Anti-metastatic therapy that simultaneously leads to both loss of cancer stem-like cell property and MET (mesenchymal to epithelial transition) in head and neck cancer
| Project/Area Number |
19K09876
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 56050:Otorhinolaryngology-related
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| Research Institution | International University of Health and Welfare (2020-2022)
Keio University (2019) |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | 頭頸部癌 / 咽頭扁平上皮癌 / 転移 / 頸部リンパ節 / EMT（上皮間葉転換） / 癌幹細胞特性 / Cox-2 / EP2 / 舌口腔癌 / 咽喉頭癌 / 経口切除術 / 独立規定因子 / 健側頸部リンパ節転移 / 傍神経浸潤(PNI) / 間葉上皮転換(MET) / 治療施設類型 / 咽頭癌 / 手術 / perineural invasion / がん幹細胞特性 / 口腔癌 / 化学放射線治療 / 独立予後因子 / AGR / 間葉上皮転換（MET） / E-cadherin / 導入化学療法 / 間葉上皮転換 / 癌幹細胞 / 薬剤耐性 |
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| Outline of Research at the Start |
頭頸部癌の治療成績向上には癌細胞の浸潤転移と薬剤耐性の制御が不可欠である。そこで癌細胞の間葉上皮転換と幹細胞形質喪失を同時誘導する新たな治療戦略の確立を目的に本研究を行う。関連する分子機構としてCox2/PGE2/EP2，VEGF-C/Flt-4/CNTN-1，およびVEGF-C/Flt-4/Cox-2のシグナル経路を標的とし，その制御による抗腫瘍効果をHNSCCモデルを用いて多角的に評価する。
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| Outline of Final Research Achievements |
1) In pharyngeal squamous cell carcinoma (PSCC) cells, selective inhibition of Cox2 and its downstream EP2 (PGE2 receptor) showed antitumor effects by suppressing cell proliferation and migration via MET-induction (EMT-reversal) through downregulation of various EMT-TFs. Histopathological analysis of hypopharyngeal carcinoma specimens suggested a profound involvement of EMT, characterized by decreased E-cadherin expression and increased Cox2 expression, in cervical lymph node metastasis.
2) Selective Cox2 and EP2 inhibition of PSCC cells attenuates anchorage-independent cell proliferative ability by down-regulating several CSC-related molecules such as Oct3/4 and Nanog, thereby enhancing chemosensitivity to docetaxel. Immunohistochemical analysis of oro-hypopharyngeal carcinoma specimens before and after induction chemotherapy displayed a significant inverse correlation between pre-treatment Cox2 expression and the histological therapeutic effect of induction chemotherapy.
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| Academic Significance and Societal Importance of the Research Achievements |
頭頸部扁平上皮癌における治療成績向上の最大の障壁は制御困難な転移にある。本研究の結果は，癌転移と薬剤抵抗性の双方に関わるEMT（上皮間葉転換）と癌幹細胞能を同時に誘導する分子機構の一端を明らかにすることにより，その関連分子を指標とする転移リスク評価の有用性，およびそれらを標的とする治療の有効性を示唆するもので，癌診療の新たな戦略の実現可能性が期待される。
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Report
(5 results)
Research Products
(31 results)
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[Journal Article] Midline involvement and perineural invasion predict contralateral neck metastasis that affects overall and disease-free survival in locally advanced oral tongue squamous cell carcinoma2022
Author(s)
Maki Akamatsu,Takuma Makino,Shinya Morita,Yohei Noda,Shin Kariya,Tomoo Onoda,Mizuo Ando,Yoshihiro Kimata,Kazunori Nishizaki,Mitsuhiro Okano,Aiko Oka,Kengo Kanai,Yoshihiro Watanabe,Yorihisa Imanishi
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Journal Title
Front Oncol
Volume: 12
Pages: 1010252-1010252
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Pretherapeutic Predictive Factors for Histological High-Grade Parotid Gland Carcinoma2022
Author(s)
Takuya Mikoshiba, Hiroyuki Ozawa, Yoshihiro Watanabe, Miho Kawaida, Mariko Sekimizu, Shin Saito, Keisuke Yoshihama, Shintaro Nakamura, Ryoto Nagai, Yorihisa Imanishi, Kaori Kameyama, Kaoru Ogawa
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Journal Title
Laryngoscope
Volume: 132
Issue: 1
Pages: 96-102
DOI
Related Report
Peer Reviewed
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[Journal Article] Selective EP2 and Cox-2 inhibition suppresses cell migration by reversing epithelial-to-mesenchymal transition and Cox-2 overexpression and E-cadherin downregulation are implicated in neck metastasis of hypopharyngeal cancer2020
Author(s)
Watanabe Y, Imanishi Y, Ozawa H, Sakamoto K, Fujii R, Shigetomi S, Habu N, Otsuka K, Sato Y, Sekimizu M, Ito F, Ikari Y, Saito S, Kameyama K and Ogawa K
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Journal Title
Am J Transl Res
Volume: 12
Pages: 1096-1113
Related Report
Peer Reviewed / Open Access
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