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Carcinogenesis

Overview

Chief Takatsugu Ishimoto, M.D., Ph.D.

Genetic factors, viral infection, and chronic inflammation are known to be risk factors in the cancer incidence. These factors not only accumulate direct damage to the cells from which cancer originates, but also dynamically alter the surrounding environment. Our previous studies have shown that interactions between cancer cells and the surrounding tumor microenvironment, such as immune cells and fibroblasts, can lead to cancer progression and resistance to the treatment. By recognizing cancer as a highly diverse tissue, we aim for radical cure of cancer by simultaneously blocking multiple targets.

Research

  1. Elucidation of the mechanism of tumor fibrosis
  2. Establishment of cancer treatment strategies and biomarkers targeting tumor stroma
  3. Research on tissue stem cells and cancer stem cells during carcinogenesis
  4. Elucidation of the mechanism of cancer progression caused by multi-organ interactions

Publications

Akiyama T, Yasuda T, Uchihara T, Yasuda-Yoshihara N, Tan BJY, Yonemura A, Semba T, Yamasaki J, Komohara Y, Ohnishi K, Wei F, Fu L, Zhang J, Kitamura F, Yamashita K, Eto K, Iwagami S, Tsukamoto H, Umemoto T, Masuda M, Nagano O, Satou Y, Saya H, Tan P, Baba H, Ishimoto T (*corresponding author).
Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors.
Cancer Res. 2023 Mar 2;83(5):753-770.
Kumar V, Ramnarayanan K, Sundar R, Padmanbahan N, Srivastava S, Koiwa M, Yasuda T, Koh V, Huang K, Tay S, Ho S, Tan A, Ishimoto T, Kim G, Shabbir A, Chen Q, Biyan Z, Xu S, Lam K, Lum H, Teh M, Yong W, So J and Tan P.
Single-cell atlas of lineage states, tumor microenvironment and subtype-specific expression programs in gastric cancer.
Cancer Discov. 2022 Mar 1;12(3):670-691.
Itoyama R, Yasuda-Yoshihara N, Kitamura F, Yasuda T, Bu L, Yonemura A, Uchihara T, Arima K, Hu X, Jun Z, Okamoto Y, Akiyama T, Yamashita K, Nakao Y, Yusa T, Kitano Y, Higashi T, Miyata T, Imai K, Hayashi H, Yamashita YI, Mikawa T, Kondoh H, Baba H, Ishimoto T (*corresponding author).
Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer.
Cancer Lett. 2021 Dec 28;523:29-42.
Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H*, Ishimoto T*. (*corresponding author)
Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination.
Cell Rep. 2021 Feb 23;34(8):108779.
Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani JA, Tan P, Baba H*, Ishimoto T*. (*corresponding author)
Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance.
Cancer Res. 2020 Aug 15;80(16):3222-3235.
Arima K, Ohmuraya M, Miyake K, Koiwa M, Uchihara T, Izumi D, Gao F, Yonemura A, Bu L, Okabe H, Imai K, Baba Y, Chikamoto A, Yamashita YI, Furukawa T, Araki K, Baba H*, Ishimoto T*. (*corresponding author)
Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas.
Oncogene. 2019 Feb;38(8):1211-1224.
Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H*, Ishimoto T*. (*corresponding author)
Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.
J Pathol. 2018 Aug;245(4):445-455.
Izumi D, Ishimoto T* (*corresponding author), Miyake K, Eto T, Arima K, Kiyozumi Y, Kurashige J, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Takamori H, Tan P, Baba H.
Colorectal cancer stem cells acquire chemoresistance through the upregulation of FBXW7 and the consequent degradation of c-Myc.
Stem Cells 2017 Sep;35(9):2027-2036.
Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang KK, Lin SJ, Kalpana R, Tay ST, Suzuki Y, Cho BC, Kuroda D, Arima K, Izumi D, Iwatsuki M, Baba Y, Oki E, Watanabe M, Saya H, Hirakawa K, Baba H*, Tan P*.
Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells.
Gastroenterology. 2017 Jul;153(1):191-204.
Sawayama H, Ishimoto T (As co-first author), Watanabe M, Yoshida N, Sugihara H, Kurashige J, Hirashima K, Iwatsuki M, Baba Y, Oki E, Morita M, Shiose Y, Baba H*.
Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer.
Cancer Res. 2014 Jan 15; 74(2):575-85.
Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H, Watanabe M, Beppu T, Tamada M, Nagano O, Saya H, Baba H*.
CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma.
Cancer Res. 2012 Jul 1;72 (13):3414-23.
Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H and Nagano O*.
Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell.
Nat. Commun. 2012 Jun 6;3:883.
Ishimoto T, Nagano O*, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H, Saya H.
CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth.
Cancer Cell 2011 Mar 8;19(3):387-400.
Ishimoto T, Oshima H, Oshima M, Kai K, Torii R, Masuko T, Baba H, Saya H, Nagano O*.
CD44+ slow-cycling tumor cell expansion is triggered by the cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis.
Cancer Sci. 2010 March; 101(3): 673-678.

Contact

Takatsugu Ishimoto
Japanese Foundation for Cancer Research (JFCR)
3-8-31 Ariake Koto-ku Tokyo, 135-8550
Tel. +81-3-3570-0462
E-mail: takatsugu.ishimoto@jfcr.or.jp

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