Elucidation of the role of bone marrow-derived cells in the formation of pre-metastatic niche in oral squamous cell carcinoma.

• Project/Area Number: 18K17224
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Okayama University
• Principal Investigator: Kawai Hotaka 岡山大学, 医歯薬学域, 助教 (10803687)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 口腔扁平上皮癌 / 腫瘍微小環境 / 前転移niche / 転移niche / 骨髄由来細胞 / 癌微小環境 / 口腔癌 / 扁平上皮癌 / 遠隔転移 / GFP骨髄移植マウス / 動物モデル

Outline of Final Research Achievements

When tumors metastasize to distant organs, the ease of metastasis varies from organ to organ. In recent years, it has become clear that this difference is related to a microenvironment called the "pre-metastatic niche. The "pre-metastatic niche" is a microenvironment formed in remote organs under the influence of tumors, and tumor metastasis is established using this microenvironment as a foothold.
In this study, we examined the properties of bone marrow-derived cells in high-metastasis and low-metastasis organs by using tumor-transplanted mice with good tumor growth and mice with poor tumor growth. The results showed that Arginase1-positive MDSCs were more abundant in high metastatic organs and were involved in the formation of metastatic niche.

Academic Significance and Societal Importance of the Research Achievements

これまでの研究により、肺癌や肝臓癌、大腸癌、卵巣癌などにおいて前転移nicheが形成されているとの報告があるが、本研究の結果により、口腔癌においても一部遠隔臓器で自身の免疫応答を抑制しながら前転移nicheを形成し、腫瘍の転移を促進していることが明らかとなった。したがって、口腔癌において前転移niche形成を抑制することで、腫瘍の転移を事前に制御することが可能になると考える。

