Padera, Timothy, PhD
Pathophysiology of tumor associated lymphatic vessels and lymphatic metastasis
Lymphatic vessels are responsible for draining interstitial fluid from tissues and for transporting immune cells to lymph nodes to maintain the body’s immune surveillance. Thus, lymphatics are important in maintaining both tissue fluid balance and proper function of the immune system. Predictably, disruptions of the lymphatic system lead to lymphedema and the conditions for chronic infections. Lymphatic vessels also facilitate the dissemination of cancer cells from a primary tumor to regional lymph nodes. My research group looks to understand the mechanisms behind the growth, maturation and function of lymphatic vessels and how these mechanisms can contribute to the pathogenesis of lymphedema, chronic infections and cancer dissemination.
In order to study the role of the lymphatic system in a variety of disease states, we have developed novel animal models which mimic certain aspects of human disease. Using intravital microscopy, we have investigated the individual steps of lymphatic metastasis. We can monitor the lymphatic vessels in the tumor margin, observe tumor cells moving in lymphatic vessels, measure lymph flow and quantify the number of tumor cells that arrive in the draining lymph node. Our studies have shown that VEGF-C, which is associated with lymphatic metastasis in patients, increases the size of the tumor margin lymphatic vessels, making them more vulnerable to invasion. Our data suggests that VEGF-C needs to be blocked very early in the metastatic process to be able to reduce VEGF-C enhanced lymphatic metastasis. Furthermore, we have shown that VEGFR targeted agents are not effective in preventing the growth of cancer cells that have seeded the lymph node, questioning the ability of these therapies to be used in the adjuvant setting.
To further study the growth of metastasis in the lymph node, we have developed a novel model that allows chronic imaging of a tumor draining lymph node. Using our model, we will ask fundamental questions underlying the growth of cancer cells in the lymph node and begin to identify molecular targets for future therapies aimed at eradicating lymphatic metastasis.
In addition, we have begun to study the pathogenesis of lymphedema by unraveling the molecular underpinnings of autonomous contraction of collecting lymphatic vessels using a novel animal model. We have shown that the spatial and temporal gradients of nitric oxide, which are disrupted during inflammation, are critical for lymphatics to drive lymph forward. Furthermore, when lymphatic contractions are disrupted, the immune response to a foreign antigen is muted. Thus disruption of lymphatic function has consequences for the overall immune function. We will test whether cancer or bacterial infections invoke similar regulatory dysfunction of lymphatic contraction. This work may lead to new targets to combat lymphedema and infections.
Our future studies will continue to dissect the physical and molecular determinants of lymphatic vessel function, lymphangiogenesis and lymphatic metastasis. Through the use of our novel imaging technologies and animal models, we will answer timely questions that can lead to the development of treatments for lymphedema, chronic infections and lymphatic metastasis.