Organochlorine and gene/environment interaction in Non-Hodgkin's Lymphoma

Non-Hodgkin’s lymphoma (NHL) is the fifth most common cancer in Canada, and incidence has been increasing steadily for the past 30 years. However, at present, little is known about the risk factors for developing this cancer of the lymphatic system. Danhong Shu is examining whether exposure to organochloride compounds (chemicals such as DDT and PCB) increases the risk for developing Non-Hodgkin’s lymphoma, and whether certain genetic factors may also contribute to increased or decreased susceptibility to NHL. Using blood and mouthwash samples from 1,600 test subjects, she is comparing organochlorine levels between people with NHL and those who are cancer free. In addition, Danhong is using these samples to compare genetic patterns that may point to increased susceptibility to this type of cancer, focusing on genes involved in the metabolism of organochlorines (Ahr and CYP1A1). This research could confirm environmental risks and genetic susceptibility for Non-Hodgkin’s lymphoma, and help explain how the disease develops. Ultimately, the information may lead to preventive measures to limit environmental exposures and reduce the risk of NHL.

UV exposure and effects of gene interactions with UV exposure as risk factors in Non-Hodgkin's lymphomas (NHL)

Non-Hodgkin’s lymphomas (NHL) are cancers of the lymphatic system, which is responsible for the body’s immune response to fight disease. People with suppressed immune systems are at increased risk for Non-Hodgkin’s lymphoma, but little is known about other risk factors. Some evidence points to ultraviolet (UV) exposure from sunlight as a possible risk factor. For example, the incidence of NHL has increased in parallel with some skin cancers. The risk of these skin cancers and NHL increase with proximity to the equator, suggesting sunlight or UV exposure is a risk factor in NHL, as has been proven for skin cancer. Certain groups with higher exposure to sunlight have increased risk of developing NHL. And UV radiation is known to suppress the immune response, which is associated with NHL. Carmen Ng is investigating genetic and environmental risks for NHL. She is also examining whether variations in two genes, XRCC1 and MC1R, affect the risk of Non-Hodgkin’s lymphomas due to UV exposure. This study will help explain the causes of NHL, which can be used to develop preventive measures and better treatments for the disease.

Effect of drugs on the tumour microenvironment

One challenge with treating solid tumours is ensuring the effective delivery of chemotherapy drugs to all the cells within a tumour. Inefficient penetration of an anti-cancer drug results in insufficient doses reaching cells distant from the tumour’s blood vessels. As a result, these cells may survive and proliferate, allowing the tumour to re-grow. In addition, a low drug exposure may actually contribute to tumour cells developing resistance to a drug. Lynsey Huxham is examining the tumour microenvironment after drug administration and determining which drugs penetrate well. She is focusing on the effects of a drug by examining dividing cells and those undergoing apoptosis (cell death) in relation to their distance from blood vessels. By understanding the process of extra-vascular drug distribution, she hopes to aid efforts to improve the administration and delivery of cancer drugs, as well as offer insight into the design of new chemotherapy drugs.

High resolution analysis of rearrangements in follicular lymphoma genomes using high-throughput BAC clone fingerprinting

Follicular lymphoma is a cancer of the lymphocytes (cells of the immune system) and is the most prevalent type of lymphoma in Canada. Most follicular lymphomas are associated with defective cells resulting from the gene regulation process (the process through which the cell determines when and where genes will be activated) resulting in increased production amounts of the protein Bcl-2. This protein prevents lymphocytes from dying at the end of their natural lifespan, causing these altered cells to persist in the body, gain abnormal alterations in their genomes, and eventually develop into cancerous cells. Anca Petrescu is examining how chromosomes in follicular lymphoma are structurally different and rearranged relative to the normal genome, and how these differences may cause cancer. She is studying ten follicular lymphoma genomes and will profile each to discover the rearrangements they harbour. Common rearrangements will be analyzed in detail to determine their exact properties, and their effect on genes. Anca hopes her research will provide insight into the role of recurrent rearrangements in follicular lymphoma, and allow for further research to identify key genes that may be may be of potential diagnostic or therapeutic use.

Molecular characterization of Ahi-1, a novel signaling molecule with an SH3 and multiple WD40-repeat domains, in normal and leukemic hematopoiesis

Because many forms of leukemia originate in blood stem cells, uncovering the changes that occur in these cells is crucial to understanding how these diseases develop and progress. Dr. Xiaoyan Jiang is studying Ahi-1, a newly-discovered oncogene (cancer causing gene) that is involved in murine leukemia development (leukemia in mice) and shows abnormal expression in human leukemic cells, including leukemic stem cells from patients with chronic myeloid leukemia and Sezary cancer cells from patients with cutaneous T-cell lymphoma. Her research team recently found that over-expression of Ahi-1 gene alone can cause leukemia in mouse models and suppression of Ahi-1 gene can normalize its transforming activity in human leukemia cells, a strong indicator that Ahi-1 is likely to be an important new oncogene involved in the development of leukemia in humans. Dr. Jiang’s research will explore the normal function(s) of Ahi-1 in the development of blood cells, and how this is altered when cells become leukemic. This research will also begin to identify new intracellular molecules that interact with Ahi-1 and the cellular and molecular pathways through which these interactions occur. Understanding how and by which pathways Ahi-1 contributes to the development of leukemia may provide important new molecular targets for the development of targeted cancer treatment that will be more effective and have fewer side effects than currently used chemotherapy.

