Metastasis is the major complicating factor of most carcinomas, however a full understanding of the molecular mechanisms involved in the migration of tumor cells remains elusive. The most common metastatic route for certain tumors, including mammary adenocarcinomas, is via the regional lymphatics. In order to reach the blood and the systemic circulation, an individual tumor cell must separate from the original mass, traffic via the regional lymphatics to the local lymph nodes, transit those lymph nodes, and enter the blood via the efferent lymph. While lymphocyte and tumor entry into the local lymphatics may be passive, cellular release in the efferent lymph is a highly regulated process. The broad, long term goal of this proposal is to define the molecular mechanisms used by cells to exit lymph nodes in the efferent lymph, and the role of lymph-node segregation in the immune response. To accomplish this goal, we have 4 specific aims: 1) To define soluble factors which induce tumor cell retention within lymph nodes; 2) To define the molecular basis of cytokine or immunosuppressant-based tumor cell retention; 3) To inhibit metastasis with these mediators in an in vivo rodent model; 4) To introduce undergraduate students to basic research design and techniques in oncology. Our primary hypothesis is that metastatic tumor cells, like lymphocytes, can be """"""""trapped"""""""" in lymph nodes as a consequence of appropriate stimulation. To examine this question, we will use a defined model of trans-nodal traffic where it is possible to directly examine the ability of tumor cells to transit from afferent-to-efferent lymph in the presence and absence of inhibitory factors. Using a combination of molecular and cytometry-based assays, we will monitor differences in protein and gene expressions on treated and untreated cells, and use this knowledge to test the role of local tumor cell retention in established rodent models of breast cancer. While the objective of this proposal is to isolate molecular processes used by metastatic tumor cells to transit lymph nodes, the proposed studies are directly relevant to future development of novel anti-tumor therapies. As part of a growing oncology research core in South Dakota, these studies will introduce undergraduate research students to basic research.
