文章：

胶质瘤侵袭的分子机制：蛋白酶的作用

Molecular mechanisms of glioma invasiveness: the role of proteases

原文发布日期：2003-07-01

DOI: 10.1038/nrc1121

类型: Review Article

开放获取: 否

要点：

1. Gliomas encompass all primary central nervous system (CNS) tumours of glial-cell origin. The invasive nature of brain cancer cells has an important role in the ineffectiveness of current treatment modalities, as the remaining cancer cells inevitably infiltrate the surrounding normal brain tissue and lead to tumour recurrence.
2. This process of invasion includes increased synthesis and secretion of several proteases, such as cysteine, serine and metalloproteinases, to degrade extracellular-matrix (ECM) components selectively. These proteases also have a role in establishing and maintaining a microenvironment that facilitates tumour-cell survival. Interference with proteases might therefore inhibit tumour growth.
3. The ECM — which is a key component of the tissue destroyed by tumour-cell invasion — is a dynamic environment that has a pivotal role in regulating cellular functions during normal and pathological remodelling processes, such as embryonic development, tissue repair, inflammation, and tumour invasion and metastasis.
4. Protease profiling studies have indicated that expression of the serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR), of the cysteine protease cathepsin B and of the matrix metalloproteinases MMP2 and MMP9 is increased in high-grade astrocytomas compared with low-grade astrocytomas or the normal brain.
5. Strategies to prevent the expression of uPA and uPAR at the molecular level have led to significant reduction/inhibition of tumour invasion and growth.
6. Downregulation of MMP2 and MMP9 expression through approaches such as MMP inhibitors or antisense vectors results in less tumour-cell invasion and the inhibition of tumour growth and angiogenesis.
7. Recent studies of cathepsin B using antisense vectors and its natural inhibitor, cystatin C, have shown significantly reduced tumour invasiveness and formation.
8. Reports indicate that these proteases interact with each other and can directly and indirectly facilitate the expression of other proteases. As such, the downregulation of expression of one molecule seems to cause the inhibition of other molecules and/or pathways.
9. Further research on these proteases at the molecular level should lead to the development of target-selective clinical treatments for patients with gliomas.

要点翻译：

1. 胶质瘤包括所有起源于神经胶质细胞的原发性中枢神经系统肿瘤。脑癌细胞的侵袭特性是当前治疗手段效果不佳的重要原因，因为残留的癌细胞会不可避免地浸润周围正常脑组织并导致肿瘤复发。
2. 这一侵袭过程涉及多种蛋白酶（如半胱氨酸蛋白酶、丝氨酸蛋白酶和基质金属蛋白酶）合成与分泌的增加，从而选择性降解细胞外基质成分。这些蛋白酶还在建立和维持有利于肿瘤细胞存活的微环境中发挥作用。因此，干扰蛋白酶活性可能抑制肿瘤生长。
3. 作为被肿瘤细胞侵袭破坏的组织关键组分，细胞外基质是一个动态环境，在胚胎发育、组织修复、炎症反应及肿瘤侵袭转移等正常与病理性重塑过程中对调节细胞功能起核心作用。
4. 蛋白酶谱分析研究表明，与低级别星形细胞瘤或正常脑组织相比，高级别星形细胞瘤中丝氨酸蛋白酶尿激酶型纤溶酶原激活物及其受体、半胱氨酸蛋白酶组织蛋白酶B以及基质金属蛋白酶MMP2和MMP9的表达均有所增加。
5. 在分子水平上阻止uPA和uPAR表达的策略已显著减少/抑制了肿瘤侵袭和生长。
6. 通过MMP抑制剂或反义载体等方法下调MMP2和MMP9表达，可减少肿瘤细胞侵袭并抑制肿瘤生长和血管生成。
7. 最近使用反义载体及其天然抑制剂胱抑素C对组织蛋白酶B进行的研究显示，肿瘤侵袭性和肿瘤形成显著降低。
8. 有报道表明这些蛋白酶相互关联，能直接或间接促进其他蛋白酶的表达。因此，下调某个分子的表达似乎可抑制其他分子和/或通路。
9. 在分子水平上对这些蛋白酶开展进一步研究，将有望为胶质瘤患者开发出靶点选择性的临床治疗方案。

英文摘要：

The invasive nature of brain-tumour cells makes an important contribution to the ineffectiveness of current treatment modalities, as the remaining tumour cells inevitably infiltrate the surrounding normal brain tissue, which leads to tumour recurrence. Such local invasion remains an important cause of mortality and underscores the need to understand in more detail the mechanisms of tumour invasiveness. Several proteases influence the malignant characteristics of gliomas — could their inhibition prove to be a useful therapeutic strategy?

摘要翻译： 

脑肿瘤细胞的侵袭性是导致当前治疗方式无效的重要原因，因为残留的肿瘤细胞不可避免地会浸润周围正常脑组织，从而导致肿瘤复发。这种局部侵袭仍是致死的重要原因，凸显了对肿瘤侵袭机制进行更深入理解的必要性。多种蛋白酶影响胶质瘤的恶性特征——抑制它们是否可能成为一种有用的治疗策略？

原文链接：

Molecular mechanisms of glioma invasiveness: the role of proteases