Plexiform neurofibromas are complex tumors characterized by tumorigenic Schwann cells, inflammatory cells, neoangiogenesis and alterations of the extracellular matrix. Our previous work provided genetic, cellular, and biochemical evidence that haploinsufficiency of Nfl alters Ras activity and cell fates in mast cells and that ckit activation of the hematopoietic system is required in the initiation of plexiform tumor formation in a murine model. In this application, we propose to build oh these observations to identify the underpinning mechanisms of how c-kit mediates its biological effects, and to identify experimental processes that would complement ckit mediated experimental therapeutics in the clinic. Three basic processes will be examined. First, kit activation is known to cooperate with integrin signals in enabling myeloid cells to adhere to blood vessel walls and emigrate from the blood to the emerging tumor. We have recently established that Nf 1 +/- mast cells preferentially adhere to alpha4beta1, an integrin that has a key role in mast cell adhesion to endothelium and in local sites of inflammation. We hypothesize that alpha4beta1 is crucial in the recruitment of Nf1+/- mast cells to the tumor microenvironment in promoting local mast cell proliferation and survival, and in the secretion of molecules that promote neoangiogenesis. We propose studies to test this hypothesis in vitro and in vivo. Second, MMPs are secreted molecules that promote the release of preformed growth factors to the circulation and degrade the extracellular matrix of tissues allowing invasion of inflammatory and stromal cells leading to tumor progression. In preliminary studies we detect one specific MMP that is preferentially expressed and activated. Studies to specifically test the role of this protease are proposed. Finally, the specific downstream paracrine signals that lead to alterations of the extracellular matrix and neoangiogenesis are incompletely understood. Tumor-associated macrophages are known to enhance neoangiogenesis and facilitate malignant outgrowth. We recently established that large populations of angiogenic macrophages are found in peripheral blood and in the neurofibromas of Krox20;Nfl flox/- mice. We hypothesize that macrophage recruitment and their role in neoangiogenesis is a key downstream event following mast cell recruitment to the tumor and, therefore, processes that inhibit this activity will prevent or delay tumor progression. Adoptive transfer experiments are proposed to test this hypothesis.
This is an application that focuses on the use of a genetically engineered murine model to identify key molecular processes in plexiform neurofibroma progression. Studies utilize genetic intercrosses and adoptive transfer experiments to test the proposed hypotheses.
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