Dendritic cells in autoimmunity and cancer

Dendritic cells play a vital role in regulating the immune response. They are the only cells capable of activating T cells that have not previously been exposed to a particular antigen (immune threat) to recognize and mount an attack on these foreign proteins. This process ensures an appropriate immune response against potentially harmful antigens. Dendritic cells are also thought to have the ability to instruct the immune system to ignore certain antigens, establishing a state of immune tolerance in the body. When the balance between immune activation and immune tolerance is disrupted, the result may be the development of autoimmune disorders in which the immune system attacks body tissue or cancer in which tumour cell growth goes unchecked. Dr. Cheryl Helgason is studying the biology of dendritic cells and the mechanisms by which they interact with T cells to activate an immune response or to establish immune tolerance. Such research could suggest ways of manipulating immune function to develop new methods of treating cancers, autoimmunity and other diseases involving immune dysfunction.

Bioinformatic approaches to cancer research

Genes – the functional units of DNA – are involved in all aspects of normal human development and human disease. Although most cells have a core set of active genes, selective activation of other genes is necessary to produce different types of specialized cells, such as muscle cells, nerve cells and skin cells. Malfunction in the normal pattern of gene activation is implicated in many diseases, including cancer. Dr. Jones uses sophisticated computational techniques to analyze the activation of genes involved in the formation and development of mammalian organs and tissues and to explore genes that are activated in specific cell types such as muscle and neural cells. His goal is to develop software that will allow researchers to predict the behaviour of genes by indicating when they are switched “on” or “off”. Besides improved understanding of normal growth and development, this research will help clarify the changes in activation patterns that give rise to cancer, potentially leading to new ways of detecting cancer risk and the earliest stages of cancer onset.

Cell therapies for the treatment of hematopoietic malignancies

Though small in numbers, stem cells are responsible for the continued production of blood cells throughout a person’s life. They are also responsible for regenerating the blood-forming system following a bone marrow transplant in people with leukemia and other blood diseases. While blood stem cell transplantation is a promising therapy, its use is currently restricted because researchers have not yet found a way to reproduce these cells in large enough numbers for effective transplantation. Dr. Clayton Smith’s research is devoted to developing a better understanding of blood-forming stem cells so they can be effectively isolated and manipulated. Using leading-edge bioengineering and computer-based technologies, he is systematically exploring how the body’s environment affects stem cell growth, to see if these conditions can be replicated outside the body. He is also studying the function of certain genes that may be important to stem cell growth. Ultimately, he hopes to learn enough about stem cells to be able to grow them in large numbers outside the body for use in blood stem cell transplantation.

The demand for hereditary cancer services

The Hereditary Cancer Program at the BC Cancer Agency provides genetic testing and counseling services. The demand for these services in BC depends on many factors, each of which is subject to change. Factors include the growing knowledge in basic, applied and social sciences relating to hereditary cancer; the size of BC’s population and its characteristics in terms of age, ethnicity and family size; the evolving criteria by which people are deemed eligible for services; and people’s desire for these services. Through his research, Dr. Chris Bajdik is determining the demand for hereditary cancer services in BC and predicting how this demand may change in the future. He has created a computerized simulation model of the BC population, based on information about demography, cancer epidemiology and etiology, genetics, genetic technology, and human behaviour. The results from this model will help the BC Cancer Agency plan its services and assess the health benefits and costs of its Hereditary Cancer Program.

Mechanisms and functions of activin/nodal signaling in early embryogenesis

We all start as a single cell, which divides and eventually forms the body. A great deal of cell communication goes into making decisions about this body plan. My research examines how cells communicate with one another during embryonic development. The body plan is set up by organizing centres, or groups of cells that dictate signals to other parts of the early embryo. Two centres have been identified in mammals: the anterior visceral endoderm (AVE) coordinates the development of the head, and the node arranges the trunk into front, back, left and right. The way these organizing centres control growth of the embryo, and the cell-to-cell signalling involved in the process, are poorly understood. The same signalling systems used in creating an embryo break down during cancer. Ultimately, if we can identify what happens under normal circumstances, we can better understand what goes wrong with signalling pathways during the development of cancer or congenital defects. The results of my research also have implications for stem cell research. Stem cells have the potential to differentiate into various types of cells. If we can determine the signals that cause particular cells to become liver, brain or kidney cells during embryonic development, researchers should be able to cue stem cells to differentiate into specific cell types.

