Date of Award
Master of Science (MS)
The lymphatic system is responsible for immune circulation and fluid balance in the body. It accomplishes this by draining interstitial fluid from local tissue and transferring it to lymph nodes and back into blood circulation. However, this process is implicated in many pathologies, one of the most dangerous being breast cancer metastasis to the lymph nodes. The largest factor in breast cancer patient mortality is metastasis. Lymphangiogenesis, the growth of new lymphatic vessels, has been thought to play a dynamic role in aiding breast cancer metastasis. Breast cancer tumor cells have been shown to remodel the functionality of local lymph vessels to better aid in metastatic escape, possibly by creating mechanical and biochemical gradients. However, the complete relationship between breast cancer and the lymphatic system is not fully understood. Current models, such as mouse models or 2-D cell culture methods, lack the ability to study phenotypical changes in lymphatics and the relationship between lymphatics and breast cancer over time and in three dimensions. To understand this relationship and overcome experimental limitations, novel microfluidic devices are proposed here in order to model and track normal and cancer-associated lymphangiogenesis as well as the functional interaction between cancer cells and the lymphatic system. The multi-chamber devices allow for lymphatic cells to be physically separated from breast cancer cells but the interaction between them to be studied. In addition, biochemical and mechanical cues of lymphangiogenesis are isolated to further investigate the function of each. Under conditions of interstitial flow, lymphatic endothelial cells are shown to have increased lymphangiogenic sprouting. In addition, it is shown that mechanical cues may play a larger role than biochemical cues in inducing lymphangiogenesis. The microfluidic devices presented show immense promise in modeling the interaction between lymphatics and the cancer tumor microenvironment.
Jason Weber Department of Medicine
Greg Longmore, Amit Pathak