Analysis of a role for Hippi / IFT57 in regulation of embryonic laterality and sonic hedgehog signalling

Research has shown that defects in cilia, small hair-like structures on the outside of cells, are the cause of many disorders including infertility, blindness, deafness, kidney defects and breathing difficulties. It has been shown that some of these defects arise when there are mutations in components of these cilia known as “”Intraflagellar Transport proteins”” (IFTs). These faults may render the cilia immobile, shorter than normal, or even completely absent and can lead to alterations in the normal layout of adult organs such as the heart, liver, and lungs. There are an increasing number of diseases linked with the IFT family of genes. Dr. Robin Dickinson is studying the role of one of them, known as Hippi / IFT57. Robin is investigating what these genes do when active, and examining the effects of their loss. Robin hopes that research into their function will lead to development of therapies for diseases caused by defects in cilia.

Role of SPARC in cancer therapy

Colorectal cancer (CRC) is the third most common cancer in both men and women, and was responsible for an estimated 8,300 deaths in 2004 in Canada. While there has been an overall decline in the incidence and mortality of CRC in the past two decades because of better cancer prevention, the overall five-year survival rate continues to be poor. This is due in part to chemotherapy resistance, which is common in many solid tumours. Dr. Isabella Tai’s research is directed at understanding the mechanisms enabling cancer cells to become resistant to cancer drugs and other therapies. Using a high-throughput “genomics” approach, her research team has developed a comprehensive list of genes involved in chemo- and radiotherapy resistance. One such gene, SPARC, had low levels of expression in colorectal cancer cells that were resistant to several chemotherapy agents. By increasing the levels of SPARC in therapy refractory cells, response to radiotherapy and chemotherapy was restored and tumor size reduction was observed. Dr. Tai’s team is now examining the general applicability of SPARC-based therapy in other cancer model systems, how it promotes tumor regression, and whether patients who are likely to become resistant to therapy can be identified based on a potential diagnostic marker. The results of the project could lead to improvements in cancer treatment and potentially provide a diagnostic marker to identify individuals likely to develop chemotherapy resistance.

Identifying direct target genes of Notch signaling in endothelial cells during endothelial-to-mesenchymal transition

Congenital heart defects due to anomalies in heart development occur in one percent of newborns. A critical event during heart development is the transformation of a subset of cells that line the inside of the heart, called endocardial cells, into mesenchymal cells. This process, termed endothelial-to-mesenchymal transition (EMT), generates cells to form heart valves and walls that divides the adult heart into chambers and regulates blood flow. If EMT does not progress properly, normal heart development is disrupted, resulting in the most common type of congenital heart defects. Notch proteins (signaling molecules that trigger genes to activate) play an important role in EMT as the activation of Notch signaling induces the EMT process in endothelial cells. Dr. Yangxin Fu’s research goal is to identify the direct target genes of Notch signaling that are critical to EMT. Using cell culture and molecular biology tools, including a cutting-edge, high throughput technique, Yangxin is analyzing thousands of candidate genes and searching for Notch target genes critical for EMT and heart development. This study will help to understand the molecular mechanism underlying the role of Notch signaling in EMT and in the long term it may find potential target molecules to prevent and treat the heart defects caused by disruption of Notch signaling.

Notch signaling in Lymphoid Neoplasia

A common theme in cancer is the dysregulation of a normal developmental process that either directly causes cells to grow in an uncontrolled manner, or renders them susceptible to cellular damage that, in turn, leads to uncontrolled growth. One example of this process occurs with a normal cellular gene called Notch, which is inappropriately activated in a large fraction of cases of a certain type of blood cancer called T cell acute lymphoblastic leukemia (T-ALL). During normal development of the immune system, regulated Notch activity is required for formation of mature lymphocytes that protect the body from infection. When activated, Notch promotes the formation of normal T lymphocytes, but if this signal is not turned off in time, these T cells can undergo malignant change and become cancerous. Dr. Andrew Weng is studying the signals that are generated by Notch activation and the context in which these signals are received by the cell. By understanding the role of Notch in cancer development, he hopes to develop methods for manipulating Notch activity to shut down the growth of established cancer cells, and perhaps also to prevent it from occurring in the first place.

Novel strategies for genetic modification and expansion of hematopoietic stem cells

Throughout life, blood cell production is dependent on a rare cell found in the bone marrow called the hematopoietic stem cell. This cell has the unique ability to divide and make identical copies of itself and also to generate progeny cells that can expand and acquire the specialized properties of mature circulating blood cells. Stem cells underpin a wide range of transplantation-based therapies for cancer, leukemia and genetic disorders. The use of these cells for therapeutic purposes requires genetic manipulation of hematopoietic stem cells, which involves inserting gene products directly into the cell’s genome. This procedure can also negatively affect chromosomes flanking the insertion site, causing variations in normal gene expression and malignant growth. Dr. Eric Yung is addressing these issues by developing methods to introduce new genes into stem cells without inserting them directly into the host genome. His strategy is to adapt and modify the ability of certain viruses to insert genetic material into cells. These methods may provide safer and more robust ways to achieve high level expression of genes. They may also aid understanding of the function of specific genes (for example genes that cause cancer) and the development of new methods to expand stem cells and develop new therapies for genetic disorders.