Angiogenesis in ischemia

I am examining angiogenesis – the process of how blood vessels grow – to learn how to make more blood vessels grow and discover ways to stop their growth. New blood vessels sprout from existing blood vessels. In addition, stem cells from bone marrow go to areas that require new blood vessels and differentiate into blood vessel-lining cells called endothelial cells. Endothelial cells line the inside of every blood vessel. My research lab has confirmed that when we turn on a protein receptor on the surface of the endothelial cells, we can block blood vessels from growing. We are also studying whether blocking this receptor will have the opposite effect of increasing blood vessel growth. All tissue needs blood to deliver nutrients to survive and grow. In heart disease, blood vessels are blocked by hardening of the arteries. When not enough blood gets to the heart, tissue dies, causing a heart attack. If we can make new blood vessels grow and bypass the blockage, heart tissue could potentially survive without surgery. Cancer tumours also require blood vessels to grow, and will only grow to 1-2 millimetres without a blood supply. If we can stop the growth of blood vessels to this tissue, tumour growth could be blocked. Stopping blood vessel growth could also stop tumours from spreading. Blood vessel growth also promotes chronic inflammatory conditions such as rheumatoid arthritis and psoriasis, so blocking growth may ultimately help treat these conditions as well.

The Genome Sciences Centre: a platform for large-scale high-throughput genomics in British Columbia

Our genes play a major role in our health and in our susceptibility to disease. In fact, the course of every disease is thought to be influenced to some extent by genetic factors. Confounding researchers’ attempts to understand the genetic basis of health and disease are the very large number of human genes (estimated at between 30,000 and 40,000) and the limitations in technology that, up until recently, allowed researchers to study only one or a few genes at a time. At the BC Cancer Agency Genome Sciences Centre, a new laboratory unique in Canada, we are developing and using state-of-the-art technology to examine thousands of genes simultaneously, searching for those that play a role in cancer. These genes will ultimately provide new tools for early diagnosis, improved treatment strategies and discovering cures to a disease that has touched the lives of almost all of us.

Cell adhesion and signaling in oncogenesis

The main objective of my research is to understand the molecular basis of how cancer progresses and to use the knowledge to identify new cancer therapies. To achieve this, my research team is studying receptors found on the surface of most cells that cause them to attach to other cells. We want to determine how the receptors communicate information they detect on the outside of the cell to the inside of the cell. We have identified proteins that interact with these receptors on the inside of the cell and are responsible for transmitting information to other parts of the cell to control cell division, cell death, cell differentiation and cell movement. We are focusing on one protein – Integrin Linked Kinase (ILK) – whose function is tightly regulated in normal cells, where its activity rapidly turns on and off. But in cancer cells, ILK is on all the time, leading to increased cell division, decreased cell death and increased cell movement. We have determined that ILK is at least partly responsible for the abnormal behaviour of cancer cells, and ILK activity is considerably elevated in many types of cancer. We have also identified specific chemical inhibitors of ILK activity, which are currently being evaluated in pre-clinical trials. The results to date show these inhibitors are effective in blocking growth and spread of tumours. ILK is present in many tissue types, and it is likely that it plays a critical role in the development and function of these tissues, and in other diseases of chronic inflammation such as arthritis, asthma, kidney disease and heart disease. To investigate this further we are using genetic techniques to alter ILK expression and function in a tissue-specific manner. Such studies will lead to a better understanding of the role of ILK and related proteins in nomal and diseased tissues.

P-glycoprotein, ABC transporters and genomics in cancer research

My research focuses on genes that play a role in the development of cancer, with a particular interest in genes that help malignant cells survive by limiting the effects of anti-cancer drugs. Our research team was the first to discover a protein (P-glycoprotein) on the surface of cancer cells that resists multiple cancer drugs. The protein protects cancer cells by pumping out drugs before they inflict lethal damage. With recent advances in genome science, the team has learned that proteins similar in structure to this one are present in more than 50 genes in the human genome. What these genes do in normal cells or in malignant ones is not yet fully understood. This is one of the questions that our team of more than 40 clinicians and scientists in the Cancer Genomics Program are working to answer. By analyzing how these genes act in normal tissue, and in cancers that are or are not responsive to drug therapy, we hope to identify markers (changes in the molecular structure or function of cells) that will be useful in diagnosing specific cancers earlier. Our goal is more effective treatment and, better still, more effective preventive measures.