Blood Clots
The major focus of basic research at the Florida Hospital Institute of Translational Research (FHITR) is the relationship between the body's blood clotting system and the ways that cancers grow and spread. Doctors have known for many years that cancer patients are more likely to suffer a blood clot (thrombosis) than healthy people. In fact, a blood clot may be the first sign that a cancer is present.
Understanding why a cancer spreads (metastasizes) is important because this complicates treatment and may ultimately lead to death of the patient. Many cancers spread through the bloodstream, using it as a highway to move to another part of the body. Thus, in order to spread, a cancer cell must first escape from the initial (primary) tumor, enter the bloodstream, travel to another site, leave the circulating blood and re-enter the tissues to grow as a secondary tumor.
FHCI researchers are particularly interested in what happens when cancer cells enter the blood. This is a critical stage for successful spread of many cancers, and it is while these cancer cells are in the blood that they are most vulnerable. We know that this process is already very inefficient - probably only about 1% of cancer cells that enter the blood, actually make it out into the tissues where the successful cells can form a secondary tumor.
Our research has shown that many cancer cells contain a protein known as Tissue Factor (TF). This is the same protein that is used by the body to start the blood clotting process following an injury. TF is not normally present in the blood - if it was, our blood would clot. It is normally found on the outside of blood vessels and only comes in contact with the blood following damage to the blood vessels. Thus, it is ideally placed to start the clotting process as soon as bleeding occurs. It does this by combining with a blood protein known as Factor VII (seven) to create a so-called 'procoagulant' that rapidly starts the clotting process.
When cancer cells carrying TF enter the blood, small clots are formed on the surfaces. In the picture on the right, the strands of blood clot are stained red - the cancer cells appear green. The blood platelets, which are small cells that stick to injured blood vessels to help prevent blood loss, then stick to the clot-covered cancer cell. This sticky 'sandwich' of cancer cell, blood clot and platelets is able to stick to the inside of the blood vessel wall. This provides a '"safe haven" for the cancer cell, giving it the time it needs to squeeze between the cells that line the blood vessel and escape into the tissues, where it can multiply into a secondary tumor.
The goal of the FHCI researchers is two-fold: First, we want to understand more about the ways in which cancer cells can activate the blood clotting system and blood platelets. Second, we want to use this information to develop new treatments. The idea is that, by preventing the cancer cells from creating blood clots, or by preventing the blood platelets from sticking to the clot-covered tumor cell, we could deny the cells "safe haven" and keep them circulating in the blood. Thus, the cancer cells would quickly die, unable to form secondary cancers.
Since we began this research in the mid-1980's, we have tried several ways to prevent cancer cells from activating blood platelets and the coagulation system. These have included the use of common "blood thinning" drugs such as coumadin and heparin. Although these drugs showed some success, both in the laboratory and in the clinic, they are not as effective as we would like. We have also tried drugs that reduce the 'stickiness' of blood platelets. While these were effective in the laboratory, they carry a risk of excessive bleeding and are probably not well suited to use in cancer patients.
More recently, we have tried a relatively new type of heparin - so-called low molecular weight heparin (LMWH). This drug worked very well in the laboratory and is known to be safe for patients. Several clinical trials of LMWH in cancer are currently ongoing around the world. We hope to begin a clinical trial of LMWH in brain cancers at Forida Hospital by mid-2003.
FHCI scientists believe that targeting the Tissue Factor protein could be an effective anti-cancer strategy. We know that this protein is important for the cancer cell to activate blood clotting and platelets and that these are involved in cancer spread through the blood. We also know that TF may have other important functions in cancer - particularly in stimulating growth of new blood vessels. This process, known as angiogenesis, is very important for both primary tumor growth and subsequent metastatic spread. Since TF is not normally present in the blood, giving drugs that prevent this protein from working should affect only cancer cells that are circulating at the time.
In one approach, FHCI researchers used an antibody that homes in on TF and prevents it from causing blood clots. In the laboratory, this very effectively prevented clotting activation, and in experimental models, greatly reduced tumor formation. This is a promising strategy, and one which we hope to test in clinical trials at Florida Hospital before the end of 2003.
Another approach taken by FHCI scientists is to harness the power of the body's natural antidote to TF - a protein known as Tissue Factor Pathway Inhibitor (TFPI). This protein is normally released by the cells that line the blood vessels to prevent blood clotting caused by TF from getting out of control. This insures that the blood clot only forms where it is needed - at the site of injury.
In experimental models, TFPI reduces the ability of cancer cells to form both clots and secondary tumors.Unfortunately TFPI is expensive to produce and we are now working with scientists at the University of Central Florida to make this protein, in larger amounts, in tobacco plants. This will give us larger quantities of material to test, and is also a step along the way to another goal of FHCI scientists - the creation of a type of TFPI that can be given in oral (pill) form.
We hope that antibodies to TF or the TFPI protein will be safe and effective treatments that will both prevent the formation of blood clots in cancer patients (a significant cause of death) and reduce the risk of cancer spread.