Research Products

• [Journal Article] Extracellular vesicles of P. gingivalis-infected macrophages induce lung injury. (2021)
  • Author(s): Kayo Yoshida, Kaya Yoshida, Natsumi Fujiwara, Mariko Seyama, Kisho Ono, Hotaka Kawai, Jiajie Guo, Ziyi Wang, Yao Weng, Yaqiong Yu, Yoko Uchida-Fukuhara, Mika Ikegame, Akira Sasaki, Hitoshi Nagatsuka, Hiroshi Kamioka, Hirohiko Okamura, Kazumi Ozaki
  • Journal Title: Biochim Biophys Acta - Molecular Basis of Disease Volume: 1867 Issue: 11 Pages: 166236-166236
  • DOI: 10.1016/j.bbadis.2021.166236
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preparation of Absorption-Resistant Hard Tissue Using Dental Pulp-Derived Cells and Honeycomb Tricalcium Phosphate (2021)
  • Author(s): Takabatake Kiyofumi、Nakano Keisuke、Kawai Hotaka、Inada Yasunori、Sukegawa Shintaro、Qiusheng Shan、Fushimi Shigeko、Tsujigiwa Hidetsugu、Nagatsuka Hitoshi
  • Journal Title: Materials Volume: 14 Issue: 12 Pages: 3409-3409
  • DOI: 10.3390/ma14123409
  • NAID: 120007099350
  • Peer Reviewed / Open Access
• [Journal Article] The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma (2021)
  • Author(s): Omori Haruka、Shan Qiusheng、Takabatake Kiyofumi、Nakano Keisuke、Kawai Hotaka、Sukegawa Shintaro、Tsujigiwa Hidetsugu、Nagatsuka Hitoshi
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3491-3491
  • DOI: 10.3390/cancers13143491
  • NAID: 120007126502
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-Associated Stromal Cells Promote the Contribution of MMP2-Positive Bone Marrow-Derived Cells to Oral Squamous Cell Carcinoma Invasion (2021)
  • Author(s): Oo May Wathone、Kawai Hotaka、Takabatake Kiyofumi、Shan Qiusheng、Eain Htoo Shwe、Sukegawa Shintaro、Nakano Keisuke、Nagatsuka Hitoshi
  • Journal Title: Cancers Volume: 14 Issue: 1 Pages: 137-137
  • DOI: 10.3390/cancers14010137
  • NAID: 120007185107
  • Peer Reviewed / Open Access
• [Journal Article] A Pilot Study of Seamless Regeneration of Bone and Cartilage in Knee Joint Regeneration Using Honeycomb TCP (2021)
  • Author(s): Takabatake Kiyofumi、Tsujigiwa Hidetsugu、Yoshida Aki、Furumatsu Takayuki、Kawai Hotaka、Oo May Wathone、Nakano Keisuke、Nagatsuka Hitoshi
  • Journal Title: Materials Volume: 14 Issue: 23 Pages: 7225-7225
  • DOI: 10.3390/ma14237225
  • Peer Reviewed / Open Access
• [Journal Article] Maxillofacial Trauma Surgery Patients With Titanium Osteosynthesis Miniplates (2020)
  • Author(s): Sukegawa Shintaro、Masui Masanori、Sukegawa-Takahashi Yuka、Nakano Keisuke、Takabatake Kiyofumi、Kawai Hotaka、Nagatsuka Hitoshi、Furuki Yoshihiko
  • Journal Title: Journal of Craniofacial Surgery Volume: - Issue: 5 Pages: 1338-1342
  • DOI: 10.1097/scs.0000000000006352
  • Peer Reviewed / Open Access
• [Journal Article] Knockout of MMP3 Weakens Solid Tumor Organoids and Cancer Extracellular Vesicles (2020)
  • Author(s): Taha EA, Sogawa C, Okusha Y, Kawai H, Oo MW, Elseoudi A, Lu Y, Nagatsuka H, Kubota S, Satoh A, Okamoto K, and Eguchi T
  • Journal Title: Cancers (Basel). Volume: 12(5). Issue: 5 Pages: 1260-1260
  • DOI: 10.3390/cancers12051260
  • NAID: 120006864120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. (2020)
  • Author(s): Sogawa C, Eguchi T, Tran MT, Ishige M, Trin K, Okusha Y, Taha EA, Lu Y, Kawai H, Sogawa N, Takigawa M, Calderwood SK, Okamoto K, Kozaki KI.
  • Journal Title: Cancers (Basel). Volume: 12(2). Issue: 2 Pages: 523-523
  • DOI: 10.3390/cancers12020523
  • NAID: 120006840778
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver. (2020)
  • Author(s): Seyama M, Yoshida K, Yoshida K, Fujiwara N, Ono K, Eguchi T, Kawai H, Guo J, Weng Y, Haoze Y, Uchibe K, Ikegame M, Sasaki A, Nagatsuka H, Okamoto K, Okamura H, Ozaki K.
  • Journal Title: Biochim Biophys Acta Mol Basis Dis. Volume: 1866(6) Issue: 6 Pages: 165731-165731
  • DOI: 10.1016/j.bbadis.2020.165731
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biomechanical Loading Comparison between Titanium and Bioactive Resorbable Screw Systems for Fixation of Intracapsular Condylar Head Fractures (2020)
  • Author(s): Sukegawa Shintaro、Yamamoto Norio、Nakano Keisuke、Takabatake Kiyofumi、Kawai Hotaka、Kanno Takahiro、Nagatsuka Hitoshi、Furuki Yoshihiko
