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Metastasis

The most deadly aspect of cancer is its ability to spread, or metastasize. Cancer cells initially group together to form a primary tumor. Once the tumor is formed, cells may begin to break off from this tumor and travel to other parts of the body. This process is metastasis. These cancer cells that travel through the body are capable of establishing new tumors in locations remote from the site of the original disease. Metastasis is a very complicated process that still has yet to be completely understood.

To metastasize, a cancer cell must break away from its tumor, invade either the circulatory or lymph system, which will carry it to a new location, and establish itself in the new site. The body has many safeguards to prevent cells from doing this, yet many cancer cells have the ability to overcome these safeguards. Research is now focused on understanding in what ways cancer cells have mutated to circumvent the body's defenses and freely travel to other locations.

When cancer is diagnosed, it may be discovered in a site that is not the location of the primary tumor. Through various means of testing, doctors will locate the primary tumor, and determine to what extent it has spread from that location to other areas of the body. Localized tumors that have not had the opportunity or time to metastasize have the best prognosis for cure. Cancers which have metastasized usually indicate a later stage disease, and treatment becomes more complicated, with poorer outcomes. In late stages, patients with oral cancer for example, may succumb to a cancer in the lungs or the brain, which was not the location of the original, primary tumor.

Metastasis most commonly occurs by way of the bloodstream or the lymphatic system. Just like normal cells, cancer cells must have a blood supply in order to function. They have access to the bloodstream just as healthy cells do. This access allows detached malignant cells from the tumor to enter the bodies' general bloodstream. Once in the bloodstream, the cancer cells now have access to every portion of the body. The lymphatic system has its own channels throughout the body like the circulatory system, through which a malignant cell can travel. When surgeons remove a tumor, they may also remove nearby portions of the lymph system including the lymph nodes, as these are frequently the first sites of the cancers' metastasis. Once metastasis to the lymphatic system has occurred, the prognosis for cure drops significantly.

To begin the process of metastasis, a malignant cell must first break away from the cancerous tumor. In normal tissue, cells adhere both to one another and to a mesh of protein filling the space between them. This protein mesh is known as the extracellular matrix. This attachment between the cells and the extracellular matrix is particularly characteristic of the epithelia, which are the cell layers that form the skin and the lining of the mouth, stomach, lungs, and other organs. For a malignant cell to separate, it must break away,

not only from the cells around it, but also from the extracellular matrix. Cells are held together with cell-to-cell adhesion molecules. This adhesion also allows interactions between numerous proteins on the cell surface. In cancer cells, the adhesion molecules seem to be missing or are compromised. Cadherins, a family of intercellular adhesion protein molecules, play a big part in keeping cells together. One subtype in this family, E-cadherin, is the adhesion molecule found in mammalian cells. This molecule seems to be the important factor in cell-cell adhesion. In cancer cells, E-cadherin is either partly or entirely missing. This allows cancer cells to detach from each other, and from the matrix which holds everything in place. Clinical studies involving the manipulation of E-cadherin, have proven that this molecule is important to stopping metastasis. One study has shown that blocking E-cadherin in cancer cells turns them from noninvasive to invasive. This work established the importance of cell adhesion. These studies revealed cell adhesion's ability to inhibit a cancer cell's capacity to invade, by keeping it bound to other cells. If cell adhesion is compromised, cancer cells have the opportunity to metastasize and invade other areas of the body. Relating to oral cancer, research has shown that saliva provides a good environment for metastasis. Saliva is rich in naturally occurring hyaluronic acid (HA), a molecule that binds to the surface of a cell, making it easier for the cell to move around. This helps the cell escape adhesion to other cells and allows it to move more freely.

Besides binding to each other, cells also adhere to the extracellular matrix. The matrix is composed of connective tissue proteins such as collagen and elastin which interact to form highly insoluble materials. The extracellular matrix not only binds cells together, it also allows cells to survive and proliferate. Research has shown that cells have anchorage dependence. This means that a cell cannot reproduce unless it is attached to a surface. This attachment is made possible through cell surface molecules called integrins, which bind to the extracellular matrix. Only after the cell has attached to a surface will it begin its reproductive cycle. Unattached cells neither reproduce, nor grow. A nuclear protein called E-CDK2 regulates the growth and division of cells. If a cell is not attached to anything, inhibitory substances in the nuclei shut down E-CDK2, and the cell stops growing. Many cells that cannot find anchorage, not only stop reproducing and growing, but they also begin apoptosis, or programmed cell death.

