A growing body of evidence suggests that pro-inflammatory cytokine signaling cooperates with Ras pathway hyperactivation to drive tumor development. Thus, targeted anti-cytokine therapy might serve a useful adjunct to conventional therapeutic approaches. Plexiform neurofibroma (PNF) is a benign tumor of the nerve that arises from the Schwann cell lineage after biallelic loss of Nf1, a negative regulator of Ras. PNF causes significant early and lifelong morbidity in persons with the common genetic disorder, Neurofibromatosis type 1 (NF1). Prior work by our group and others has shown both that leukocyte recruitment is critical for plexiform neurofibroma development in mice, and that injury-associated nerve inflammation can facilitate PNF development in mice. Here we identify a cytokine overexpressed in the peripheral nerves of our PNF mouse model, whose receptor is necessary for the development of PNF. The Cxcr3 cytokine signaling pathway has known roles in the recruitment of leukocytes, and is reported to directly contribute to tumor cell growth and cancer. Our general hypothesis is that signaling through this cytokine pathway contributes to plexiform neurofibroma development through direct effects on the Nf1-null Schwann cell lineage, and/or indirectly through leukocyte recruitment. Deletion of Cxcr3 rescues Schwann cell hyperplasia, and alters leukocyte recruitment in our mouse model. We propose to further elucidate the role of this pathway in PNF development by carrying out the following specific aims: (1) determine the effects of receptor inhibition on established plexiform neurofibroma; (2) identify the relative contributions of receptor expression on hematopoietic and non- hematopoietic cells on PNF development; (3) determine if genetic deletion of the over-expressed Cxcr3 ligand recapitulates receptor deletion. Drugs antagonizing the effects of this pathway are currently in phase II trials for several inflammatory diseases. This experiments outlined represent a critical first step in investigating the therapeutic potential of anti-cytokin treatments in plexiform neurofibroma.
to public health Plexiform neurofibroma is a benign tumor that causes significant early and lifelong morbidity in the persons with the common genetic disorder Neurofibromatosis type I. In their preliminary experiments, the authors found that loss of the gene Cxcr3 prevents the development of this tumor. The experiments outlined in this proposal seek to determine how Cxcr3 contributes to plexiform neurofibroma development and the potential of Cxcr3 inhibitors as a novel treatment for this disease.
