Cathepsin S expression in astrocytomas – its invasion and potential value as a therapeutic target. (Dr. D. McCormick)
3 year project with grant funding of £70,170.00
2001 - 2004
Successful treatment of brain tumours depends on eradicating cell invasion. However, in order to achieve this it is essential to know more about how cells invade and then to use this knowledge to propose and test methods for preventing invasion or for killing invasive cells.
An enzyme (Cathepsin S) with biochemical properties has been identified that suggests that it is well equipped to play an important role in invasion. Pilot studies have shown that for the first time it is present in primary brain tumour cells, but not in normal brain cells. Its significance was further increased when discovered that the most malignant brain tumours produce much higher levels of Cathepsin S than low grade tumours. This adds strength to the proposal that it plays a part in tumour progression and specifically in invasion.
A laboratory model will be used to test this hypothesis, and by then using a number of different strategies to interfere with Cathepsin S function will be able to measure the effect on the rate of invasion. If invasion is reduced we will have strong evidence that Cathepsin S plays an important role in brain tumour invasion. In this case Cathepsin S will become a target for anti-invasive therapy and Dr. McCormick will initiate in vitro testing of Cathepsin S inhibitors with a view to identifying potential therapeutic agents.
Early local invasion by astrocytoma cells results in tumour recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumour cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells. Microglial cells and macrophages were also positive. Assays of specific activity in 59 astrocytoma biopsies confirmed CatS expression and in addition demonstrated that the highest levels of activity were expressed in grade IV tumours. CatS activity was also present in astrocytoma cells in vitro and the extracellular levels of activity were highest in cultures derived from grade IV tumours. In vitro invasion assays were carried out using the U251MG cell line and the invasion rate was reduced by up to 61% in the presence of the selective CatS inhibitor 4-Morpholineurea-Leu-HomoPhe-vinylsulphone. We conclude that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion.
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