Mast Cells and Tumor Progression.

Abstract SCI-33

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Neurofibromas form in association with peripheral nerves and are composed of Schwann cells, blood vessels, fibroblasts and degranulating mast cells. Genetic studies in engineered mice indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation in a genetically engineered murine model and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Recent studies in our group have focused on evaluating the role of bone marrow-derived cells, and particularly mast cells, in the tumor microenvironment. Previous work by our group established that human and murine Nf1 deficient Schwann cells secrete high concentrations of kit-ligand. Kit-ligand has a central role in multiple mast cell functions including chemotaxis, proliferation and degranulation. In a series of bone marrow transplantation studies, we established that Nf1 haploinsufficiency in bone marrow is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling diminishes neurofibroma initiation and progression. Collectively, the studies implicate mast cells as active participants in tumor formation and identify therapeutic targets for human phase 1-2 clinical trials.