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 Ratner
Original Paper

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; Nf1flox/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.

Keywords

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

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)

References

  1. 1.
    Anthony SP, Puzanov PS, Lin KB, Nolop B, West DD, Von Hoff (2011) Pharmacodynamic activity demonstrated in phase I for PLX3397, a selective inhibitor of FMS and Kit. J Clin Oncol 29:suppl; abstr 3093Google Scholar
  2. 2.
    Bahrami F, Morris DL, Pourgholami MH (2012) Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem 12(1):44–52PubMedCrossRefGoogle Scholar
  3. 3.
    Daginakatte GC, Gutmann DH (2007) Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet 16(9):1098–1112PubMedCrossRefGoogle Scholar
  4. 4.
    DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1(1):54–67. doi:10.1158/2159-8274.CD-10-0028 PubMedCrossRefGoogle Scholar
  5. 5.
    Dineen SP, Lynn KD, Holloway SE, Miller AF, Sullivan JP, Shames DS, Beck AW, Barnett CC, Fleming JB, Brekken RA (2008) Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res 68(11):4340–4346PubMedCrossRefGoogle Scholar
  6. 6.
    Donovan S, Shannon KM, Bollag G (2002) GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta 1602(1):23–45PubMedGoogle Scholar
  7. 7.
    Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39(5):311–314PubMedCrossRefGoogle Scholar
  8. 8.
    Galarneau H, Villeneuve J, Gowing G, Julien JP, Vallieres L (2007) Increased glioma growth in mice depleted of macrophages. Cancer Res 67(18):8874–8881PubMedCrossRefGoogle Scholar
  9. 9.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674 pii:S0092-8674(11)00127-9PubMedCrossRefGoogle Scholar
  10. 10.
    Heerva E, Alanne MH, Peltonen S, Kuorilehto T, Hentunen T, Vaananen K, Peltonen J (2010) Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation. Bone 47(3):583–590 pii:S8756-3282(10)01294-9PubMedCrossRefGoogle Scholar
  11. 11.
    Held-Feindt J, Hattermann K, Muerkoster SS, Wedderkopp H, Knerlich-Lukoschus F, Ungefroren H, Mehdorn HM, Mentlein R (2010) CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Exp Cell Res 316(9):1553–1566 pii:S0014-4827(10)00067-4PubMedCrossRefGoogle Scholar
  12. 12.
    Hirota S, Nomura S, Asada H, Ito A, Morii E, Kitamura Y (1993) Possible involvement of c-kit receptor and its ligand in increase of mast cells in neurofibroma tissues. Arch Pathol Lab Med 117(10):996–999PubMedGoogle Scholar
  13. 13.
    Keepers TR, Gross LK, Obrig TG (2007) Monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic–uremic syndrome. Infect Immun 75(3):1229–1236. doi:10.1128/IAI.01663-06 PubMedCrossRefGoogle Scholar
  14. 14.
    Lasater EA, Li F, Bessler WK, Estes ML, Vemula S, Hingtgen CM, Dinauer MC, Kapur R, Conway SJ, Ingram DA Jr (2010) Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. J Clin Invest 120(3):859–870. doi:10.1172/JCI41443 PubMedCrossRefGoogle Scholar
  15. 15.
    Ling BC, Wu J, Miller SJ, Monk KR, Shamekh R, Rizvi TA, Decourten-Myers G, Vogel KS, DeClue JE, Ratner N (2005) Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell 7(1):65–75PubMedCrossRefGoogle Scholar
  16. 16.
    Liu HM, Yang LH, Yang YJ (1995) Schwann cell properties: 3. C-fos expression, bFGF production, phagocytosis and proliferation during Wallerian degeneration. J Neuropathol Exp Neurol 54(4):487–496PubMedCrossRefGoogle Scholar
  17. 17.
    Ma J, Li M, Hock J, Yu X (2012) Hyperactivation of mTOR critically regulates abnormal osteoclastogenesis in neurofibromatosis Type 1. J Orthop Res 30(1):144–152. doi:10.1002/jor.21497 PubMedCrossRefGoogle Scholar
  18. 18.
    Maertens O, Brems H, Vandesompele J, DeRaedt T, Heyns I, Rosenbaum T, DeSchepper S, DePaepe A, Mortier G, Janssens S, Speleman F, Legius E, Messiaen L (2006) Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat 27(10):1030–1040PubMedCrossRefGoogle Scholar
  19. 19.
    Markovic DS, Glass R, Synowitz M, Rooijen N, Kettenmann H (2009) Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA 106(30):12530–12535PubMedCrossRefGoogle Scholar
  20. 20.
    Markovic DS, Glass R, Synowitz M, Rooijen N, Kettenmann H (2005) Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol 64(9):754–762PubMedCrossRefGoogle Scholar
  21. 21.
    McCaughan JA, Holloway SM, Davidson R, Lam WW (2007) Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1. J Med Genet 44(7):463–466. doi:10.1136/jmg.2006.048140 PubMedCrossRefGoogle Scholar
