Scientists in Germany believe they have found the mechanism that cancer cells use to coax blood platelets to “open doors” in blood vessel walls so they can pass through and get into new organs.

Once cancer spreads from the primary tumor to other parts of the body, a process known as metastasis, the prognosis worsens. More than 90% of cancer deaths occur because of metastasis, much of which results from cancer cells getting into the bloodstream.

Scientists had already noticed cancer cells that migrate through the bloodstream manage somehow to enlist the help of blood platelets to penetrate the normally impervious blood vessel wall. It is as though they coax them to open a door.

(Other researchers have suggested that the cancer cells themselves also have to undergo a change in order to be able to pass through the blood vessel wall and that this change occurs under the influence of blood platelets.)

In a new study, published recently in Cancer Cell, a team at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, describe how they uncovered the mechanism that the cancer cells use to get the blood platelets to open a door in the blood vessel wall.

Senior author Stefan Offermanns, Director of the Department of Pharmacology at the Institute in Bad Nauheim, says in a statement:

“It has long been known that metastasising tumour cells are capable of establishing close contact with blood platelets and activating them. Animal experiments have shown that tumour cells form far fewer metastases in the absence of blood platelets.”

Offermanns and his team discovered that by activating the blood platelets they coax them to release a chemical that interacts with a receptor on the lining of blood vessel walls that facilitates an opening, helping them pass through and reach new organs.

They suggest blocking the receptor could be a way for new drugs to stop metastasis.

Blood platelets are small sticky blood cells that have no nucleus. If there are too many of them in the blood, then blood clots can form, and if there aren’t enough of them, then excessive bleeding is the greater risk.

When a blood vessel is injured, blood platelets aggregate at the wound to ensure its rapid closure. They quickly form a plug to seal the wound. The platelets release a cascade of signal molecules to coordinate this rapid response and trigger more long term wound repair.

Under the influence of these signals, the platelets quickly transform from passive passengers in the bloodstream to active agents at the site of injury. The result is they very quickly “hermetically seal” the wound.

Many malignant tumors that set up secondary tumors in other parts of the body by sending cancer cells through the bloodstream, enlist the help of blood platelets to get them through the blood vessel wall.

Studies show that patients who receive long-term treatment with platelet inhibitors such as acetylsalicylic acid have a lower risk of developing metastasising tumors.

In their study, Offermanns and colleagues give a detailed description of the process and its steps.

Once activated to respond to injury, blood platelets release large amounts of various molecules. One of these is adenosine triphosphate (ATP), which the team experimented with.

When they blocked ATP release from the platelets, they found it significantly reduced the amount of tumor cells travelling through the blood vessel walls.

Co-lead author Dagmar Schuhmacher explains how they investigated this further:

“We succeeded in demonstrating the same phenomenon in experiments on mice, in which the release of ATP from blood platelets was blocked. In this case too, far fewer tumour cells slipped through the endothelial barrier and fewer metastases formed.”

But what is happening exactly in the normally impervious blood vessel wall that allows the tumor cells to pass through?

The team found that ATP from the activated blood platelets binds with P2Y2 receptors on the surface of endothelial cells lining the blood vessel wall.

Boris Strilic, also a co-lead author, explains:

“When ATP binds to these receptors, small openings form between the individual endothelial cells. The tumour cells exit the blood vessel through these openings and migrate into the organ.”

Thus the cancer cells activate the platelets, these send out ATP signals, these ATP signals activate the P2Y2 receptors in the blood vessel walls, effecting an “open Sesame” response that then allows the cancer cells to pass through.

The researchers believe their discovery offers some starting points for new anti-metastasis therapies.

Offermanns says they now plan to “test whether specific blockers for the P2Y2 receptor or substances that inhibit the release of ATP from blood platelets can suppress tumour cell metastasis in different animal models.”

They expect this will be quite tricky, because blood platelets have a job to do, namely to maintain the balance between excessive bleeding and clotting (the process of haemostasis). They will have to find a way to block the the P2Y2 receptor without disrupting this important life-preserving process.

Written by Catharine Paddock PhD