Projects / Programmes
Role of the proteolytic systems in the malignancy of brain tumour stem cells.
| Code |
Science |
Field |
Subfield |
| 1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
angiogenesis, apoptosis, brain tumours, gene expression, invasion, protease inhibitors, proteolytic enzymes, stem cells
Researchers (11)
Organisations (3)
Abstract
Recently, small subpopulations of cells have been identified in several types of cancer that can, when injected in animal models, generate tumours that closely resemble the main histologic, cytologic and architectural features of the human disease. These cells have been termed tumour stem cells (TSC), and are now believed to be responsible for tumour formation and its maintenance. Thus these cells emerge now as a clear target for more effective and specific cancer therapies. TSC have also been found in brain tumours (brain TSC, BTSC), among them in glioblastoma, the most aggressive form of glioma. They are likely to play a key role in the recurrences that occur after current treatments. Development of anti-cancer approaches that eliminate this population of cells, will require an in-depth knowledge of their biology, which is lacking at the moment. The aim of our proposed project is to investigate the proteolytic profile of brain tumour stem cells and correlate it to their malignant properties in vitro and in vivo. Proteases are a clear choice when studying possible mechanisms that contribute to tumourigenesis. They are involved in tumour invasion and angiogenesis, hallmarks of malignant dedifferentiation of glioma; this makes them very promising targets for the development of anticancer drugs. Activation of proteolytic pathways involves complex and sequential interactions between different proteases and other molecules. Different proteins have different functions at different stages of tumour development, which precludes the use of broad-spectrum inhibitors. Study of BTSC will allow the identification of any early changes in the activation of the proteolytic cascade that contribute to the malignancy of these cells, pointing at specific targets for anti-protease treatments. In addition, study of protease expression patterns during malignant progression in an experimental animal model will lead to the isolation of possible prognostic factors for the severity of the disease. Furthermore, BTSC are the best model identified to date for testing anti-cancer treatments, since none of the tumours obtained when transplanting available brain tumour cell lines, resemble the primary tumour as closely as those obtained with BTSC. Moreover, cancer stem cells are more likely to express drug resistance and anti-apoptotic genes than differentiated cells, and they may account for some of the resilience of malignant cells to cytotoxic agents. A wide range of proteinase inhibitors will be tested on these cells, aiming at identifying compounds that in some way impair the malignant potential of BTSC.
