文章：

半胱氨酸组织蛋白酶：癌症进展和治疗反应的调节因子

Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response

原文发布日期：2015-11-24

DOI: 10.1038/nrc4027

类型: Review Article

开放获取: 否

要点：

1. In many cancer types cathepsin proteases are upregulated and display altered trafficking and localization. Increased cathepsin expression generally correlates with increased malignancy and poor patient prognosis.
2. Secretion of cathepsin proteases by cancer cells and infiltrating immune cells into the extracellular space disrupts intercellular adhesion complexes, induces angiogenesis and drives local invasion by tumour cells.
3. Genetic experiments have identified crucial non-redundant roles for individual cathepsin proteases in the tumorigenesis of multiple genetically engineered mouse models.
4. The pro- or antitumorigenic properties of individual cathepsins are context dependent and specific to the tissue and cell of origin or site of metastasis.
5. Cathepsin activity exists within a larger integrated network of protease activity known as the protease web. Through interactions with other proteases and their inhibitors, cathepsins can alter general proteolytic activity within the tumour microenvironment.
6. Cathepsin proteases have demonstrated roles in intrinsic and acquired resistance to radiation and chemotherapy. Concurrent inhibition of cathepsins with different therapeutic modalities improves outcome in preclinical models.

要点翻译：

1. 在许多癌症类型中，组织蛋白酶表达上调，并呈现转运和定位的改变。组织蛋白酶表达增加通常与恶性肿瘤进展及患者不良预后相关。
2. 癌细胞和浸润免疫细胞将组织蛋白酶分泌至细胞外间隙，破坏细胞间粘附复合体，诱导血管生成并驱动肿瘤细胞的局部侵袭。
3. 遗传学实验证实，在多种基因工程小鼠模型中，单个组织蛋白酶在肿瘤发生过程中具有不可替代的关键作用。
4. 单个组织蛋白酶促肿瘤或抑肿瘤的特性具有情境依赖性，其作用取决于原发组织、起源细胞或转移部位。
5. 组织蛋白酶的活性存在于一个更庞大的蛋白酶活性整合网络——蛋白酶网络中。通过与其他蛋白酶及其抑制剂的相互作用，组织蛋白酶能够改变肿瘤微环境中的整体蛋白水解活性。
6. 研究证实组织蛋白酶在内在性和获得性放化疗耐药性中发挥作用。在临床前模型中，联合使用组织蛋白酶抑制剂与不同治疗方式可改善治疗效果。

英文摘要：

Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment.

摘要翻译： 

半胱氨酸组织蛋白酶活性在肿瘤转化过程中常常失调。蛋白酶在肿瘤微环境中的活性增强和异常定位，对推动癌症进展、增殖、侵袭和转移具有强大作用。近期研究还发现，组织蛋白酶在多种恶性肿瘤中对抑制治疗反应具有功能。然而，组织蛋白酶既可促进肿瘤，也可抑制肿瘤，具体取决于环境，这强调了通过严谨体内分析明确其功能的重要性。本文综述了支持组织蛋白酶在癌症中作用的基础研究与临床发现，并为将靶向组织蛋白酶药物合理整合进临床治疗提供了路线图。

原文链接：

Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response