For breast cancer to be fatal, the tumour has to send out metastases to other parts of the body. The cancer cells are spread via the blood vessels, and a research team at Lund University in Sweden has now proven that the protein ALK1 determines the extent of the tumour's spread in the body. The higher the levels of the protein on the surface of the blood vessels, the greater their permeability to tumour cells and therefore the greater the risk of metastases.
The new study also shows that the drug Dalantercept can prevent the spread of tumour cells in breast cancer by blocking ALK1, thereby closing off the exit routes for the cells.
Breast cancer is currently the largest malignant tumour disease in women, with 1.7 million new cases in the world every year. The prognosis for breast cancer patients is relatively good when the disease is discovered at an early stage and, in Sweden, 90 per cent of patients are still alive five years after their diagnosis. But among the 10–15 per cent of women in whom the disease recurs, metastases are the cause of 90 per cent of deaths.
"Previous research has been very much concerned with the primary tumour, but it is the spread of metastases that leads to fatal outcomes", says Kristian Pietras, principal investigator and professor of molecular medicine at the Department of Laboratory Medicine.
What has also become increasingly clear is that tumours cannot grow without the support of surrounding tissue. You could say the the tumours trick the body's other cells into helping them by providing support. Blood vessel formation in the tumour is a good example of how tumour cells manipulate the surrounding tissue to enable growth.
Cancer cells need oxygen and nutrients to grow and this is supplied by the blood vessel system, which is lured into growing into the tumour. The blood vessels which infiltrate the tumour also become a route for the cancer cells to wander out into the body, thereby spreading metastases. This was previously considered a passive process but, in recent years, researchers have learned that the blood vessels have an active part in allowing the tumour cells to penetrate them. This is the ALK1 protein, found on the surface of the blood vessel cells, which has proven to play an important role in whether or not tumour cells gain access to the blood vessels.
"We have studied ALK1 for a long time and realised that the protein is central to the new formation of blood vessels in tumours. By investigating almost 2000 breast tumours, we found in the present study that patients with high levels of ALK1 in the tumour blood vessels were much more likely to develop metastases. Women with a low level of the protein consequently had fewer relapses and thereby survived longer".
In experiments on mice, the research team discovered that they could prevent the tumour cells from getting through the blood system to form metastases in the lung by using the drug Dalantercept. The drug blocked the activity of ALK1, thereby preventing the metastatic spread of the tumour. In combination with chemotherapy, the treatment was even more effective.
"Our findings indicate that high levels of ALK1 in the breast tumour's blood vessels lead to a higher risk of future metastatic spread and thereby a worse prognosis for the patient. So far, the drug is being tested in early clinical trials on patients and is not generally available. Of course we now hope that the next step will be to test the drug on breast cancer patients", concludes Kristian Pietras, whose professorship at Lund University is the result of a donation from Göran and Birgitta Grosskopf.
Kristian Pietras, professor of molecular medicine at Lund University
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