Nick Oropall
FYS
12/10/08
Chemokines: Cancer’s Nemesis?
Solution structure of interleukin-8, a chemokine of the CXC subfamily
Cells, the so called building blocks of life, are comprised by something smaller, something more complex. Molecular machines control many activities in the cell in surprisingly robotic or even humanistic ways. From molecular tweezers, which can hold guests between its arms, to molecular sensors which interact with abnormalities in order to make it recognizable, there are all types of molecular machines for all types of jobs. Simply put, be it the most feasible or complex jobs within a cell are done by one or a grouping of molecular machines. Though scientists have created methods to halt and even cure types of cancers, the power of bionanomachines has yet to be completely harnessed in the fight against cancer. The key to unlocking this enigma may lie in a type of protein called a Chemokine.
Chemokines come from a grouping of proteins secreted by cells, otherwise known as cytokines. Chemokines are classified as proteins that have characteristics such as small size and a three dimensional shape due to the presence of four cysteine residues. Chemokine can be categorized into four groups but overall they fit into two basic groups: pro-inflammatory and homeostatic. They can be found in many types of living organisms such as all vertebrate and some viruses and bacteria, yet none have been found in any invertebrate. The pro-inflammatory can promote cells of the immune system to a site of infection during an immune response. The homeostatic are responsible for controlling the movement of cells during tissue maintenance or development. The chemokines biological effects are shown when they interact with chemokine receptors found on the surface of their target cells.
Proteins are not just classified into the chemokine family because of their ability to attract cells. They are put into the category based on their structure. One defining characteristic is that chemokines are all very small. Chemokines have 20-50% in common with each other. This means that their amino acids are very similar and put in a similar order. Every chemokine also contains the amino acids necessary to form its three dimensional (tertiary) structure. Generally these amino acids are four cysteines. These cysteines work in pairs to form the “greek key” shape that is a major characteristic in chemokines. Each cystein is put in a specific place. The first and second are located near the N-terminal end. These two are the only two that are close together. The third is found near the center of the molecule. Finally, the fourth is found near the C-Terminal end. The first two cysteines have a loop of approximately ten amino acids that follow them called the N-loop. The chemokine then gets even more complex and the N-loop is followed by more loops called the 30s, 40s, and 50s loops. These loops are made of a single-turn helix, called a 310-helix, three β-strands and a C-terminal α-helix. The third and fourth cysteins are found in the 30s and 50s loops.
If the protein was not shaped the way it was it would not be able to bind with its receptors and carry out its jobs. In order for a chemokine to bond to a receptor it has to mold to fit the shape. This molding would not be possible without the flexible N terminus. This conformation completed by the N terminus allows the chemokine to fit the shape of the receptor and carry out activation. There are many different variations of chemokines but because of their largely identical shapes and amino acid patterns they all function in almost the same way.
The most important and main function of chemokine is to control migration of cells. The homeostatic chemokines are secreted without any need to stimulate its source cell. These chemokines “round up” the cells of the immune system and bring them where they need to be in order to aid in immune response. Lymphocides and lymph nodes are an example of the cells of the immune system the homestatic chemokines control. The lymphocites and lymph nodes screen for pathogens residing in tissue. A second job of chemokine is to control the growth of new blood vessels, otherwise known as angiogenesis. Along with the growth of new blood vessels chemokine is also in control of cellular maturation. Like the foreman of a job chemokine guides cell tissues which in tern provide the specific signals necessary for cellular maturation. Inflammatory chemokines which provide possibly the most relevant job are key to the immune system and immune response. Inflammatory chemokines are released from a plethora of cells in order to combat bacterial infection, viruses, and anything in general harming the body. Specific inflammatory chemokines trigger cells to begin the immune response as well as promote wound healing.
In many types of cancers there is an extensive chemokine network. It is very likely that these networks influence the growth and behavior of angiogenesis, the leukocytes, tumor cell growth, and migration. The presence of leukocytes in both tumor and stromal cells can be attributed to chemokines. Although there is an abundance of chemokine in epithelial tumors, there has been no discovery of chemokine receptors on the infiltrating leucocytes. However, in certain forms of ovarian cancer there have been an abundance of chemokine receptors found on leukocytes.
In certain types of tumors, chemokine doing its job may be directly contributing to the problem. As the foreman of the job chemokine controls the movement of cells and calls cells to “worksites.” It’s possible that certain cells the chemokine attracts not only do not help, but may even contribute to the immunosuppressive environment. Another example of how chemokine doing its job may be promoting the opposite affect than originally intended is with its abilty to promote cell growth. Excessive chemokine receptors have been found in melanoma cells which may mean that chemokine is actually contributing to the tumor’s growth and survival. Chemokine receptors such as CCR7 have been found on many different cancerous cells, which lead scientists to believe that chemokine could be a definite aid to tumors.
Although there is certainly a recipe for disaster with the combination of chemokine and cancer, there is also a bright light for success. This could prove to be a difficult task, yet, in order to fight cancerous cells and tumors, chemokine’s control over cells would need to be harnessed. If the chemokine did not attract the leukocytes to inhibit the cancerous cells it could prevent angiogenesis, survival and spread of tumor cells. Another method to halt the development of cancerous cells would be to decrease the amount of chemokine or chemokine receptors. In order for chemokine to fully function it needs its receptor and it would have nothing to affect if there were no leucocytes. The three need to be present in order to have an affect so the depletion of one would be sufficient to inhibit growth of cancerous cells. Coincidentally, another approach that has been tested that would not involve directly affecting the work the chemokine does, is by overflowing the cancerous cell with chemokine. Over expression of certain chemokine types can suppress tumor growth, by attraction dendritic cells which activate tumor specific cytotoxic T lymphocytes.
The full extent of chemokines and their work on cancer has not been completely explored, yet, further research is certainly warranted, and will yield positive results. With work the power of molecular machines in general can be used to achieve and aid in many things. Chemokine in particular has serious potential involving the immune system, and experiments already suggest that it can aid in not only the fight against cancer but also against HIV.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WWY-4C9HJ21-5&_user=793338&_coverDate=06%2F30%2F2004&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000029698&_version=1&_urlVersion=0&_userid=793338&md5=a9b33661e2e30c402694238ebbd12f5b
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-42P62MN-N&_user=793338&_coverDate=02%2F17%2F2001&_fmt=full&_orig=search&_cdi=4886&view=c&_acct=C000029698&_version=1&_urlVersion=0&_userid=793338&md5=72550f23c961c543e06015651696766e&ref=full
http://en.wikipedia.org/wiki/Chemokine
http://en.wikipedia.org/wiki/Cancer
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