2024年8月21日出版的《自然》杂志发表了日本东京大学Hiroshi Takayanagi、Masayuki Tsukasaki课题组的最新研究成果。他们发现骨膜是防止癌症细胞侵入骨骼的基质防御系统。

研究人员发现骨膜反应对癌症侵入骨骼发挥保护作用。对人类头颈部鳞状细胞癌（HNSCC）病变的组织学分析表明，骨膜增厚发生在肿瘤附近。研究人员建立了一种可进行基因解剖的HNSCC小鼠模型，并证明诱导性清除骨膜细胞可加速癌细胞对骨骼的侵袭。

单细胞RNA测序表明，在肿瘤入侵前期，骨膜中蛋白酶抑制剂TIMP1的编码基因表达会明显增加。这种增加是由于肿瘤微环境中HIF1α的表达上调，增加的TIMP1可使基质降解蛋白酶失活，促进骨膜增厚，从而抑制癌症的侵袭。缺失Timp1基因会影响骨膜扩张，加剧骨侵袭，降低肿瘤小鼠的存活率。这些数据共同表明，骨膜反应可作为阻止肿瘤进展的功能性基质屏障，是基质细胞介导组织免疫的一个独特实例。

据介绍，骨膜是几乎覆盖所有骨骼表面的一层细胞。在感染、损伤或恶性肿瘤发生时，骨表面会出现新的生长-骨膜反应，但这一过程的机制和生理作用仍然未知。

附：英文原文

Title: The periosteum provides a stromal defence against cancer invasion into the bone

Author: 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

Issue&Volume: 2024-08-21

Abstract: 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 HIF1α 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.

DOI: 10.1038/s41586-024-07822-1

Source: https://www.nature.com/articles/s41586-024-07822-1