Our focus is the interaction of the lymphatic and immune systems in cancer and in the immune response. These interests developed from our discovery of lymph node alterations in mice that precede and promote cancer metastasis.
NOTICE: The Ruddell Lab has moved to the University of Washington in Seattle as of December 2012. To learn more or contact Dr. Ruddell, please send inquiries to Alanna Ruddell or call (206)685-1216.
Cancer cell detection in tumor-draining lymph nodes (TDLNs) is used clinically to diagnose metastasis of many types of human cancers, suggesting that the lymphatic pathway is a common initial route of tumor spread. Immunocompetent mouse models show modest growth of tumor lymphatic vessels (lymphangiogenesis). However, extensive lymphatic sinus growth arises in tumor-draining lymph nodes (TDLNs), even before metastasis is initiated. This is associated with increased lymph drainage, suggesting the hypothesis that TDLN lymphatic sinus growth and accelerated lymph flow actively drive tumor dissemination into draining lymph nodes.
Abnormal accumulation of B cells throughout TDLNs is required to promote lymphatic alterations and metastasis, as B cell-deficient mice with melanoma do not develop TDLN lymphangiogenesis, increased lymph flow, or metastasis. Conversely, preneoplastic E-µ-c-myc transgenic mice that feature pre-existing LN B cell accumulation, lymphangiogenesis, and increased lymph flow show accelerated tumor metastasis to TDLNs, demonstrating that TDLN alterations actively promote tumor dissemination via the lymphatics. Mice bearing benign tumors do not develop these TDLN alterations, supporting the idea that TDLN B cells regulate metastatic potential. The involvement of TDLN B cells and lymphatic alterations in metastasis is a major area of interest.
Non-invasive imaging tests could improve diagnosis of cancer metastasis, to identify those patients needing aggressive intervention. The mouse cancer models identified abnormal and increased TDLN lymph flow as diagnostic features in mice developing metastatic tumors. MRI and optical imaging assays are being used to characterize the mechanism by which tumors increase lymph drainage, and to develop diagnostic imaging tests for cancer patients.
The lymphatic circulation drains fluid and cells from the periphery through LNs, facilitating immune responses to lymph-borne antigens. A 10.1.1 monoclonal antibody to a lymphatic endothelial surface antigen was developed as a specific reagent for murine lymphatic vessel detection. The 10.1.1 antigen encodes the mCLCA1 protein, which demonstrates strong affinity for the LFA-1 and Mac-1 adhesion molecules expressed on lymphocytes and leukocytes. Investigation of mCLCA1 contributions to leukocyte trafficking and the immune response could provide new insights to lymphatic/immune system interactions.