Key Points
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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.
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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.
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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.
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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.
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Strategies to prevent the expression of uPA and uPAR at the molecular level have led to significant reduction/inhibition of tumour invasion and growth.
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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.
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Recent studies of cathepsin B using antisense vectors and its natural inhibitor, cystatin C, have shown significantly reduced tumour invasiveness and formation.
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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.
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Further research on these proteases at the molecular level should lead to the development of target-selective clinical treatments for patients with gliomas.
Abstract
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?
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Acknowledgements
I appreciate the contribution of the members of my lab, S. Mohanam, S. Lakka and C. Gondi, for the preparation of this manuscript. I also thank S. Jasti for editorial review and K. Minter for technical support. This work was supported by grants from the National Institutes of Health.
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Glossary
- RETICULOENDOTHELIAL SYSTEM
-
A group of cells that have the ability to sequester organic and inorganic particles. Cells include macrophages, monocytes, reticular cells of the lymphatic system, endothelial cells of the spleen sinusoids, and microglia.
- COMPUTED TOMOGRAPHY
-
(CT). As generated X-rays pass through different types of tissue, they are deflected or absorbed to different degrees. CT uses X-rays to obtain three-dimensional images by rotating an X-ray source around the subject and measuring the intensity of transmitted X-rays from different angles.
- MAGNETIC RESONANCE IMAGING
-
(MRI). A powerful diagnostic imaging method that uses radiowaves in the presence of a magnetic field to extract information from certain atomic nuclei (most commonly, hydrogen). It is mainly used for producing anatomical images, but also gives information on the physico-chemical state of tissues, flow, diffusion, motion and, more recently, molecular targets.
- INTEGRINS
-
A family of more than 20 heterodimeric cell-surface extracellular-matrix (ECM) receptors. They connect the structure of the ECM with the cytoskeleton and can transmit signalling information.
- MATRIGEL
-
The extracellular matrix secreted by the Engelbrecht–Holm– Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and so resembles the basement membrane.
- BAX
-
(BCL2-associated X protein). A pro-apoptotic member of the BCL2 family.
- K14–HPV16
-
A transgenic mouse strain that expresses human papillomavirus type 16 (HPV16) early-region genes, including the E6 and E7 oncogenes, under the control of the human keratin-14 promoter (K14), in basal keratinocytes. Invasive squamous carcinomas of the epidermis develop through characteristic stages.
- RIP1–TAG2
-
A transgenic mouse strain that expresses the simian virus 40 (SV40) large T antigen (TAg) under the control of the rat insulin II promoter (RIP) in pancreatic-islet cells. Carcinomas develop in the pancreatic islets and progress through characteristic stages.
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Rao, J. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3, 489–501 (2003). https://doi.org/10.1038/nrc1121
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DOI: https://doi.org/10.1038/nrc1121
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