Aspirin, one of the oldest and safest of anti-inflammatory drugs, was in the news lately as a means to reduce cancer risk. We have known for quite some time (several decades) that drugs of this class can slow the progression of certain cancers in mice – especially colorectal cancer. The data on people has been controversial though. By this I mean that over the years a number of clinical trials have been performed and some clinical trials showed an effect but others did not. As each of these clinical trials was carefully dissected and better trials designed, the cancer protection effect got smaller – making this bet worse and worse. Then, it occurred to doctors studying this phenomenon that it might be worthwhile to look again at the patients that were part of some of the first trials. They also combined all of the data from as many trials as they could reasonably lump together for analysis and through this they found something important. It seems that if people take low dose aspirin daily for at least 5 years, their cancer risk drops by about 20% for certain cancers. If they continue in this fashion for 20 years the decreased risk extends to virtually all cancers examined. Twenty percent is not a lot but given the cheapness of the drug and the smallness of the dose (meaning few side effects) this seems to be worth the trouble. “So what does this have to do with diabetes?” you are probably asking about now….
Diabetes and Cancer are obviously quite different but they share the property of having an inflammatory component. Remember we started with aspirin which is an anti-inflammatory drug. The role of inflammatory cells in cancer is currently a hot topic. Many of us have been involved in examining how a particular kind of cell, called a macrophage, can play a supporting role to tumor cells. It seems that these macrophages help the tumor cell in a variety of ways and we have found that in experimental genetic models that if we alter the genes available to the macrophages we can alter the growth of the cancer. In the case of both type I and type II diabetes, destruction of the pancreas also takes place within an inflammatory environment.
Macrophages are incredibly dynamic cells that can take on many roles. They can be soldiers. They can gather information. They can even be healers. Keep in mind that inflammation often arises from trauma and that after infection is dealt with tissue healing must begin. The role of a cell is determined by the genes that it expresses. These genes (made of DNA) are translated into proteins (made of amino acids) which serve as the infrastructure that makes everything happen. Not all genes are available to all cells. The DNA that comprises our genome is the same from cell to cell but it is incredibly compacted. Indeed it is the most compacted biological material we know of. The DNA that needs to be available for copying gene information extends from this compacted mass in great loops. Your kidney cells have different loops of DNA extending out from the compacted chromatin mass than do neurons in your brain or pancreatic beta cells or macrophages. I think you get the idea. Interestingly, data from a number of groups suggests that a macrophage that starts out as a soldier can become a healer. In other words all of the genes necessary for both of these identities are freely available such that the macrophage can dynamically switch from one job to another. How this works is still a mystery but it is an important one in that as we develop a better understanding we will have new molecular targets for therapies that can drive macrophages towards one or the other function depending on need.
We cannot forget that macrophages, along with another kind of cell called a dendritic cell, are information gatherers. They are very good at a process called phagocytosis. This is the ability of the cell to engulf another cell (usually a pathogen or a dead cell) and digest it. They take the broken bits of the engulfed cell and they display them on their surface. We then have a special name for these bits. We call them antigens because they are displayed within a special protein (the major histocompatibility complex) that will show these bits to T cells. Macrophages also are on the lookout for special signals that let them know that they are dealing with a pathogen. Studies of evolution at the molecular level have been particularly useful here. We have come to realize that there exists a family of molecular shapes that are used by unicellular organisms (pathogens) but not by us multicellular types. We call them “Pathogen Associated Molecular Patterns” or PAMPs. Macrophages have a family of receptors that are dedicated to recognizing these PAMPs. Thus when a macrophage engulfs a pathogen, not only does it display all sorts of antigens on its surface, but it also displays a crucial molecular signal which is activated by the binding of these PAMPs to their receptors within the macrophage. The result is that the T cell now realizes that these antigens are representative of an infection and that we are now at war.
This is all well and good if the T cell matches the right antigen to the infection. This is one spot where things can go quite wrong. Focusing on type I diabetes, if the T cell incorrectly chooses a pancreatic antigen it ensures that the pancreas will be attacked and destroyed. Indeed certain viral infections are known to induce the onset of type I diabetes.
So, why is this important? Well, we would like to know; since diabetes and cancer both have inflammatory components and aspirin does something good for decreasing cancer risk – how about diabetes? Now that the stage is set, we’ll get into this in more depth in the next post.