Acta Neuropathologica

, Volume 125, Issue 1, pp 159–168 | Cite as

Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition

  • Carlos E. Prada
  • Edwin Jousma
  • Tilat A. Rizvi
  • Jianqiang Wu
  • R. Scott Dunn
  • Debra A. Mayes
  • Jose A. Cancelas
  • Eva Dombi
  • Mi-Ok Kim
  • Brian L. West
  • Gideon Bollag
  • Nancy RatnerEmail author
Original Paper


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.


Macrophages Neurofibromatosis type 1 Neurofibromin Fms c-kit Minocycline Mouse model 



This work was supported by grants from the NIH (NS28840 and P50-NS057531), and the Department of Defense Program on Neurofibromatosis (W81XWH-11-1-0057) to NR. We thank Margaret Collins, MD for providing human tissue sections.

Supplementary material

401_2012_1056_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)
401_2012_1056_MOESM2_ESM.tif (25.1 mb)
Supplementary material 2 (TIFF 25709 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Carlos E. Prada
    • 1
    • 5
  • Edwin Jousma
    • 2
  • Tilat A. Rizvi
    • 2
  • Jianqiang Wu
    • 2
  • R. Scott Dunn
    • 3
  • Debra A. Mayes
    • 2
  • Jose A. Cancelas
    • 2
  • Eva Dombi
    • 6
  • Mi-Ok Kim
    • 4
  • Brian L. West
    • 7
  • Gideon Bollag
    • 7
  • Nancy Ratner
    • 2
    Email author
  1. 1.Division of Human GeneticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Division of Experimental Hematology and Cancer BiologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  3. 3.Division of Imaging Resource CenterCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  4. 4.Division of BiostatisticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  5. 5.Center for Genomic Medicine and Metabolism, Cardiovascular Foundation of ColombiaFloridablancaColombia
  6. 6.Pediatric Oncology Branch, National Cancer InstituteBethesdaUSA
  7. 7.Plexxikon IncBerkeleyUSA

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