Harvard Catalyst Profiles

As part of the Edwin L. Steele Laboratories for Tumor Biology, the Padera Laboratory examines the function of lymphatic vessels in health and disease, with an emphasis on the 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. Lymphatic vessels also facilitate the dissemination of cancer cells from a primary tumor to regional lymph nodes. The mechanisms used by cancer cells to form lymph node metastasis are starting to be understood, with the hope of identifying treatment strategies to lower mortality due to disseminated cancer. In contrast to hematogenous metastasis, in which the primary tumor has functional blood vessels for cancer cells to invade, the story for lymphatic metastasis is likely more complicated as solid tumors seem to lack functional intratumor lymphatic vessels. Functional lymphatic vessels in the margin of tumors, however, seem sufficient for lymphatic metastasis to occur.

Using intravital microscopy, we have investigated the individual steps of lymphatic metastasis. We can monitor 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.

In addition to our work on metastasis, we have studied the molecular mechanisms that regulate the autonomous lymphatic contractions that drive lymph flow. Using novel animal models and intravital microscopy, we have shown that normal lymphatic contractions are reliant upon nitric oxide that is produced in specific locations at specific times. When the spatial and temporal control is lost during inflammation, the contractions stop and lymph function is impaired.

Our future studies will continue to dissect the physical and molecular determinants of lymphatic vessel function and lymphangiogenesis in both normal and disease states. In addition we will continue to understand the mechanisms of cancer dissemination through lymphatic vessels and subsequent growth in lymph nodes. 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 lymphatic metastasis and lymphedema.