  • Journal Title: Materials Volume: 13 Issue: 14 Pages: 3153-3153
  • DOI: 10.3390/ma13143153
  • Peer Reviewed / Open Access
• [Journal Article] High-mobility group box 1 induces bone destruction associated with advanced oral squamous cancer via RAGE and TLR4 (2020)
  • Author(s): Sakamoto Yumi、Okui Tatsuo、Yoneda Toshiyuki、Ryumon Shoji、Nakamura Tomoya、Kawai Hotaka、Kunisada Yuki、Ibaragi Soichiro、Masui Masanori、Ono Kisho、Obata Kyoichi、Shimo Tsuyoshi、Sasaki Akira
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 531 Issue: 3 Pages: 422-430
  • DOI: 10.1016/j.bbrc.2020.07.120
  • NAID: 120006890006
  • Peer Reviewed / Open Access
• [Journal Article] Triple knockdown of CDC37, HSP90-alpha, and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer. (2020)
  • Author(s): Ono K, Sogawa C, Kawai H, Tran MT, Taha EA, Lu Y, Oo MW, Okusha Y, Okamura H, Ibaragi S, Takigawa M, Kozaki K, Nagatsuka H, Sasaki A, Okamoto K, Calderwood SK, Eguchi T
  • Journal Title: J Extracell Vesicles Volume: in press Issue: 1 Pages: 1769373-1769373
  • DOI: 10.1080/20013078.2020.1769373
  • NAID: 120006956812
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of the Stroma on the Biological Characteristics of the Parenchyma in Oral Squamous Cell Carcinoma (2020)
  • Author(s): Takabatake Kiyofumi、Kawai Hotaka、Omori Haruka、Qiusheng Shan、Oo May Wathone、Sukegawa Shintaro、Nakano Keisuke、Tsujigiwa Hidetsugu、Nagatsuka Hitoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 20 Pages: 7714-7714
  • DOI: 10.3390/ijms21207714
  • NAID: 120006900773
  • Peer Reviewed / Open Access
• [Journal Article] Notch Signaling Affects Oral Neoplasm Cell Differentiation and Acquisition of Tumor-Specific Characteristics (2019)
  • Author(s): Nakano Keisuke、Takabatake Kiyofumi、Kawai Hotaka、Yoshida Saori、Maeda Hatsuhiko、Kawakami Toshiyuki、Nagatsuka Hitoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 8 Pages: 1973-1973
  • DOI: 10.3390/ijms20081973
  • NAID: 120006765095
  • Peer Reviewed / Open Access
• [Journal Article] Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (2019)
  • Author(s): Miyake Saki、Higuchi Hitoshi、Honda-Wakasugi Yuka、Fujimoto Maki、Kawai Hotaka、Nagatsuka Hitoshi、Maeda Shigeru、Miyawaki Takuya
  • Journal Title: PLOS ONE Volume: 14 Issue: 5 Pages: 0217209-0217209
  • DOI: 10.1371/journal.pone.0217209
  • Peer Reviewed / Open Access
• [Journal Article] Biomechanical Loading Comparison between Titanium and Unsintered Hydroxyapatite/Poly-L-Lactide Plate System for Fixation of Mandibular Subcondylar Fractures (2019)
  • Author(s): Sukegawa Shintaro、Kanno Takahiro、Yamamoto Norio、Nakano Keisuke、Takabatake Kiyofumi、Kawai Hotaka、Nagatsuka Hitoshi、Furuki Yoshihiko
  • Journal Title: Materials Volume: 12 Issue: 9 Pages: 1557-1557
  • DOI: 10.3390/ma12091557
  • NAID: 120006816641
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemistry of YAP and dNp63 and survival analysis of patients bearing precancerous lesion and oral squamous cell carcinoma (2019)
  • Author(s): Ono Sawako、Nakano Keisuke、Takabatake Kiyofumi、Kawai Hotaka、Nagatsuka Hitoshi
  • Journal Title: International Journal of Medical Sciences Volume: 16 Issue: 5 Pages: 766-773
  • DOI: 10.7150/ijms.29995
  • NAID: 120006860083
  • Peer Reviewed / Open Access
• [Journal Article] Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer. (2019)
  • Author(s): Yoshida S, Kawai H, Eguchi T, Sukegawa S, Oo MW, Anqi C, Takabatake K, Nakano K, Okamoto K, Nagatsuka H.
  • Journal Title: Cells. Volume: 8(7). Issue: 7 Pages: 761-761
  • DOI: 10.3390/cells8070761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma (2019)
  • Author(s): Takabatake K, Shimo T, Murakami J, Anqi C, Kawai H, Yoshida S, Wathone Oo M, Haruka O, Sukegawa S, Tsujigiwa H, Nakano K, Nagatsuka H.
  • Journal Title: Int J Mol Sci Volume: 20(22) Issue: 22 Pages: 5779-5779
  • DOI: 10.3390/ijms20225779
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma. (2019)
  • Author(s): Shimizu R, Ibaragi S, Eguchi T, Kuwajima D, Kodama S, Nishioka T, Okui T, Obata K, Takabatake K, Kawai H, Ono K, Okamoto K, Nagatsuka H, Sasaki A.
