The periosteum provides a stromal defence against cancer invasion into the bone
成果类型：
Article
署名作者：
Nakamura, Kazutaka; Tsukasaki, Masayuki; Tsunematsu, Takaaki; Yan, Minglu; Ando, Yutaro; Huynh, Nam Cong-Nhat; Hashimoto, Kyoko; Gou, Qiao; Muro, Ryunosuke; Itabashi, Ayumi; Iguchi, Takahiro; Okamoto, Kazuo; Nakamura, Takashi; Nakano, Kenta; Okamura, Tadashi; Ueno, Tomoya; Ito, Kosei; Ishimaru, Naozumi; Hoshi, Kazuto; Takayanagi, Hiroshi
署名单位：
University of Tokyo; University of Tokyo; University of Tokyo; University of Tokyo; Tokushima University; University of Texas System; University of Texas Southwestern Medical Center; Hochiminh City University of Medicine & Pharmacy; Tokyo University of Science; Kanazawa University; Tokyo Dental College; Japan Institute for Health Security (JIHS); National Center for Global Health & Medicine - Japan; Nagasaki University; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU)
刊物名称：
Nature
ISSN/ISSBN：
0028-5134
DOI：
10.1038/s41586-024-07822-1
发表日期：
2024-10-10
关键词：
摘要：
The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth-the periosteal reaction-but the mechanism and physiological role of this process remain unknown1,2. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1 alpha expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells. Experiments in mouse models and histology of human head and neck squamous cell carcinomas show that TIMP1-mediated periosteal thickening in proximity to tumours acts as a barrier to cancer invasion of the bone.