Development of a novel therapy targeting cancer stem-ike cells in Esophageal Cell Carcinoma

• Project/Area Number: 25860512
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: NATSUIZAKA Mitsuteru 北海道大学, 大学病院, 助教 (80642446)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 食道扁平上皮癌 / 癌幹細胞 / 上皮間葉転換 / ＣＤ４４ / ＥＭＴ

Outline of Final Research Achievements

Cancer stem-like cells (CSCs) have been identified in many cancers and are thought to attribute to aggressive tumor behavior. CSCs can self-renew and have extremely high tumor initiating capacity. Furthermore, CSCs are highly invasive and resistant to conventional chemotherapy and radiation. Such characteristics of CSCs lead to recurrence, metastasis and inadequate response to the conventional therapies. A novel therapy targeting CSCs is needed to improve prognosis of Esophageal squamouscell carcinoma (ESCC).
We have reported that Notch and TGF pathways are important in regulation of CSCs in ESCC. We have examined effects of Notch and TGF inhibitors on CSCs in the present study. These inhibitors suppress epithelial-mesenchymal transition (EMT) and significantly reduce CSCs in ESCC both in vitro and in vivo experiments. Notch and TGF pathways could be novel therapeutic targets against CSCs in ESCC.

Research Products

• [Journal Article] IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment (2014)
  • Author(s): Natsuizaka M, Kinugasa H, Kagawa S, Whelan KA, Naganuma S, Subramanian H, Chang S, Nakagawa KJ, Rustgi NL, Kita Y, Natsugoe S, Basu D, Gimotty PA, Klein-Szanto AJ, Diehl JA, Rustgi AK and Nakagawa H.
  • Journal Title: American journal of cancer research Volume: 4 Pages: 29-41
  • Peer Reviewed
• [Journal Article] Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor κB/mitogen-activated protein kinase. (2014)
  • Author(s): Chuma M, Sakamoto N, Nakai A, Hige S, Nakanishi M, Natsuizaka M, Suda G, Sho T, Hatakaka K, Matsuno Y, Yokoo H, Kamiyama T, Taketomi A, Fujii G, Tashiro K, Hikiba Y, Fujimoto M, Asaka M, Maeda S
  • Journal Title: Carcinogenesis Volume: Epub ahead of print Issue: 2 Pages: 272-281
  • DOI: 10.1093/carcin/bgt343
  • Peer Reviewed
• [Journal Article] CTNNB1 mutational analysis of solid-pseudopapillary neoplasms of the pancreas using EUS-guided fine-needle aspiration and next-generation deep sequencing (2014)
  • Author(s): Kubota Y, Kawakami H, Natsuizaka M, Kawakubo K, Marukawa K, Kudo T, Abe Y, Kubo K, Kuwatani M, Hatanaka Y, Mitsuhashi T, Matsuno Y, Sakamoto N.
  • Journal Title: Journal of gastroenterology Volume: in press
  • Peer Reviewed
• [Presentation] EGFR inhibitors eliminate esophageal cancer stem cells by suppressing epithelial-mesenchymal transition. (2014)
  • Author(s): Mitsuteru Natsuizaka, Bongani Kaimila, Yoshimasa Kubota, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Fumiyuki Sato, Shunsuke Ohnishi, Goki Suda, Shinya Ohashi, Shingo Kagawa, Kelly Whelan, Anil K Rustgi, Hiroshi Nakagawa, Naoya Sakamoto
  • Organizer: Digestive Disease Week and the 115th annual meeting of the American Gastroenterological Association
  • Place of Presentation: McCormick Place (Chicago, USA)
  • Year and Date: 2014-05-03 – 2014-05-06
• [Presentation] TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma (2014)
  • Author(s): Natsuizaka M, Kagawa S, Whelan K, Ohashi S, Ohnishi S, Suda G, Sakamoto N, Rustgi AK, Nakagawa H
  • Organizer: An AACR special conference on cellular heterogeneity in the tumor microenvironment.
  • Place of Presentation: The Westin San Diego Gaslamp Quarter (San Diego, USA)
• [Presentation] Transforming Growth Factor-beta and Notch1 Cooperate to Repress NOTCH3 to Facilitate Epithelial-Mesenchymal Transition and Tumor Initiating Capability in Esophageal Squamous Cell Carcinoma (2013)
  • Author(s): Natsuizaka M, Kagawa S, Whelan KA, Chang S, Kinugasa H, Ohashi S, Naganuma S, Sakamoto N, Klein-Szanto AJ, Gimotty PA, Diehl JA, Herlyn M, Rustgi AK, Nakagawa H.
  • Organizer: Digestive Disease Week and the 114th annual meeting of the American Gastroenterological Association
  • Place of Presentation: Orange county convention center (Orlando, USA)
• [Presentation] 上皮間葉移行（EMT）による食道扁平上皮癌がん幹細胞維持・増幅機構 (2013)
  • Author(s): 夏井坂光輝、中川裕、坂本直哉
  • Organizer: 日本消化器病関連週間2013 ワークショップ「消化器癌における幹細胞研究の現状と展望」
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
• [Presentation] TGF-β changes a switch of Notch1-mediated signaling to maintain tumor-initiating cells in esophageal SCC (ESCC) (2013)
  • Author(s): Natsuizaka M, Ohashi S, Naganuma S, Ohnishi S, Kuwatani M, Kawakami H, Chuma M, Komatsu Y, Kato M, Sakamoto N
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜）