Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

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.

Simon Leedham

Adult gastrointestinal stem cells

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. Professor Simon Leedham's current research focuses on the cell-signaling pathways that control intestinal stem cells and the dysregulation of these pathways in cancer.

More podcasts related to Cancer

Raghib Ali: INDOX Cancer Research Network

Cancer Ex-faculty podcasts Global Health

INDOX is a collaboration between Oxford and twelve leading cancer centres in India. It aims to develop effective and affordable cancer treatments in low and middle income countries, to improve the early detection of cancer, and to reduce the incidence of cancer by establishing the population specific risk factors.

Vincenzo Cerundolo: Cancer immunology

Cancer Ex-faculty podcasts

The development of therapeutic vaccines is more challenging. Current lines of research include the development of antibodies blocking inhibitory T cell signals, and the characterisation of adjuvants.

David Jackson: The Lymphatic System in Immunity and Cancer

Cancer Ex-faculty podcasts

Our lymphatic system protects us against pathogens: it collects micro-organisms and carries them to the lymph nodes where they will meet and activate T cells and B cells. Cancer cells also migrate to the lymph nodes, but instead of activating the immune system they actually suppress it. A better understanding of these mechanisms might help us better control the spread of tumours, and also block unwanted immune responses in autoimmune diseases, block tissue rejection and make vaccines more effective.

Tim Key: Role of Lifestyle and Diet in Cancer

Cancer Ex-faculty podcasts

We know that although smoking is still the most important cause of cancer, obesity and high intakes of alcohol increase the risk for several types of cancer. The role of diet in the development of cancer is much less clear, but there is a lot of evidence suggesting that diet does matter.

Patrick Pollard: Cancer Metabolism

Cancer Ex-faculty podcasts

Dr Pollard’s work is focused on a form of kidney cancer for which no effective therapy exists once it metastasizes. By integrating analyses of these cancer cells and novel models he hopes to provide insights into altered cancer metabolism and a real, innovative route into the design of therapies for various cancers.

Catherine Green: DNA replication and Cancer

Cancer Genetics

The process of DNA replication is complex, and mistakes can lead to genome instability. Surveillance systems are not always successful which results in mutations that have the potential to inactivate genes or change their activity. This can lead to cancer, and many chemotherapeutic drugs are designed to disrupt DNA replication. A better understanding of these mechanisms can help us develop new drugs with reduced side effects.

Skirmantas Kriaucionis: Epigenetic modifications and cancer

Cancer

Although all cells in our body have the same genome, they look different and perform different functions. Epigenetic modifications such as methylations ensure which sets of genes are expressed in specific cells and how this specificity is inherited. Cancer cells show particular epigenetic abnormalities which can be targeted for cancer therapies.

Ross Chapman: Repairing DNA damage

Cancer

Whilst controlled DNA breaks allow for our vast repertoire of antibodies, DNA damage happening out of context can lead to cancer or predisposition to cancer. Recent developments in personalised medicine exploit the DNA repair weaknesses of cancer cells to selectively kill them. A better understanding of the underlying mechanisms can help develop innovative and targeted therapies.

John Christianson: Cleaning up misfolded proteins

Cancer

Misfolded proteins can either create the loss of a cellular function, or escape degradation, causing aggregation diseases. Better knowledge of these mechanisms helps us understand the root cause of different kind of diseases, and also develop targets for therapeutic intervention.

Robert Gilbert: Targeting cancer mechanisms

Cancer

Switching mechanisms within our cells are in part responsible for their development. MicroRNAs control a whole set of proteins associated with stem cell biology, particularly cancer stem cells. Targeting these components raises the potential for new anti-cancer therapeutics, which work by switching off protein production rather than inhibiting them later.

Translational Medicine

From Bench to Bedside

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.