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Lymphatic Vessels in Inflammation and Cancer Metastasis

Final Report Summary - LYVICAM (Lymphatic Vessels in Inflammation and Cancer Metastasis)

The project aimed to better understand the biological role of lymphatic vessels in inflammatory diseases and in cancer progression, and to develop new tools for the quantitative imaging of lymphatic vessel function in vivo and for the therapeutic targeting of lymphatic vessels. A major finding of these studies was that activation of lymphatic vessels inhibits inflammation, and a new fusion protein was developed that specifically activates lymphatic vessels in inflamed tissues. Systemic application of this fully human protein potently inhibited inflammation in two different models of skin inflammation and in an experimental model of arthritis without apparent adverse effects, indicating possible translation to human diseases. Another major achievement was made by screening chemical and natural extract libraries, leading to the identification of a small molecule that potently activates lymphatic vessel function in vitro and in vivo. This molecule has the potential for clinical development towards the treatment of impaired wound healing and post-surgical lymphedema. A major achievement was the development of new near-infrared imaging tracers and of new quantitative in vivo imaging technologies to measure the function of lymphatic vessels under normal and diseased conditions. In particular, a delivery device with microneedle patches was developed for the noninvasive skin application of a near-infrared tracer to measure lymphatic vessel drainage in humans. This could be used as a biomarker to evaluate therapeutic efficacy of therapeutic compounds or the risk for lymphedema development after surgery. In addition, new genetic models for the preclinical imaging of lymphatic vessels were established. In experimental cancer models, new insights were found into the mechanisms how tumors activate lymphatic vessels to promote their metastastic spread to lymph nodes and beyond, in part by inhibiting the immune response, and in part by providing a niche for the prolonged survival of cancer cells with stem cell properties. These studies identified potential targets for limiting cancer spread.