  22. 22.
    Monk KR, Wu J, Williams JP, Finney BA, Fitzgerald ME, Filippi MD, Ratner N (2007) Mast cells can contribute to axon-glial dissociation and fibrosis in peripheral nerve. Neuron Glia Biol 3(3):233–244. doi:10.1017/S1740925X08000021 PubMedCrossRefGoogle Scholar
  23. 23.
    Mueller M, Wacker K, Ringelstein EB, Hickey WF, Imai Y, Kiefer R (2001) Rapid response of identified resident endoneurial macrophages to nerve injury. Am J Pathol 159(6):2187–2197. doi:10.1016/S0002-9440(10)63070-2 PubMedCrossRefGoogle Scholar
  24. 24.
    Nakagawa J, Saio M, Tamakawa N, Suwa T, Frey AB, Nonaka K, Umemura N, Imai H, Ouyang GF, Ohe N, Yano H, Yoshimura S, Iwama T, Takami T (2007) TNF expressed by tumor-associated macrophages, but not microglia, can eliminate glioma. Int J Oncol 30(4):803–811PubMedGoogle Scholar
  25. 25.
    Plotkin SR, Bredella MA, Cai W, Kassarjian A, Harris GJ, Esparza S, Merker VL, Munn LL, Muzikansky A, Askenazi M, Nguyen R, Wenzel R, Mautner VF (2012) Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis. PLoS ONE 7(4):e35711. doi:10.1371/journal.pone.0035711 PubMedCrossRefGoogle Scholar
  26. 26.
    Prada CE, Rangwala FA, Martin LJ, Lovell AM, Saal HM, Schorry EK, Hopkin RJ (2012) Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr 160(3):461–467 pii:S0022-3476(11)00881-XPubMedCrossRefGoogle Scholar
  27. 27.
    Riccardi VM (1987) Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen. Arch Dermatol 123(8):1011–1016PubMedCrossRefGoogle Scholar
  28. 28.
    Rizvi TA, Huang Y, Sidani A, Atit R, Largaespada DA, Boissy RE, Ratner N (2002) A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve. J Neurosci 22(22):9831–9840PubMedGoogle Scholar
  29. 29.
    Sadis S, Mukherjee A, Olson S, Dokmanovich M, Maher R, Cai C-H (2009) Safety, pharmacokinetics, and pharmacodynamics of PD-0360324, a human monoclonal antibody to monocyte/macrophage colony stimulating factor, in healthy volunteers. Arthr Rheum 60(Suppl 10):408. doi:10.1002/art.25491 Google Scholar
  30. 30.
    Smith MJ, Plotkin SR (2010) Neurofibromatosis and Schwannomatosis. Princ Clin Cancer Genet 181–193. doi:10.1007/978-0-387-93846-2_13
  31. 31.
    Takata M, Imai T, Hirone T (1994) Factor-XIIIa-positive cells in normal peripheral nerves and cutaneous neurofibromas of type-1 neurofibromatosis. Am J Dermatopathol 16(1):37–43PubMedCrossRefGoogle Scholar
  32. 32.
    Villeneuve J, Tremblay P, Vallieres L (2005) Tumor necrosis factor reduces brain tumor growth by enhancing macrophage recruitment and microcyst formation. Cancer Res 65(9):3928–3936PubMedCrossRefGoogle Scholar
  33. 33.
    Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87(12):4828–4832PubMedCrossRefGoogle Scholar
  34. 34.
    Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N (2008) Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13(2):105–116 pii:S1535-6108(08)00003-2PubMedCrossRefGoogle Scholar
  35. 35.
    Wu J, Dombi E, Jousma E, Scott Dunn R, Lindquist D, Schnell BM, Kim MO, Kim A, Widemann BC, Cripe TP, Ratner N (2012) Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox);DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr Blood Cancer 58(2):173–180. doi:10.1002/pbc.23015 PubMedCrossRefGoogle Scholar
  36. 36.
    Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR, Clegg T, White H, Mead L, Wenning MJ, Williams DA, Kapur R, Atkinson SJ, Clapp DW (2003) Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1± mast cells. J Clin Invest 112(12):1851–1861. doi:10.1172/JCI19195 PubMedGoogle Scholar
  37. 37.
    Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, Yan J, Morgan T, Li X, Yuan J, Hock J, Ingram DA, Clapp DW (2006) Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest 116(11):2880–2891. doi:10.1172/JCI29092 PubMedCrossRefGoogle Scholar
  38. 38.
    Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW (2008) Nf1-dependent tumors require a microenvironment containing Nf1± and c-kit-dependent bone marrow. Cell 135(3):437–448 pii:S0092-8674(08)01130-6PubMedCrossRefGoogle Scholar
  39. 39.
    Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345(6274):442–444. doi:10.1038/345442a0 PubMedCrossRefGoogle Scholar

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
  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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