A specific signalling pathway mediating blood vessel formation has brought two ETH Zurich researchers of the Institute of Pharmaceutical Sciences the Pfizer Research Prize 2008 in the field of fundamental cardiovascular research.
André Brändli, Professor at the Institute of Pharmaceutical Sciences, and his former doctoral student Roland Kälin researched a signalling pathway that is universal in vertebrates and mediates the formation of blood vessels (vascularisation) both in embryos and tumours. The research into this mechanism opens up new opportunities to develop novel medicines for cancer treatment.
Universal in vertebrates
André Brändli and Roland Kälin discovered that the formation of new blood vessels needs a particular cellular signal path that is the same in the development of vertebrate embryos and in cancerous diseases.
The APJ receptor protein acting as a receiver is located on the surface of blood vessels. The corresponding messenger is the protein Apelin which is secreted by cells and activates APJ. The genes carrying the information for APJ and Apelin are now activated during the formation of new blood vessels, thus initiating production of the two proteins. This can be demonstrated both in clawed frog tadpoles or mouse embryos and in human blood vessel cells. This means the signalling pathway is universal and has remained unchanged throughout the history of vertebrate evolution. Furthermore the production of Apelin is highly localised, occurring only where new blood vessels start to form (neovascularisation).
Blocking the signal stops growth
The studies by Brändli and Kälin also showed that this signalling pathway is reactivated in pathological vascularisation of the kind observable in cancer growth. The researchers found no Apelin and little APJ on the blood vessels in healthy brain tissue. However, the genes coding for Apelin and APJ are highly active in the oxygen-depleted areas of malignant brain tumours and their blood vessels. If the Apelin/APJ signal path is blocked, new blood vessels are unable to grow and tumour formation is suppressed. This was shown by studies on tadpoles.
The experiments showed that although Apelin cannot affect the rate of cell division, it does effectively trigger new blood vessel formation and stimulates the migration of blood vessel cells.
Basis for new medicines
The fact that Apelin and APJ are strongly present in the origination and growth of brain tumours could be useful in the diagnosis and prognosis of brain tumours. New medicines could interfere with the Apelin/APJ signal path to control vascularisation. APJ might be especially suitable for this purpose, since medicines which are aimed at such so-called G-protein linked receptors, and which inhibit them, are already licensed nowadays. Specific antibodies could also be used to inhibit Apelin. The work by Brändli and Kälin has laid a foundation for further research and the development of therapeutic agents.
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