  • Journal Title: International Journal of Oncology Volume: 54（1） Pages: 283-294
  • DOI: 10.3892/ijo.2018.4631
  • NAID: 120006786204
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis (2018)
  • Author(s): Kawai Hotaka、Tsujigiwa Hidetsugu、Siar Chong Huat、Nakano Keisuke、Takabatake Kiyofumi、Fujii Masae、Hamada Mei、Tamamura Ryo、Nagatsuka Hitoshi
  • Journal Title: International Journal of Medical Sciences Volume: 15 Issue: 12 Pages: 1406-1414
  • DOI: 10.7150/ijms.24370
  • Peer Reviewed / Open Access
• [Journal Article] The role of bone marrow-derived cells during ectopic bone formation of mouse femoral muscle in GFP mouse bone marrow transplantation model. (2018)
  • Author(s): Takabatake K, Tsujigiwa H, Song Y, Matsuda H, Kawai H, Fujii M, Hamada M, Nakano K, Kawakami T and Nagatsuka H.
  • Journal Title: Int J Med Sci Volume: 15 Issue: 8 Pages: 748-757
  • DOI: 10.7150/ijms.24605
  • Peer Reviewed / Open Access
• [Journal Article] Oropharyngeal adenoid cystic carcinoma invading the mandibular bone through the mandibular foramen (2018)
  • Author(s): Takeshita Yohei、Okada Shunsuke、Hisatomi Miki、Matsuzaki Hidenobu、Kawai Hotaka、Noda Yohei、Murakami Jun、Fujita Mariko、Nagatsuka Hitoshi、Yanagi Yoshinobu、Asaumi Junichi
  • Journal Title: Oral Radiology Volume: Epub Issue: 3 Pages: 335-340
  • DOI: 10.1007/s11282-018-0359-3
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the Geometrical Structure of a Honeycomb TCP on Relationship between Bone / Cartilage Formation and Angiogenesis (2018)
  • Author(s): Matsuda Hiroyuki、Takabatake Kiyofumi、Tsujigiwa Hidetsugu、Watanabe Satoko、Ito Satoshi、Kawai Hotaka、Hamada Mei、Yoshida Saori、Nakano Keisuke、Nagatsuka Hitoshi
  • Journal Title: International Journal of Medical Sciences Volume: 15 Issue: 14 Pages: 1582-1590
  • DOI: 10.7150/ijms.28452
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of lipid efflux pump ABCG1 triggers the intracellular accumulation of extracellular vesicles and reduces aggregation and tumorigenesis of metastatic cancer cells. (2018)
  • Author(s): Namba Y, Sogawa C, Okusha Y, Kawai H, Itagaki M, Ono K, Murakami J, Aoyama E, Ohyama K, Asaumi J, Takigawa M, Okamoto K, Calderwood SK, Kozaki K, Eguchi T.
  • Journal Title: Frontiers in Oncology Volume: 8（376） Pages: 1-16
  • DOI: 10.3389/fonc.2018.00376
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma. (2018)
  • Author(s): Hasegawa K, Okui T, Shimo T, Ibaragi S, Kawai H, Ryumon S, Kishimoto K, Okusha Y, Monsur Hassan NM, Sasaki A.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 11 Pages: 3317-3317
  • DOI: 10.3390/ijms19113317
  • Peer Reviewed / Open Access
• [Presentation] CCL2-CCR2 axisを介した癌関連線維芽細胞による骨髄由来細胞の動員 (2021)
  • Author(s): 河合 穂高,、メイワトウ、高畠 清文、大森 悠加、中野 敬介、長塚 仁
  • Organizer: 第１１０回日本病理学会総会
• [Presentation] 癌微小環境における口腔癌間質細胞と骨髄由来細胞の 関係性について (2021)
  • Author(s): 河合 穂高、 メイ ワト ウ、 高畠 清文、中野 敬介、長塚 仁
  • Organizer: 第６７回日本病理学会秋期特別総会
• [Presentation] 口腔癌間質細胞が骨髄由来細胞の動員に与える影響 (2020)
  • Author(s): 河合 穂高, メイ・ワト ウ , 辻極 秀次, 高畠 清文, 大森 悠加, 藤井 昌江, 中野 敬介, 長塚 仁
  • Organizer: 第１０９回日本病理学会総会
• [Presentation] 口腔扁平上皮癌における間質細胞が与える骨髄由来細胞の動員への影響 (2020)
  • Author(s): 河合 穂高, メイ ワト ウ, 髙畠 清文, 伏見 滋子, 稲田 靖則, 中野 敬介, 長塚仁
  • Organizer: 第３１回日本臨床口腔病理学会 学術大会
• [Presentation] 動物モデルを用いた高転移臓器における転移促進的微小環境の検討 (2019)
  • Author(s): 河合穂高 辻極秀次 May Wathone Oo 高畠清文 中野敬介 吉田沙織 長塚仁
  • Organizer: 日本病理学会
• [Presentation] マウス肺癌移植モデルにおける骨髄由来細胞の肺癌移植マウス高転移臓器における骨髄由来細胞の局在と役割の検討全身的局在と役割 (2018)
  • Author(s): 河合 穂高、辻極 秀次、信長 ひかり、高河合穂高、辻極秀次、藤井昌江、高畠清文、中野敬介、吉田沙織、浜田芽衣、長塚 仁畠 清文、中野 敬介、 松田 寛之、伏見 滋子、長塚 仁
  • Organizer: 第１０７回日本病理学会総会
• [Presentation] 肺癌移植マウスを用いた高転移臓器における骨髄由来細胞の局在と役割の検討 (2018)
  • Author(s): 河合穂高、辻極秀次、信長ひかり、高畠清文、中野敬介、長塚 仁
  • Organizer: 第２２回日本がん免疫学会総会
• [Presentation] 腫瘍移植マウスの高転移臓器における骨髄由来細胞の局在と役割の検討 (2018)
  • Author(s): 河合穂高、辻極秀次、信長ひかり、高畠清文、中野敬介、長塚 仁
  • Organizer: 第２９回日本臨床口腔病理学会 総会・学術大会
• [Presentation] 生体活性 / 吸収性骨接合材料 SuperFIXSORB MXを科学する 口腔病理医の立場から (2018)
  • Author(s): 河合 穂高
  • Organizer: 第６６回NPO法人日本口腔科学会中国・四国地方部会
  • Invited
• [Patent(Industrial Property Rights)] 組織再生材料およびその製造方法 (2020)
  • Inventor(s): 河合穂高
  • Industrial Property Rights Holder: 河合穂高
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020