Grant: Operating Grant

There is gradually emerging information that shows that the immune system can not only serve to fight cancers, but in some situations, can actually promote the growth of tumors. There are many different types of T lymphocytes, a cell of the immune system that is responsible for reacting against invading bacteria and viruses, as well as inciting chronic inflammation that can result in tumor development. T cell populations often bring about their effects by releasing different types of proteins known as 'cytokines' that can trigger inflammation, with the pattern of cytokines being made determining the type of inflammation that will occur. Other T cells, known as regulatory T cells, act to suppress inflammation by control the activities of other T cells. The balance between these two forces determines both the severity, character of, and longevity of the inflammatory response. We have developed a genetically engineered mouse having a defect in a gene (known as Smad4) in certain T cell populations. These animals are interesting because as they age, they develop large pre-cancerous growths (polyps) in their stomach; these are similar to a condition in humans known as 'gastric hyperplastic polyps'. We have evidence that the polyps are due to an abnormal T cell-induced inflammatory condition that is taking place immediately beneath the stomach's surface lining cells. We hypothesize that the inflammation we see is being caused by an imbalance between aggressive and suppressive T cells, and that this, in turn, is leading to the release of cytokines that stimulate the abnormal growth of the stomach lining, leading to polyp formation. In terms of relevance to human cancer, our studies may be able to show how certain T cell populations are able to stimulate the development of cancers, not only in the stomach, but potentially at other sites as well. This information will be critical when one considering use of techniques aimed at harnessing the immune system to fight cancers.