Grant: Operating Grant

Blood clotting helps tumours with new blood vessel growth and with spread around the body. The protein that is responsible for these effects is called tissue factor (TF), and is produced in large amounts by some cancer cells. Indeed, cancer cells are not equal. Some of them, the so called cancer stem cells (CSCs) or tumour initiating cells (TICs), are believed to be essential for starting tumour growth (tumour initiation). They are also involved in diesase spreading and failure of treatment. In contrast, the majority of other tumour cells are thought to be less deadly at causing the disease, and they may eventually stop dividing by themselves. For this reason much research now focuses on eliminating CSCs. Our laboratory discovered that some CSCs express high levels of TF, provoke blood clotting and use such clots as protective and nurishing nests, the so called CSC 'niches'. CSCs may also exploit normal cells as a source of TF and clotting niches. We would like to explore these new findings further, and in the context of presently incurable brain tumours (gliomas), where the clotting system is activated and may contribute to the disease. We will study how CSCs 'talk' to the clotting system and whether we can change their properties by depriving them of TF (e.g. by using certain antibodies). We will also test whether the surrounding host cells are induced to provide their own TF activity to 'help' CSCs in forming a tumour. We have unique mice which make low levels of TF and could mimick this situation. We will also study what do CSCs 'sense' when they come into contact with the activated clotting proteins and wheter they can be made more vulnerable to therapy when such contacts are interrupted (e.g. by antibodies or blood thinners), Ultimately we aim at finding ways to deny CSCs in the brain the support of the clotting system, to devise new treatments for this devastating disease.