"mCLCA1 Regulation of Lymph Node Lymphangiogenesis"
Lymph node (LN) lymphangiogenesis occurs in tumor-draining LNs and inflammation and is thought to regulate lymphocyte-antigen interaction to promote an effective immune response and to regulate tolerance to self antigen.This LN lymphangiogenesis both predicts and promotes metastasis and is B cell-dependent. mCLCA1 (10.1.1) is a lymphatic endothelial cell (LEC) marker that interacts with LFA-1 on lymphocytes. Injection of mice with 10.1.1 antibody induces rapid lymphangiogenesis within 1 day resembling that observed in tumor-draining LNs. This leads us to propose that 10.1.1 antibody mimics lymphocyte LFA-1 binding to mCLCA1 on LECs. We propose to use this rapid 10.1.1 antibody-induced lymphangiogensis model to establish the mechanism of LN lymphatic sinus growth. 10.1.1 antibody induces some LEC proliferation; however, the majority of proliferating cells are not LECs, leading us to the hypothesis that multiple cell types contribute to lymphangiogenesis. Using flow cytometry and fluorescently tagged mouse models, we propose to identify the cell types proliferating in response to 10.1.1 antibody. We also propose the use of in vitro models to establish the mechanism by which 19.1.1 binding to LECs promotes non-LEC proliferation. We also propose to use both in vivo and invitro models to establish the mechanism by which these cells contribute to lymphangiogenesis. These studies may lead to the development of novel anti-cancer therapies to block lymphangiogenesis and metastasis.