organizer
The 14th Japanese-Korean Lymphoreticular Workshop 2018
Related Report
Int'l Joint Research
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[Presentation] Onionin A, a sulfur-containing compound isolated from onions, impairs tumor progression by inhibiting the protumoral functions of macrophages.2017
Author(s)
Yukio Fujiwara, Junko Tsuboki, Hasita Horlad, Daisuke Shiraishi, Toshihiro Nohara, Yoshihiro Komohara, Motohiro Takeya.
Organizer
Keystone Symposia, Mononuclear Phagocytes in Health, Immune Defense and Disease (D3)
Related Report
Int'l Joint Research
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