The potential importance of lymphoproliferative angiogenesis arises from two critical observations: 1) the association of disease progression with increased angiogenic activity;and 2) the assocation of clinical efficacy in pilot studies with anti-angiogenic therapy. We have shown that the vascular composition of human lymphoproliferative subtypes reflects differential recruitment and assembly of either hemangiogenic (CD68+VEGFR-1+) cells or mesenchymal smooth muscle cells.- The mechanisms leading to the recruitment and assembly of these cells are largely unknown. Annexin 2 (A2) is a fibrinolytic protease receptor that binds plasminogen and tissue plasminogen activator (tPA) at the surface of endothelial cells and monocyte/macrophages. Deficiency in A2 impairs effective neo-angiogenesis, and results in failure of lymphoproliferative progression in A2-null mice. Ongoing preliminary studies in primary human lymphoproliferative specimens indicate that A2 is predominantly expressed by neovascular endothelial cells, perivascular CD68+ hematopoietic cells, and smooth muscle pericytes. The objective of this project is to define the function of A2 in directing lymphoproliferative neovascular formation, with the hope to gain insights into the biology, pathogenesis and therapeutics of the disease. We hypothesize that A2 critically supports lymphoproliferative neo-angiogenesis by mediating vascular and stromal cell recruitment, migration, and assembly via cell surface plasmin generation and matrix metalloproteinases activation. We propose to: 1) establish whether lymphoproliferative angiogenesis is dependent on A2-mediated vascular and perivascular cell recruitment and assembly in a mouse model, 2) define the molecular and biochemical mechanisms by which A2 supports lymphoproliferative angiogenesis, 3) determine whether delineation of subpopulations of A2+ vascular and perivascular cells has prognostic significance in human patients. This proposal describes a 5 year career development program in academic translational medicine. The principal investigator has completed structured residency and fellowship training in Hematology-Oncology, and now will expand her scientific skills through a unique intergration of interdepartmental resources at Weill Cornell Medical Center under the mentorship of Dr. Katherine A. Hajjar, a recognized leader in the field of vascular biology, who is fully committed to the independence of the applicant.
