Collagen imitations as anti-coagulants

Image taken with an electron microscope of an inactive blood platelet (left) and of one activated by collagen (right).
© J. A. Eble

Project title: The role of integrins in platelet cohesion with tumor cells and platelet-mediated tumor cell adhesion
Principal investigators: Johannes A. Eble, Carsten Höltke
Project time: 11/2017 - 12/2018
Project code: FF-2017-08

In the case of diseases such as arteriosclerosis or fibrosis, the wound-healing process gets out of control. The problem lies in the faulty contact made between collagen, blood platelets and the cells responsible for the healing process. The same components play a major role when tumour cells migrate via the blood vessels to the places where they later form metastases. In their research project, biochemist Prof. Johannes Eble and chemist Dr. Carsten Höltke are looking into how exactly the contact between collagen and blood platelets, or between collagen and a tumour cell, comes about. The researchers aim to imitate collagen in order to prevent thromboses or block the interaction between tumour cells and blood platelets. The reason they are doing this is that with a suitable collagen imitation they want to occupy the potential contact spots on blood platelets in such a way that they can no longer pick up signals from genuine collagen – or only to a limited extent. In this way, blood platelets and possibly also tumour cells would no longer be subject to such rapid and excessive aggregation.

The approach taken by the researchers is to examine primarily two of the three possibilities that collagen has to make contact with blood platelets and tumour cells. These contact spots are two receptors on the blood platelets – to be precise: α2β1 integrin and glycoprotein VI (GPVI). In this project, the researchers are aiming to develop collagen imitations for the two receptors and to improve existing ones. For the receptor α2β1, the research team led by Johannes Eble has already developed a collagen imitation which “deactivates” the receptor, i.e. prevents platelets from being activated. This imitation is based on the snake venom rhodocetin and is to be improved for handling purposes in the laboratory. There is, as yet, no collagen imitation for the receptor GPVI, and it can in fact be produced only chemically. This is where Carsten Hölke’s team of researchers comes in: they have methods for synthesizing the hydroxylated peptides needed.

The imitations need to be as practicable as possible for use in the lab. The researchers also intend to mark the imitations with fluorescence dyes so that under the microscope they can study not only the connection between collagen and cell, but also the process whereby contact is made.

In a second step, the researchers then intend to use the imitations for cancer research, because the contact made between collagen and blood platelets plays a decisive role in the formation of metastases. Cancer cells in the blood often surround themselves with blood platelets, enabling them to hide from immune cells. With the aid of the receptors on the blood platelets, the cancer cells attach themselves to vascular walls and can form metastases.

In this project, the development of collagen imitations is focusing initially on scientific use. Only further research projects will be able to show whether any active agents for the possible treatment of patients can be developed as a result of the findings.