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Role of Cdc42 in cancer cell adhesion to endothelial cells and platelets

Periodic Reporting for period 1 - Cdc42Adhere (Role of Cdc42 in cancer cell adhesion to endothelial cells and platelets)

Reporting period: 2015-05-11 to 2017-05-10

The process by which cancer spreads from its initial location to distant locations in the body is called metastasis. Unfortunately, when cancers spread from one part of the body to another, they are difficult to cure. It is well known that most deaths from prostate and breast cancers are due to the spread of cancer cells to different parts of the body, including bone, lung and brain. Therefore it is important to identify new cancer treatments aimed specifically at reducing metastasis.

When cancers spread by metastasis, tumour cells get into the blood vessels, which carry them to other sites in the body. If the cancer cells attach to the blood vessel wall, they can get out of the blood vessels and grow to form a secondary tumour, or metastasis. When cancer cells are in the bloodstream, tiny cells called platelets stick to the cancer cells. The normal function of platelets is to clot the blood when blood vessels are cut. Platelets see the cancer cells as a ‘cut’ and clot around them. The platelets then help the cancer cells to attach to the blood vessel walls, leading to metastasis.

Our research aimed to find out how prostate and breast cancer cells stick to both platelets and blood vessels walls. We discovered that three different genes in cancer cells have a role in the attachment of tumour cells to blood vessel walls. These genes are called FMNL1, FMNL2 and FMNL3. We hope this will contribute to increase the knowledge about the development of metastasis and thus bring us closer to improve the management of breast and prostate cancer metastasis.
Previous studies from this laboratory demonstrated that β1-integrin, a molecule that is on the surface of many cell types, is needed for cancer cells to attach to blood vessel walls before they form a secondary tumour. If we could find ways to reduce β1-integrin in tumours, it might be possible to decrease cancer metastasis.
Small Interfering RNAs (siRNAs) are short RNA sequences that can be introduced in the cell to turn off the expression of single genes. We used siRNAs to silence genes that might affect β1-integrin. We found that three genes altered β1-integrin levels in prostate and breast cancer cells. These genes are called Formins, and control the shape and movement of cells. We also discovered that when these Formin genes, known as FMNL1, FMNL2, and FMNL3, were turned off, cancer cells had reduced attachment to the cells that line blood vessel walls, which are called endothelial cells.

We used the same siRNA approach to test whether β1-integrin and the Formins are required for cancer cell attachment to platelets. We purified platelets from the blood of volunteers. We then combined them with cancer cells to count the number of platelets stuck to cancer cells. None of the genes we tested reduced the amount of platelets attached to cancer cells, but now we have the experimental method working for platelet attachment to cancer cells, we will test other genes for effects on this attachment in the future.
This is the first study to find a link between β1-integrin levels and FMNL1, FMNL2 and FMNL3. In addition, it is also the first analysis of the role that these three Formins play in the attachment of cancer cells to endothelial cells, which line blood vessels. There is a commercially available chemical inhibitor that targets Formins but it is not specific for FMNL1-3 and shows some toxicity. Our results identify both β1-integrin and Formins as promising targets for the development of new therapies aimed specifically to fight metastatic disease.

Although the work on the interaction between cancer cells and platelets did not show any role of β1-integrin or the Formins, we set up the conditions to test cancer cell attachment to platelets, and generated preliminary data that could be used in future grant applications. This would provide the funding needed to study this key step of metastasis formation.

The results of this work were presented at three different scientific meetings held in UK:
- Actin 2015 - 10th Anniversary Meeting in Bristol (UK) on 27th November
- 28th UK ADHESION SOCIETY MEETING in London (UK) on 22nd September
- Actin 2016 Meeting in Bristol (UK) on 26th December
Cancer cells interact with endothelial cells and platelets during metastasis