中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (20): 4286-4294.doi: 10.12307/2025.698

• 组织构建综述 tissue construction review • 上一篇    下一篇

细胞外基质硬度对肿瘤进展的影响及治疗策略

吴丽娟1，王振飞2，谭晓慧1，武颍彩2，郑艳玲1，2，代风雪1，2   

  1. 1内蒙古医科大学，内蒙古自治区呼和浩特市  010059；2北京大学肿瘤医院内蒙古医院肿瘤分子诊断实验室/内蒙古医科大学附属肿瘤医院，内蒙古自治区呼和浩特市  010020
  • 收稿日期:2024-07-08 接受日期:2024-09-07 出版日期:2025-07-18 发布日期:2024-12-21
  • 通讯作者: 王振飞，博士，研究员，北京大学肿瘤医院内蒙古医院肿瘤分子诊断实验室/内蒙古医科大学附属肿瘤医院，内蒙古自治区呼和浩特市 010020
  • 作者简介:吴丽娟，女，1999年生，河北省康保县人，汉族，内蒙古医科大学在读硕士，主要从事肿瘤微环境方面的研究。
  • 基金资助:
    国家自然科学基金面上项目 (82074144)，项目负责人：王振飞；内蒙古自治区重点研发和成果转化项目(2023KJHZ0023)，项目负责人：王振飞；内蒙古医科大学科技创新团队(YKD2023TD010)，项目负责人：王振飞；内蒙古自治区高等学校科技创新团队(NMGIRT2327) ，项目负责人：王振飞；内蒙古自治区高等学校科学研究项目(NJZY22636)，项目负责人：谭晓慧

Effect of extracellular matrix stiffness on tumor progression and treatment strategies

Wu Lijuan1, Wang Zhenfei2, Tan Xiaohui1, Wu Yingcai2, Zheng Yanling1, 2, Dai Fengxue1, 2   

  1. 1Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China; 2Laboratory of Molecular Tumor Diagnosis, Inner Mongolia Hospital, Peking University Cancer Hospital/Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot 010020, Inner Mongolia Autonomous Region, China
  • Received:2024-07-08 Accepted:2024-09-07 Online:2025-07-18 Published:2024-12-21
  • Contact: Wang Zhenfei, MD, Researcher, Laboratory of Molecular Tumor Diagnosis, Inner Mongolia Hospital, Peking University Cancer Hospital, Hohhot 010020, Inner Mongolia Autonomous Region, China
  • About author:Wu Lijuan, Master’s candidate, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
  • Supported by:
     the National Natural Science Foundation of China, No. 82074144 (to WZF); Key R&D and Achievement Transformation Project of Inner Mongolia Autonomous Region, No. 2023KJHZ0023 (to WZF); Science and Technology Innovation Team of Inner Mongolia Medical University, No. YKD2023TD010 (to WZF); Science and Technology Innovation Team of Higher Education Institutions in Inner Mongolia Autonomous Region, No. NMGIRT2327 (to WZF); Scientific Research Project of Higher Education Institutions in Inner Mongolia Autonomous Region, No. NJZY22636 (to TXH) 

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摘要：

文题释义：
基质硬度：是指肿瘤微环境中细胞外基质的机械刚性，基质中的成分如胶原纤维过度沉积和交联，增强了细胞外基质的结构稳定性，肿瘤细胞及其周围细胞释放的酶和生长因子也会影响基质的合成和降解，进一步影响硬度。基质硬度的变化对肿瘤的生物学行为有重要影响，常常与肿瘤的进展和侵袭性相关。
胶原交联：是指胶原分子之间在交联酶(如赖氨酸氧化酶)的催化下通过化学键连接形成一种稳定的结构，能够提高胶原纤维的刚性和密度，该结构不仅增强了基质的机械支持功能，还会导致基质硬度增加，促进肿瘤的进展及阻碍药物的渗透。理解胶原纤维沉积和交联的形成及其对肿瘤微环境的影响，对揭示肿瘤的生物力学机制和开发新的治疗策略具有重要意义。

