The gastrointestinal tract is lined with a single sheet of epithelium that is replaced every 4-5 days. The base of a flask-shaped structured called the crypt is where the gastrointestinal stem cells are found. These divide to form daughter cells that travel up the crypt to replace these cells. Dr Simon Leedham's current research focuses on the cell-signaling pathways that control intestinal stem cells and the dysregulation of these pathways in cancer.
Chemical messages, or morphogens, control processes in gasrointestinal stem cells such as cell division, cell differentiation and specialisation. Cancer occurs when cell division becomes out of control and one of the key features of a cancer cell is that it no longer responds to morphogens that tell it to stop dividing. They can then gain mutations that lead to the development of cancer.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
Q: What are stem cells?
SL: The stem cells that most often spring to mind are the ones that hit the headlines – embryonic stem cells. This is the product of the fertilised egg and is the stem cell that gives rise to all of the cells in the developing embryo. Perhaps what is less known is that all adult tissues have stem cells as well. The characteristic features of these stem cells, which are if you like the ‘engine room’ of the tissue, is that they can divide to renew themselves and also form all of the specialised tissues that can make up the entire organ. These cells are really the driving force of every organ and they are therefore vital in the growth, daily function and repair of every adult tissue.
Q: Can you give us an example of stem cells in adults?
SL: A great example of an adult stem cell is the one that is found in the gastrointestinal tract because the gut is lined with a single sheet of epithelium that is replaced every 4-5 days to help protect it from the toxins in our food so the intestinal stem cell is working extremely hard. Recent genetic markers have allowed us to identify where these stem cells are and they are contained in the functional unit of the gut called the crypt. This is a flask shaped structure and the stem cells are right at the bottom. The daughter cells that they produced are pushed up the side of the crypt and they specialise as they move up the crypt. They shed every 4-5 days. All of these complex processes of cell division, cell differentiation and specialisation are controlled by gradients of chemical messages called morphogens. It is these morphogens that my research is particularly interested in at the present time.
Q: What’s the link between gastrointestinal stem cells and cancer?
SL: Cancer occurs when cell division is out of control and one of the key features of a cancer cell is that it no longer responds to messages to tell it to stop dividing. In the gut cancer is caused by accumulation of mistakes in the genetic instructions, DNA. These mistakes accumulate over time and cancer occurs when one of these mistakes occurs in a gene that controls cell division. Because the intestinal stem cell seems to be the only cell that hangs around long enough to accumulate these genetic mutations (everything else is shed in 4-5 days), we have therefore long believed that the intestinal stem cell is the origin of colorectal cancer and that is a very important cell to study.
Q: What are the most important lines of research that have developed in the past 5-10 years?
SL: One of the critical advances in this field has been the identification of genetic markers that allow us to identify stem cells and their daughter cells. That has allowed us to see how these different cells respond in different models. My recent research has focused on the chemical messages that dictate whether a cell is a stem or a daughter cell. We believe that disruption of some of these chemical messages can trick a daughter cell in to behaving like a stem cell. That is called plasticity and makes us believe that some of the cells that give rise to some sorts of tumours can actually be non-stem cells, or daughter cells. It is like a leopard changing its spots – it’s a daughter cell behaving like it’s a stem cell because its environment is disrupted.
Q: Why does your line or research matter and why should we put money in to it?
SL: To find any effective treatment in biology you need to understand the underpinning biology of the disease. We are beginning to get to the stage where we can detect the mutations in a patient’s tumour prior to them receiving treatment and that’s not that far off. In the future we might be able to guide or direct our treatment towards a patient’s individual mutation burden. Because all tumours contain stem cells it is very critical that we use our therapy to kill all of those stem cells as otherwise the cancer is going to come back. My line of research I believe is important because stem cell plasticity occurs if the leopard can change its spots. We need to be able to be aware of that and use our drugs to target a changing or moving target at the same time.
Q: How does your research fit in to translational medicine within the department?
SL: As a scientist and an academic gastroenterologist I am quite uniquely placed to translate some of the many questions that I get asked in the clinic or in the endoscopy suite in to research strategies. It has been a really important part of my research to be able to focus my research questions on these important clinical questions. What we tend to do is use human tissue to develop an idea or a hypothesis and then biological models to test that. I think that is a very important synergy between human and biological systems. I am also part of the Oxford Translational Gastroenterology Unit, which is a unique setting where clinicians and scientist work alongside, we borrow skills from each other and we’re able to combine those to answer some of these clinically important questions.