The halting of growth and reproduction of unattached cells is one of the body's safeguards to maintain the integrity of tissues. Normal cells have specific places in which they must stay in order to survive. However, cancer cells are able to exist without being anchored. Their E-CDK2 protein remains active and allows the cancer cells to grow and reproduce. The reason E-CDK2 remains active is unknown, but researchers think that oncogenes may be responsible. Oncogenes are mutated versions of proto-oncogenes, which are present in healthy cells, and are capable of turning normal cells into malignant cells. It is possible that in cancer cells, proteins made by oncogenes may convey a false message that the cell is attached when it is not. This allows the cancer cell to continue to grow and reproduce when it should be engaging in apoptosis, or programmed cell death.

Once a cancer cell has detached from other cells and the extracellular matrix, it must make its way into a blood or lymphatic circulatory system to transport itself. A common way for transport is the bloodstream, since blood vessels are often nearby. Tumors are capable of creating new blood vessels (angiogenesis) because of their need for nutrition, and this gives cancer cells ample opportunity for transport. Entry to the blood vessel requires penetration of the basement membrane. The basement membrane is a thin layer of specialized extracellular matrix. Basement membranes surround blood vessels but they are also present with epithelial cells. Epithelial cells which are the most common sources of cancer, have a basement membrane separating them from the rest of the body. With cancerous tumors that develop in epithelial cells, a cancer cell must penetrate two basement membranes, the epithelial and blood vessel, for transport. To breach the basement membrane cancer cells release enzymes called metalloproteinases(MMPs). These enzymes dissolve basement membranes and other extracellular matrices, allowing penetration of the basement membrane of blood vessels, giving the cancer cells access to other parts of the body.

Once in the bloodstream, the cancer cell must fight the body's defenses and try to reattach itself in a new location. Fewer than 1 in 10,000 cancer cells survive circulation to create a new tumor. The circulation of the blood plays a significant role in determining where cancer cells travel. The cancer cells usually get trapped in the first set of capillaries they encounter downstream from their point of entry. Frequently these capillaries are in the lungs, since returning deoxygenated venous blood leaving many organs is returned to the lungs for reoxigenation. From the intestines, the blood goes to the liver first, so cancer cells leaving the intestines will go there. The lungs and the liver are the two most common sites for metastasis in the human body. Once in a new site, the cells must again penetrate the basement membrane of the blood vessel and establish itself in the new tissue.

In the primary tumor itself, only certain cancer cells can metastasize. Not all cancer cells have the tools to survive the journey to another area of the body. Many circulating cancer cells die because they are not equipped for the entire process of metastasis. Properties in the tumor itself, such as deformability, aggregation, and expression of adhesive molecules, prevent cancer tumor cells from surviving detachment from the tumor. The host also has weapons, such as blood turbulence, platelets, T cells, natural killer cells, and macrophages, that kill circulating cancer cells. Tumor cells that reach their destination may not be able to respond to specific organ factors, and this will kill the tumor cells as well. A study done on mice found that less than .1% of injected B16 melanoma (a malignant tumor) cells survived to metastasize. This small survival rate encourages the idea that a selective growth of unique subpopulations of tumor cells, endowed with special properties, exists. These cells have the tools needed to complete the process of metastasis successfully, while most of the cancer cells die at some point in the journey. In studies, these cells have been identified and isolated, proving that not all cancer cells have metastatic capabilities.

There are also studies that have led to the conclusion that certain tumors only produce metastasis to specific organs. The studies have shown that even though cancer cells may reach all organs in the body, they only have an affinity for certain organs. It is only when the cells reach those specific organs that they anchor and reproduce. Ivan Stamenkovic of Harvard Medical School supported this theory when he was able to direct the metastatic spread of tumor cells by inserting a certain adhesion molecule into a mouse's liver. The tumor cells homed in on the liver because of the inserted molecules. The inserted adhesion molecules had the right markers that tumor cells were looking to bind to. This and many other experiments show that both the tumor cells and the host tissue determine the ultimate site of metastasis.