Use of Connexin43 peptides as a treatment for glioma
The successful functioning of all tissues depends on the establishment of a structured, mature vascular (blood vessel) network. As such, the development of new blood vessels (angiogenesis) plays a critical role in healthy human development. Angiogenesis is vital for successful organ growth and also an important requirement for wound healing and tissue repair. In contrast to the healthy state, a number of human diseases including cancer show an unregulated excess of new blood vessel formation. The main purpose of the new blood vessel formation is to ensure a rich vascular supply providing nutrients and oxygen required for continuing tumour growth. Many attempts have been made to inhibit this process as a means to ‘choke off’ the supply of nutrients and oxygen to tumours. However, the unyielding drive for angiogenesis results in a tumour vascular network that is highly abnormal when compared to the organized structure of vessel networks in normal tissues. The haphazard and bizarre distribution of vessels leads to heterogeneous blood flow, sluggish in some regions and excessive in others, resulting in marked tumour permeability with excess extravasation of fluid and protein outside the vessel. This leakiness coupled with the compressive force applied by the growing mass of tumour cells cause vascular compression, an abnormal blood vessel network and a hypoxic environment. Importantly, since anti-cancer drugs are carried to tumours by the bloodstream, abnormal blood vessels structure also hampers efficient delivery of the drugs directly to the tumour.
This project which was instigated by our collaborators, Professor Helen Danesh-Meyer and Professor Colin Green (University of Auckland, New Zealand) involves the study of Connexins in brain tumour vasculature. Connexins (also known as gap junction proteins) are a family of structurally related proteins that exist in the membranes of cells that assemble to initially form hemichannels, which later combine further to form gap junctions. These gap junctions are essential for many physiological processes including endothelial cell function in blood vessel membranes. There is evidence that connexin hemichannels play a role in mediating loss of endothelial cells, ultimately damaging the vascular wall through an efflux of ions and a simultaneous influx of water causing cell swelling and loss. Connexin43 is a gap junction protein expressed in astrocytes and vascular endothelial cells.
Professor Danesh-Meyer and Professor Green have developed a connexin43 mimetic peptide strategy that can modulate the gap junction channels through attenuation of connexin43 expression in these cells. Therefore, reversal of the abnormalities, through the ‘normalizing’ and improved integrity of the tumour blood vessel system by treatment with the connexin43 peptides would ultimately lead to improved delivery of anticancer therapies directly to the tumour and also limit the off-target side effects.
Dr Stanley Stylli, Post-Doctoral Scientist
Professor Andrew Kaye, Neurosurgeon
Professor Helen Danesh-Meyer (University of Auckland, New Zealand)
Professor Colin Green (University of Auckland, New Zealand)
Friends of The Royal Melbourne Hospital Neuroscience Foundation
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