Scientists discover how ‘winning cell’ guides blood vessel growth

Cancer Research UK scientists have found for the first time that cells compete with each other to guide the ‘sprouting’ and growth of blood vessels, and they have identified how the balance of key receptors on cells control this process. Their research is published in Nature Cell Biology today.

New blood vessels in most tumours form by sprouting – like the way branches grow on trees. Tumours feed off essential nutrients and oxygen from the blood, supplied through these new vessels.

Scientists all over the world are trying to understand why blood vessels in tumours look different to normal networks of blood vessels, as they are often of poor quality and do not work properly.

Tumours receiving too few nutrients and oxygen become more invasive and are harder to treat, so scientists have been trying to either fix the vessel and to improve function, or stop tumour blood vessel growth altogether to starve the tumour to death.

Now Cancer Research UK scientists have found that the process for normal vessel sprouting involves an active competition between cells. This competition is controlled by whether the amounts of two receptors, called Vegfr1 and Vegfr2, are balanced in precise quantities. These in turn control levels of a protein called delta-like 4 that the winning cells needs to beat its competitors.

The winning cell continues to compete with its neighbouring cells in order to secure its leading place, called the ‘tip cell position’, where it can guide the blood vessel towards areas of the tumour that need more blood supply.

But crucially, the leading cell is constantly changing – the competition continues throughout sprouting – and cells that had initially lost out eventually take the leading position.

Lead author Dr Holger Gerhardt, based at Cancer Research UK’s London Research Institute, said: “This was totally unexpected, and has wide-reaching implications for our understanding of the sprouting process.

“Just like leadership in organisations and politics, the leadership period of the ‘tip cell’ in the vessel sprout is limited, and it will need to show strong leadership qualities and guidance in order to become re-elected. At the same time, the leading cell needs to instruct a group of followers, so the cells that do not become tip cells cooperate to build the new blood vessel.”

The scientists believe that this competitive process is the link between the cell’s ability to read the direction of signals coming from the tumour directly and its capacity to lead the sprout. In tumours, cells appear to cluster together at the tip instead of cooperating, leading the scientists to believe that the process is not working properly.

Dr Gerhardt continued: “If we can understand how to restore the ability of cells to compete and cooperate, we can restore the vessel’s normal function and hopefully stop the tumour from becoming more aggressive.”

The researchers used a computer model to try and understand how the cell in the tip position was selected. This model also gave them early predictions of how they could restore normal patterns in blood vessels. They then tested their theory in mice to discover exactly how the process worked.

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “Blood vessels are the lifeline of a tumour. Without these vessels a tumour can be starved of nutrients and eventually be killed off. But instead, tumours can use this to their advantage and use blood vessels as an escape route.

“This important area of research will one day be valuable to cancer treatment, and this study will help scientists in the field work towards this goal.”

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