Molecular Basis of Hedgehog Signaling and New Therapeutic Strategies for Cancer induced Bone-Destruction

Hedgehog 信号传导的分子基础和癌症引起的骨破坏的新治疗策略

• 批准号: 22H03293
• 负责人: 志茂 剛
• 金额: $ 11.07万
• 依托单位: Health Sciences University of Hokkaido
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22H03293/
• 关键词: 口腔癌; 顎骨破壊; 破骨細胞; 口腔がん; 癌; 骨破壊; 癌骨微小環境

口腔癌の顎骨浸潤は、化学療法の効果が期待できず外科療法が選択される。しかしながら、機能温存の観点から問題点も多く、顎骨切除症例における歯肉癌骨髄浸潤は予後に独立して寄与し（Yoshida, Shimo et al. Anticancer Res 2018）、癌を取り巻く微小環境が癌幹細胞維持や薬剤耐性獲得に関与することから癌骨破壊微小環境は新たな治療標的となる可能性がわかってきた。これまで申請者はSonic hedgehog (SHH)、そのシグナル分子Gli1、Gli2の口腔扁平上皮癌における発現を報告してきた。皮膚メラノーマ臨床切除標本におけるGli1、Gli2、SHHの発現の相関を検討すると、腫瘍細胞におけるGli1及びGli2とSHHの免疫染色発現強度は有意に正の相関を認めた。顎骨浸潤を伴う口腔メラノーマ切除検体において、Gli1及びGli2とSHHは腫瘍細胞、破骨細胞、腫瘍血管にその発現を認めた。申請者はマウス脛骨にマウスメラノーマB16細胞を移植し、骨破壊モデルを作成し、癌微小環境メカニズムを解析した。脛骨皮質骨周囲のTRAP陽性破骨細胞、Endomucin陽性の腫瘍血管内皮細胞の増大を認め、HedgehogシグナルGli1、Gli2阻害剤GANT61はTRAP陽性細胞、Endomucin陽性細胞数を抑制した。GANT61はMelanA陽性腫瘍細胞に対するGli1、Gli2、PD-L1陽性細胞数を抑制し、アポトーシスを促進しPD-L1発現を抑制するメカニズムが明らかになった。

Oral cancer has infiltration into the jawbone, and the effect of chemotherapy is not expected, so the surgical treatment is selected. Yoshida, Shimo et al. Anticancer Res 2018), the relationship between the acquisition of cancer stem cells and the microenvironment of cancer and the maintenance of cancer resistance and the possibility of new treatment targets in the microenvironment of cancer bone destruction. Sonic hedgehog (SHH) and oral squamous epithelial cancer molecules Gli1 and Gli2 are reported by the applicant. Skin メラノーマClinical excision specimen におけるGli1, Gli2, SHHの発appearのrelated を検 Discussion すると, The intensity of immunostaining for Gli1 and Gli2 and SHH in tumor cells was found to be positively correlated. Infiltration of the jaw bone is accompanied by oral cavity removal, removal of the body, Gli1, and SHH, and identification of the presence of tumor cells, osteoclasts, and tumor blood vessels. The applicant performed the transplantation of B16 cells into the tibia, the creation of osteoblasts, and the analysis of the cancer microenvironment. The number of TRAP-positive osteoclasts in the tibial cortical periosteal area and the endothelial cells of endothelial cells in Endomucin-positive tumors were increased. Hedgehog cells Gli1 and Gli2 inhibited GANT61 and TRAP-positive cells, and the number of Endomucin-positive cells was inhibited. GANT61, MelanA positive tumor cells, Gli1, Gli2, PD-L1 positive cells The number of inhibitors, the promotion of PD-L1 expression and the suppression of PD-L1 expression are the same.

项目成果

Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins.

用于研究 CCN 蛋白的肿瘤骨转移和侵袭的小鼠模型。

• DOI: 10.1007/978-1-0716-2744-0_24
• 发表时间: 2023
• 期刊: Methods Mol Biol.
• 作者: Shimo T;Okui T;Horie N;Yokozeki K;Takigawa M;Sasaki A.
• 通讯作者: Sasaki A.

Immunohistochemical analysis of CCN2 in experimental fracture healing models

实验性骨折愈合模型中 CCN2 的免疫组织化学分析

• DOI: 10.1007/978-1-0716-2744-0_23
• 发表时间: 2023
• 期刊: Methods Mol Biol
• 作者: Tsuyoshi Shimo;Hiroaki Takebe;Saki Fujii;Akihiro Hosoya
• 通讯作者: Akihiro Hosoya

Oral cancer induced jaw bone destruction

口腔癌引起颌骨破坏

• 发表时间: 2023
• 作者: Chiba Yuta;Yoshizaki Keigo;Sato Hiroshi;Ikeuchi Tomoko;Rhodes Craig;Chiba Mitsuki;Saito Kan;Nakamura Takashi;Iwamoto Tsutomu;Yamada Aya;Yamada Yoshihiko;Fukumoto Satoshi;黒嶋伸一郎;Tsuyoshi Shimo
• 通讯作者: Tsuyoshi Shimo