背景：细胞外基质是一个复杂的网络结构，不仅为组织构建提供了物理支撑，还在细胞的生存、增殖、分化、死亡等过程中发挥着重要调控作用。细胞外基质生物化学和生物力学性质的异常改变会显著影响肿瘤细胞的增殖、迁移、免疫逃逸及治疗抵抗等行为。硬度是细胞外基质的重要力学特性，基质硬度的异常与肿瘤进展紧密相关。
目的：通过梳理近年来关于细胞外基质硬化的机制、高硬度基质对肿瘤进展的影响以及降低基质硬度治疗癌症等方面的最新研究进展，深化对细胞外基质力学特性的理解，提升对肿瘤进展复杂机制的认识，为肿瘤治疗提供新的思路和方向。
方法：以“细胞外基质功能，细胞外基质硬度，胶原蛋白沉积交联，细胞外基质僵硬治疗，免疫治疗”为中文检索词，以“extracellular matrix function，extracellular matrix stiffness，collagen deposition cross-linking，extracellular matrix stiffness therapy，immunotherapy”为英文检索词，检索中国知网、PubMed数据库、万方数据库2016年1月至2024年6月发表的相关文献，最终纳入80篇文章进行综述。
结果与结论：①细胞外基质中胶原蛋白和弹性蛋白的沉积和过度交联导致基质重塑，进而增加基质硬度，这种硬化激活了cyclin-D1、Rho/ROCK、p-PXN-Rac1-YAP、STAT3/p-STAT3等促癌信号通路，促进了癌细胞的增殖、转移、肿瘤微血管生成及免疫逃逸等恶性行为，加速了肿瘤的进展；②减少基质蛋白的沉积和交联可以降低基质硬度，不仅可以抑制多种促癌信号通路的活化，还能够增强药物在肿瘤部位的渗透和递送，是癌症治疗的新策略；③目前，基于基质降解以降低肿瘤硬度的药物正在研发中，少数药物已进入临床试验阶段，有望为肿瘤治疗提供新的有力武器。
https://orcid.org/0009-0001-5887-7695(吴丽娟)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 基质硬度, 肿瘤细胞, 生物学行为, 癌症治疗, 免疫治疗, 细胞外基质, 工程化组织构建

Abstract: BACKGROUND: The extracellular matrix is a complex network structure, which not only builds physical support for tissue cells, but also plays an important regulatory role in cell survival, proliferation, and death. Abnormal changes in the biochemical and biomechanical properties of the extracellular matrix can significantly affect the proliferation, migration, immune evasion, and treatment resistance of tumor cells. Stiffness is an important mechanical property of the extracellular matrix, and abnormalities in matrix stiffness are closely related to tumor progression.
OBJECTIVE: By reviewing the mechanism of extracellular matrix sclerosis, the impact of high stiffness matrix on tumor progression, and the latest research progress in the treatment of cancer based on reducing matrix stiffness, to deeply understand the mechanical properties of the extracellular matrix, improve the understanding of the complex mechanism of tumor progression, and provide new ideas and directions for tumor treatment.
METHODS: “Extracellular matrix function, extracellular matrix stiffness, collagen deposition cross-linking, extracellular matrix stiffness therapy, immunotherapy” were used as the search terms in Chinese and English. Relevant literature published from January 2016 to June 2024 was searched in CNKI, PubMed, and WanFang databases, and 80 articles were finally included for review.
RESULTS AND CONCLUSION: (1) Deposition and excessive cross-linking of collagen and elastin in the extracellular matrix leads to matrix remodeling, which in turn increases matrix stiffness. This sclerosis activates pro-cancer signaling pathways such as cyclin-D1, Rho/ROCK, p-PXN-Rac1-YAP, and STAT3/p-STAT3, promotes malignant behaviors such as cancer cell proliferation, metastasis, tumor microangiogenesis and immune escape, and accelerates tumor progression. (2) Reducing the deposition and cross-linking of matrix proteins can reduce matrix stiffness, which cannot only inhibit the activation of multiple cancer-promoting signaling pathways, but also enhance the penetration and delivery of drugs at tumor sites, which is a new strategy for cancer treatment. (3) At present, drugs based on matrix degradation to reduce tumor stiffness are under development, and a few drugs have entered the clinical trial stage, which are expected to provide a new powerful weapon for tumor treatment.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: matrix stiffness, tumor cells, biological behavior, cancer treatment, immunotherapy, extracellular matrix, engineered tissue construction

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