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Matrix metalloproteinases: regulators of the tumor microenvironment. ​

文献信息 ​

DOI10.1016/j.cell.2010.03.015
PMID20371345
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2010
被引次数2373
关键词基质金属蛋白酶, 肿瘤微环境, 细胞信号通路
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN0092-8674
页码52-67
期号141(1)
作者Kai Kessenbrock, Vicki Plaks, Zena Werb

一句话小结 ​

细胞外蛋白水解在组织稳态中至关重要，而基质金属蛋白酶（MMPs）在癌症中的改变与肿瘤生长和转移密切相关。研究表明，MMPs不仅参与细胞外基质的重塑和癌细胞的迁移，还调控细胞生长、炎症及血管生成信号通路，重新塑造了对癌症治疗的理解。

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基质金属蛋白酶 · 肿瘤微环境 · 细胞信号通路

摘要 ​

细胞外蛋白水解在维持组织稳态中起着重要作用。在癌症中，蛋白水解的改变导致肿瘤生长失控、组织重塑、炎症、组织侵袭和转移。基质金属蛋白酶（MMPs）是与肿瘤发生相关的最显著的蛋白酶家族。近期技术的发展显著提升了我们对MMPs作为肿瘤微环境调节因子的理解。除了在细胞外基质更新和癌细胞迁移中的作用外，MMPs还调控控制细胞生长、炎症或血管生成的信号通路，甚至可能以非蛋白水解的方式发挥作用。这些MMP功能的各个方面正在重新塑造我们对癌症治疗的思路。

英文摘要 ​

Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to unregulated tumor growth, tissue remodeling, inflammation, tissue invasion, and metastasis. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis. Recent technological developments have markedly advanced our understanding of MMPs as modulators of the tumor microenvironment. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner. These aspects of MMP function are reorienting our approaches to cancer therapy.

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主要研究问题 ​

  1. MMPs在肿瘤微环境中具体如何调节细胞信号通路？
  2. 除了MMPs，还有哪些蛋白酶在肿瘤微环境中发挥重要作用？
  3. MMPs的非蛋白水解功能如何影响肿瘤的进展和治疗？
  4. 在不同类型的癌症中，MMPs的表达和功能是否存在显著差异？
  5. 针对MMPs的靶向治疗策略目前的研究进展如何，效果如何？

核心洞察 ​

研究背景和目的 ​

基质金属蛋白酶（MMPs）是与肿瘤微环境密切相关的蛋白酶家族，近年来的研究表明，MMPs在肿瘤的发生和发展中发挥着重要的调节作用。研究的主要目的是探讨MMPs在肿瘤微环境中的作用及其对肿瘤进展的影响，包括肿瘤生长、侵袭、转移和血管生成等过程。

主要方法/材料/实验设计 ​

本综述通过对MMPs的结构、功能及其在肿瘤微环境中的作用进行系统性分析，结合最新的实验研究成果，探讨MMPs的多重生物学功能。研究方法包括：

  • 文献回顾：综合已有研究，分析MMPs在肿瘤中的不同作用。
  • 机制探讨：研究MMPs如何通过调节细胞信号通路、影响细胞迁移和血管生成等机制促进或抑制肿瘤进展。

以下是MMPs作用机制的技术路线图：

Mermaid diagram

关键结果和发现 ​

  1. MMPs的多重功能：MMPs不仅参与基质的降解，还调节细胞生长信号、促进血管生成、影响细胞迁移和免疫反应。
  2. 肿瘤微环境的调节：MMPs通过调节细胞因子和趋化因子的活性，影响肿瘤微环境中的炎症反应。
  3. MMPs与肿瘤转移：特定MMPs（如MMP-9）在肿瘤细胞的侵袭和转移中起着关键作用。
  4. 临床试验结果：MMP抑制剂在临床试验中未能显著提高患者生存率，部分原因是由于肿瘤细胞可以通过非蛋白酶依赖的方式进行迁移。

主要结论/意义/创新性 ​

MMPs在肿瘤进展中的作用复杂且多样化，既有促进肿瘤发展的潜力，也可能在某些情况下抑制肿瘤。未来的研究需要更加深入地探讨MMPs的具体机制，以期开发出针对特定MMPs的靶向治疗策略。

研究局限性和未来方向 ​

  1. 局限性：当前对MMPs功能的理解仍不够全面，尤其是在肿瘤微环境中不同细胞类型对MMPs活性的影响尚未完全阐明。
  2. 未来方向：未来研究应聚焦于：
    • 开发针对特定MMPs的靶向抑制剂。
    • 结合成像技术，实时监测MMPs在肿瘤微环境中的活性。
    • 探索MMPs在不同类型肿瘤中的具体作用机制，以优化治疗策略。

参考文献 ​

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引用本文的文献 ​

  1. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. - Dimitra Bourboulia;William G Stetler-Stevenson - Seminars in cancer biology (2010)
  2. Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase. - Vladislav S Golubkov;Piotr Cieplak;Alexei V Chekanov;Boris I Ratnikov;Alexander E Aleshin;Natalya V Golubkova;Tatiana I Postnova;Ilian A Radichev;Dmitri V Rozanov;Wenhong Zhu;Khatereh Motamedchaboki;Alex Y Strongin - The Journal of biological chemistry (2010)
  3. Cholesterol sulfate alters substrate preference of matrix metalloproteinase-7 and promotes degradations of pericellular laminin-332 and fibronectin. - Kazuhiro Yamamoto;Kaoru Miyazaki;Shouichi Higashi - The Journal of biological chemistry (2010)
  4. Tumorigenic and adhesive properties of heparanase. - Flonia Levy-Adam;Neta Ilan;Israel Vlodavsky - Seminars in cancer biology (2010)
  5. Tumors as organs: complex tissues that interface with the entire organism. - Mikala Egeblad;Elizabeth S Nakasone;Zena Werb - Developmental cell (2010)
  6. [EMMPRIN (CD147). A prognostic and potentially therapeutic marker in urothelial cancer]. - R Nawroth;A Hartmann;P Wild;J Lehmann;R Stöhr;J E Gschwend;M Retz - Der Pathologe (2010)
  7. Activity-based protein profiling for biochemical pathway discovery in cancer. - Daniel K Nomura;Melissa M Dix;Benjamin F Cravatt - Nature reviews. Cancer (2010)
  8. TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. - Xiaoyu Xiang;Yuelong Liu;Xiaoyin Zhuang;Shuangqin Zhang;Sue Michalek;Douglas D Taylor;William Grizzle;Huang-Ge Zhang - The American journal of pathology (2010)
  9. The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis. - Vladislav S Golubkov;Alexei V Chekanov;Piotr Cieplak;Alexander E Aleshin;Andrei V Chernov;Wenhong Zhu;Ilian A Radichev;Danhua Zhang;P Duc Dong;Alex Y Strongin - The Journal of biological chemistry (2010)
  10. Inhibition of matrix metalloproteinases in Siberian hamsters impedes photostimulated recrudescence of ovaries. - Julie Whited;Asha Shahed;Carling F McMichael;Kelly A Young - Reproduction (Cambridge, England) (2010)

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