title: Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition.
abstract: Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30-50 % of affected individuals to develop plexiform neurofibromas. We found that macrophage infiltration of both mouse and human neurofibromas correlates with disease progression. Macrophages accounted for almost half of neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1(flox/flox) mouse model of GEM grade I neurofibroma. In mice aged 1-4 months, prior to development of nerve pathology and neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7-9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for neurofibroma therapy.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Prada
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.forename: Tilat A
authors.initials: TA
authors.lastname: Rizvi
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.forename: R Scott
authors.initials: RS
authors.lastname: Dunn
authors.forename: Debra A
authors.initials: DA
authors.lastname: Mayes
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009455:Neurofibroma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000648:ultrastructure; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden
chemical_list: D004791:Enzyme Inhibitors; D025542:Neurofibromin 1