Inhibition of hemorrhage factor reduces the formation of brain metastases in mice

Brain metastasis can only develop if cancer cells come out of the right blood vessels and into brain tissue. To make this step possible, cancer cells are affected by bleeding, as Heidelberg scientists from the German Cancer Research Center and from Heidelberg University Hospital have now been able to show in mice. The cancer cells actively stimulate the formation of clots, which help them in trapping the brain’s capillaries and then penetrating through the vessel wall. Clombic factor thrombin-inhibiting drugs were able to reduce the number of brain metastases in this experimental model.

Brain metastases are feared of advanced cancer. Different cancers are different in colonizing the brain. Advanced melanoma produces metastases in the brain in nearly half of the cases, and brain metastases are also very common in certain forms of breast and lung cancer.

Brain metastases often cannot be surgically removed and often do not show a long-term response to treatments. “For patients with cancers that frequently spread to the brain, it would be extremely helpful if we had a treatment that could prevent brain metastases from developing,” explained Frank Winker, head of research group at the Center. German Cancer Research and senior physician management at Heidelberg University Neurological Hospital.

It was already known from observational studies that antithrombotic drugs that inhibit bleeding can have a favorable effect on the prognosis of some cancers. It is possible that these agents influence metastasis. Winkler and his colleagues have now studied in mice whether this also applies to brain metastases and, if so, how blood and metastasis are linked. This study was made possible by a special microscopic technique (in vivo multiphoton laser-scan microscopy) that allows the researchers to look in depth at brain tension and to monitor individual cancer cells.

The mice were introduced with melanoma or breast cancer cells into the bloodstream. Individuals of the circulating tumor cells were then trapped in the blood capillaries of the brain. Only if these cells now thrive by entering the vascular wall into the cerebral cortex can they grow into brain metastasis. Winker and colleagues argued that blood clots (thrombi) often formed around the implanted tumor cells. Cancer cells that did not form such a clot failed to enter the capillary wall. “Apparently, the thrombus helps the cells hold on to the capillary for a long time preparing to move through the vessel wall,” Winkler explains.

The Heidelberg researchers found that the tumor cells appear to be directly involved in the complex inhibition of blood clotting and thus actively promote thrombus formation. They promote the formation of the clotting factor thrombin, which is essential for the formation of the long-lasting protein fibrin, in which the clot network is predominantly formed.

The formation of a thrombus, the researchers realized, is the essential precondition for leaving the tumor cells of the capillary and thus taking the crucial first step towards the formation of brain metastasis. So a thrombin-inhibiting drug would have to stop metastasis because it prevents the tumor cells from entering brain tissue. And of course: mice that received the thrombin inhibitor dabigatran, which is already approved as a drug, developed much less metastasis than untreated animals.

Inhibition of another blood factor (von Willebrand factor) by specific antibodies also reduced thrombi formation in the mice – and subsequently the number of brain metastases that developed.

These tests show that the development of brain metastases is mainly driven by the influence of cancer cells on the plasmatic coagulation factors. That’s why immune drugs should be closely targeted in this process. “

Manuel Feinauer, First Author

“Our goal is to identify drugs for the prevention of brain metastasis in high-risk patients,” Winkler said. “The studies in mice are the first step toward understanding just how thesis products can prevent tumor cells from settling in the brain. In the long run, we then want to test To do these products in clinical trials.To do this, we must first gain a better understanding of whether cancer subtypes of this mechanism are particularly important, and also whether we can even identify patients with a particularly high risk of brain metastasis. “

The researchers are optimistic that thrombin-inhibiting drugs have at least one known benefit: they have long been prescribed for stroke prevention and are therefore thought to be relatively effective. suffering, even over long periods of time.