Lymphedema research update
By Professor Spencer Gibson
Twoyears ago, I was appointed as the Dianne and Irving Kipnes Endowed Chair in Lymphatic Disorders. I established a basic/ translational research laboratory at the University of Alberta in the Department of Oncology and currently have a laboratory of seven researchers ranging from four graduate students, a postdoctoral fellow, a clinical coordinator, and a lab manager. The focus of our research is to understand the mechanisms in the microenvironment that allows some patients to develop secondary lymphedema after surgery, radiation and/or chemotherapy. In contrast, others repair the damage to their lymphatic system with no swelling or tissue changes in their legs or arms. Specifically, we are investigating environmental stress that occurs in lymphatic tissue, such as oxidative stress or hypoxia and how lymphatic endothelial cells respond to this stress.
In our preliminary findings, growth factors significantly alter lymphatic cell response to microenvironmental stress, which could weaken their ability to repair the damage. We are developing an animal model of lymphedema to evaluate further these microenvironmental stresses and factors that could alter lymphatic cell response to stress, thus leading to lymphedema (Figure 1).
Beyond the laboratory studies, we have also established a secondary lymphedema biobank where we process and store lymphedema patient blood samples and collect their clinical information. We are collecting blood samples from four sites: a cancer centre, a lymphedema
Research Program:
In secondary lymphedema, microenvironmental stress and microenvironmental factors might have a potential role in inducing lymphatic vessel dysfunction that causes the progression of lymphedema. Created in BioRender.
Spencer Gibson, Ph.D is a Professor at the University of Alberta, Department of Oncology and the first Dianne and Irving Kipnes Endowed Chair in Lymphatic Disorders. He is a Board Director of the Canadian Lymphedema Framework Board of Directors.
rehabilitation clinic, a clinical studies laboratory at U of A, and a private clinic. We currently have over 30 blood samples stored and five blood samples collected before and after compression therapy. The patients range from cancer patients to patients suffering from injury-related lymphedema. Unfortunately, we miss many patients, as lymphedema is not usually identified in the medical record. We are working to solve these challenges and hope to expand this biobank so we can capture the entire lymphedema patient population in the future.
To understand lymphedema, we teamed up with researchers at the University of Calgary (Dr. von der Weid and Dr. Liao). Their studies focus on inflammation-associated changes in the lymphatic system in the skin, gut and brain. We have established joint lab meetings and meet in person once a year to exchange results and ideas on how the lymphatic system works. It has been invaluable to my trainees and has given direction to the research projects. Indeed, Dr. von der Weid shared the primary lymphatic cells his lab generated to help us in our research projects. In the future, we hope to develop collaborative projects that will further our understanding of the lymphatic system.
Dr. von der Weid was the organizer of a Lymphatic forum meeting held in Banff in June 2023. He was gracious enough to invite me as a member of the organizing committee for the conference. It was an opportunity to review scientific abstracts for oral presentations and judge posters for awards. In addition, it allowed me to get to know the international community that researches the lymphatic system and gain knowledge about the research field. Here is my perspective on lymphatic research.
FIGURE 1
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The lymphatic system’s role in regulating disease is becoming more of a focus. In kidney disease, there is altered renal lymphatic function resulting in reduced lymphatic pumping and leakiness. In liver disease, lipoproteins drive dysfunction in the lymphatic system that could be targeted for treatment.
Lymphatic systems affect every major organ in the human body. Not so long ago, researchers would ignore lymphatic vessels in organs, as they did not know their function. This is no longer the case as the lymphatics are now found to play a role in the eye, skin, kidney, liver, heart, gut, lung, bone, brain, and many other organs. I will focus on two organs that interest me the most, the eye and the brain. The eye is one of the organs where the lymphatic system plays an important role in intraocular pressure. When this is dysfunctional, congenital glaucoma can occur. Researchers have found alterations in developmental factors in lymphatics lead to glaucoma.
The brain is the second organ where the lymphatic system plays an important role. The lymphatic system of the brain is giving new insights into how fluid and immune cells drain out of the brain. This has huge implications for brain diseases as diverse as cancer, Alzheimer’s, Parkinson’s disease, and dementia. Researchers are beginning to understand how the brain lymphatic system normally functions and impacts these diseases.
The lymphatic system regulates the immune system. It is important in healing from infections,
regulating self-antigen recognition, transporting antigens and cytokines, and activating neutrophil. In the gut, the intestines’ bacteria (microbiome) seem to influence the lymphatic system regulating immune system function.
The lymphatic system’s role in regulating disease is becoming more of a focus. In kidney disease, there is altered renal lymphatic function resulting in reduced lymphatic pumping and leakiness. In liver disease, lipoproteins drive dysfunction in the lymphatic system that could be targeted for treatment. Lymphatic dysfunction also involves activation of the Notch signalling pathway that seems to involve liver damage.
In cancer, lymphatics play an important role in immune suppression and metastasis through the lymph nodes. These events are not mutually exclusive, and researchers have shown that cancer cells in the lymph node lead to immune suppression in animal models. Furthermore, induction of lymphangiogenesis leads to fewer T cells and higher immune checkpoint receptor expression in tumours. Taken together, lymphatic systems impact many diseases.
Finally, there was progress in understanding, detecting, and treating lymphedema. During lymphedema, the skin layer thickens and
hardens. Researchers have found that keratinocytes (skin cells) proliferate when exposed to lymphedema fluid and induce inflammatory responses through the release of cytokines. This regulates the development of secondary lymphedema. Inhibition of keratinocytes proliferation using the drug teriflunomide reduced lymphedema in animal models. In addition, lymphedema is associated with leaky vessels. Researchers found that a receptor orchestrates tighter junctions between lymphatic cells preventing vessel leakage and leading to attenuation of lymphedema. This suggests that drug treatments for lymphedema are possible. In addition, imaging lymphedema is difficult. Researchers using an isotype of sodium (23Na) that can be imaged by MR lymphangiography, found sodium levels increased in lymphedema limbs even at the early stages of lymphedema. Furthermore, sodium channels responsible for smooth muscle contractions are being identified and shown to be altered in lymphedema. This illustrates that new insight into the regulation of lymphedema development, new detection methods, and new treatment targets are being developed.
The Lymphatic Forum ended with a dinner where the head of the Lymphatic Education and Research Network (LE&RN) gave an inspiring speech about patient advocacy, new funding opportunities and a growing research community focused on lymphatics. With our new research program and linkage to the greater lymphatic research community, the future is bright. We hope to contribute to new detection and treatments for lymphedema through translation from the bench side to the bedside. This will be the new frontier in lymphatic research moving forward. LP
A full set of references can be found at http://www.canadalymph.ca/ pathways-references/
