Research will include elucidation of the physiology and biochemistry of the lymphatic system, determination of risk factors and possible prevention strategies for lymphedema, exploration of circulating biomarkers of vascular disease that could hold great promise for early disease detection, improvement in diagnosis and clinical classification of lymphedema and lymphatic disorders, exploration of dietary and lifestyle changes to improve quality of life and possibly disease progression, and improvement in treatments for lymphedema.

Research Currently Underway

Imaging

Current methods routinely used for diagnostic imaging of lymphatics are not well suited for imaging the actual movement of lymph, a critical step in understanding how lymphatic vessels work. Through the Dianne and Irving Kipnes Foundation, the Snyder Institute for Chronic Diseases in the Cumming School of Medicine at the University of Calgary has built a world-class imaging suite devoted to studies of the lymphatic system. This Lymphatic Imaging Suite is part of the existing Live Cell Imaging (LCI) Facility at the Snyder Institute for Chronic Diseases, a state-of-the-art imaging infrastructure providing sophisticated tools for research in infection, inflammation and chronic diseases. These include a multiphoton resonant scanning microscope for deep tissue imaging, a resonant scanning confocal microscope for live cell imaging and an epifluorescent microscope for high speed imaging of lymphatic contraction. The Snyder Institute for Chronic Diseases is considered a global leader in the field of immune system imaging.

∗New Funding Awarded∗

ALNET is pleased to announce funding awarded by the University Hospital Foundation and the Dianne and Irving Kipnes Foundation in Edmonton, Alberta for several pilot research projects.

Nanoparticles as tools for diagnostics, imaging and assessment of lymphatic dysfunction

Despite the prevalence of lymphedema, diagnostic assessment and treatment of lymphatic dysfunction is limited by the low resolution/penetrance of current imaging techniques and the inherent difficulty to observe and image the colorless and tiny lymphatic vessels in most parts of the body. Current methods routinely used for imaging of lymphatics are limited and not well-suited for imaging the actual movement of lymph, a critical step to understand how lymphatic vessels work and how edema occurs. To help gaining a better understanding of the functions of the lymphatic system, we propose in this research project three strategies: 1) Fluorescent Si nanoparticles for imaging, 2) Dye-doped fluorescent SiO2 nanoparticles for imaging and 3) Silicon as a next generation magnetic resonance imaging (MRI) agent. These new agents will help image lymphatic vessels and assess lymph flow in preclinical models to improve our understanding of lymphatic functions. They will ultimately provide highly needed tools to better diagnose and treat lymphedema patients. Principal Investigators: Jonathan Veinot, University of Alberta, Department of Chemistry; Christopher Cairo, University of Alberta, Department of Chemistry; Shan Liao, University of Calgary, Department of Microbiology, Immunology & Infectious Diseases; Pierre-Yves von der Weid, University of Calgary, Department of Physiology & Pharmacology.

Bio-orthogonal probes for quantitative measurement of lymph flow/clearance to enable early treatment

The diagnosis and study of the lymphatic system in patients is challenging due to a lack of technologies that can quantitatively detect changes in lymph flow. There is a need for new strategies to 1) diagnose lymphatic dysfunction at an early stage and to provide rapid and simple feedback to clinicians, and 2) develop imaging tools for the study of lymph flow in pre-clinical models and the clinic. Both of these sets of tools would expand our basic understanding of lymphatic function, and could enable treatment options at an early stage of diseases, such as lymphedema, which are currently only apparent after a patient reaches later stages of the disease. Early treatment may be less invasive and more effective – but without new detection strategies these cannot be adequately implemented. We propose to develop bio-orthogonal probes for use as sensitive and quantitative diagnostics and imaging tools to be used in the study and treatment of lymphatic disorders. Principal Investigators: Christopher Cairo, University of Alberta, Department of Chemistry; Shan Liao, University of Calgary, Department of Microbiology, Immunology & Infectious Diseases; Pierre-Yves von der Weid, University of Calgary, Department of Physiology & Pharmacology.

Metabolomics/Biomarker Studies for diagnosis, prognosis and determination of risk factors of lymphedema

Metabolomics and proteomics have shown significant promise for the discovery of new biomarkers for the detection of a number of complex clinical disorders. However, the use of metabolomics and proteomics in lymphedema is relatively unexplored.

1A) We propose to identify small molecule metabolite biomarkers in blood and urine in a preclinical model of lymphedema that may lead to the identification of chemical biomarkers for the early prediction or diagnosis of lymphedema in humans. Initiating studies in preclinical models will help to narrow the focus on specific groups of metabolites that can be studies more in-depth in humans. Principal Investigators: David Wishart, University of Alberta, Department of Biological Sciences; Liang Li, University of Alberta, Department of Chemistry; Shan Liao, University of Calgary, Department of Microbiology, Immunology & Infectious Diseases; Pierre-Yves von der Weid, University of Calgary, Department of Physiology & Pharmacology.

1B) We propose to identify protein and small molecule metabolite biomarkers in blood, urine, lymph and interstitial fluid of patients with lymphedema and in normal control patients. In addition, we propose to identify protein and small molecule metabolite biomarkers in patients that may differentiate between primary and secondary lymphedema and may indicate whether a patient is at risk of developing lymphedema. We will then apply statistical tools to compare the metabolite concentration changes of the groups to determine one or a panel of metabolites that could be used for diagnosis or prognosis of lymphatic diseases. These biomarkers could be used to guide the treatment and management of the diseases. Principal Investigators: David Wishart, University of Alberta, Department of Biological Sciences; Liang Li, University of Alberta, Department of Chemistry; Jaggi Rao, University of Alberta, Department of Medicine.

2) It is generally accepted that radiation therapy as well as the removal of tumor-draining lymph nodes increases the risk of developing lymphedema. However, this has not been well investigated in clinical cohort studies. Additionally, there is no clinical standard established to determine which patients should undergo early intervention. Therefore, we aim to identify the co-relationship among the number of lymph nodes removed, the area that has received radiation, and the risk of developing lymphedema via identification of small molecule metabolite biomarkers. We hypothesize that patients who have developed new lymphatic vessels from pre-existing lymphatic vessels within the affected area may have a lower risk of developing lymphedema. We propose to test this in clinical samples and will also use preclinical breast cancer models to recapitulate lymph node removal and radiation therapy to determine the lymphatic vessel function. Principal Investigators: Shan Liao, University of Calgary, Department of Microbiology, Immunology & Infectious Diseases; Liang Li, University of Alberta, Department of Chemistry.

Examination of the link between prostate cancer metastasis and the growth of lymph vessels

Prostate cancer is the most commonly diagnosed cancer in men, but no man dies of prostate cancer that stays in his prostate. This proposal will examine a recently-discovered link between the spread, or metastasis, of prostate cancer and the growth of lymph vessels in prostate cancer tumours. This research will investigate the role of a protein called CD151, which has been implicated in both metastasis and lymph vessel development, as a target to reduce or block metastasis. We will develop new preclinical models for prostate cancer that evaluate the contribution of CD151 and other important lymph signals to metastasis and lethal disease, and engineer novel nanoparticles that target lymph vessels in prostate tumours with the goal of blocking metastasis completely. These studies will shed light on the role of lymph vessel growth in prostate cancer and may provide new tools in the fight against prostate and other metastatic cancers. Principal Investigator: John Lewis, University of Alberta, Department of Oncology.