title: Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.
abstract: Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these neurofibromas.
authors.affiliation: Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Staser
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D006413:Hematopoietic System / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000473:pathology*; D018318:Neurofibroma, Plexiform / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D025542:Neurofibromin 1; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
references.citation: Cell. 1989 Jan 13;56(1):5-8
references.pmid: 2535967
references.citation: Hum Mol Genet. 1994 Apr;3(4):639-41
references.pmid: 8069310
references.citation: Nat Genet. 1994 Jul;7(3):353-61
references.pmid: 7920653
references.citation: Science. 1990 Aug 10;249(4969):635-40
references.pmid: 2116664
references.citation: Blood. 2002 Nov 15;100(10):3656-62
references.pmid: 12393709
references.citation: N Engl J Med. 1991 May 2;324(18):1283-5
references.pmid: 1901626
references.citation: Glia. 2001 Mar 15;33(4):314-23
references.pmid: 11246230
references.citation: Cell. 1987 Jun 5;49(5):589-94
references.pmid: 2884037
references.citation: Am J Pathol. 1993 Apr;142(4):965-74
references.pmid: 7682764
references.citation: J Biol Chem. 2001 Mar 9;276(10):7240-5
references.pmid: 11080503
references.citation: Science. 1989 Jun 2;244(4908):1085-7
references.pmid: 2543076
references.citation: Annu Rev Neurosci. 2010;33:221-43
references.pmid: 20345245
references.citation: Hum Mol Genet. 2006 Aug 15;15(16):2421-37
references.pmid: 16835260
references.citation: Birth Defects Res A Clin Mol Teratol. 2010 Jan;88(1):9-14
references.pmid: 19691086
references.citation: Cancer Res. 2007 Sep 15;67(18):8588-95
references.pmid: 17875698
references.citation: Nature. 1988 Sep 1;335(6185):88-9
references.pmid: 2457811
references.citation: Blood. 2008 Dec 15;112(13):4808-17
references.pmid: 19064740
references.citation: Cancer Cell. 2008 Feb;13(2):117-28
references.pmid: 18242512
references.citation: Genes Dev. 1994 May 1;8(9):1019-29
references.pmid: 7926784
references.citation: Nat Rev Cancer. 2010 Dec;10(12):842-57
references.pmid: 21102635
references.citation: J Clin Invest. 1989 Jul;84(1):253-61
references.pmid: 2500456
references.citation: Oncogene. 1993 Mar;8(3):761-9
references.pmid: 8437860
references.citation: Cancer Res. 2008 Dec 15;68(24):10358-66
references.pmid: 19074905
references.citation: Hum Mutat. 2006 Oct;27(10):1030-40
references.pmid: 16941471
references.citation: J Clin Oncol. 2006 Jan 20;24(3):507-16
references.pmid: 16421428
references.citation: Neuron. 1993 Mar;10(3):335-43
references.pmid: 8461130
references.citation: J Pathol. 1976 Aug;119(4):193-6
references.pmid: 822142
references.citation: Cell. 1992 Apr 17;69(2):265-73
references.pmid: 1568246
references.citation: Science. 2002 May 3;296(5569):920-2
references.pmid: 11988578
references.citation: Hum Mol Genet. 2006 Jun 1;15(11):1858-69
references.pmid: 16648142
references.citation: Cell Stem Cell. 2009 May 8;4(5):453-63
references.pmid: 19427294
references.citation: Cell. 1990 Nov 16;63(4):843-9
references.pmid: 2121370
references.citation: Br J Cancer. 1964 Dec;18:686-91
references.pmid: 14264933
references.citation: Neurogenetics. 2007 Apr;8(2):121-30
references.pmid: 17216419
references.citation: Genes Chromosomes Cancer. 1999 Mar;24(3):283-5
references.pmid: 10451710
references.citation: Cell. 1990 Oct 5;63(1):213-24
references.pmid: 1698556
references.citation: Genomics. 1991 Dec;11(4):931-40
references.pmid: 1783401
references.citation: Oncogene. 2007 Jul 12;26(32):4609-16
references.pmid: 17297459
references.citation: Cell. 1990 Oct 5;63(1):225-33
references.pmid: 1698557
references.citation: Immunity. 2000 May;12(5):557-68
references.pmid: 10843388
references.citation: Am J Hum Genet. 1989 Jan;44(1):20-4
references.pmid: 2491776
references.citation: Pediatr Blood Cancer. 2012 Feb;58(2):173-80
references.pmid: 21319287
references.citation: Cancer Res. 2006 Sep 15;66(18):9054-64
references.pmid: 16982747
references.citation: Proc Natl Acad Sci U S A. 1988 Jul;85(14):5166-70
references.pmid: 2839833
references.citation: Nature. 1990 Nov 8;348(6297):125-32
references.pmid: 2122258
references.citation: Genomics. 1995 Jan 1;25(1):9-18
references.pmid: 7774960
references.citation: Glia. 2009 Aug 15;57(11):1239-49
references.pmid: 19191334
references.citation: Hum Mol Genet. 2009 Aug 1;18(15):2768-78
references.pmid: 19417008
references.citation: J Child Neurol. 2002 Aug;17(8):638-41; discussion 646-51
references.pmid: 12403563
references.citation: Hum Mol Genet. 2000 Jan 1;9(1):35-46
references.pmid: 10587576
references.citation: Nature. 1961 Mar 4;189:766-7
references.pmid: 13703263
references.citation: J Exp Med. 2001 Mar 19;193(6):F23-6
references.pmid: 11257144
references.citation: Cell. 1990 Jul 13;62(1):187-92
references.pmid: 1694727
references.citation: Nat Immunol. 2008 Nov;9(11):1215-23
references.pmid: 18936782
references.citation: Clin Cancer Res. 2004 Sep 1;10(17):5677-83
references.pmid: 15355893
references.citation: Immunology. 1995 Nov;86(3):427-33
references.pmid: 8550081
references.citation: Nature. 1991 Jan 10;349(6305):117-27
references.pmid: 1898771
references.citation: J Exp Med. 1998 Jun 1;187(11):1893-902
references.pmid: 9607929
references.citation: J Neurosci Res. 1994 Feb 15;37(3):415-32
references.pmid: 7513766
references.citation: Am J Hum Genet. 2007 Aug;81(2):243-51
references.pmid: 17668375
references.citation: Oncogene. 2001 Jan 4;20(1):97-105
references.pmid: 11244508
references.citation: Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6382-6
references.pmid: 1712491
references.citation: Mol Cell Biol. 1997 Feb;17(2):862-72
references.pmid: 9001241
references.citation: Hum Mol Genet. 2006 Jun 1;15(11):1921-30
references.pmid: 16644864
references.citation: N Engl J Med. 1991 May 2;324(18):1264-6
references.pmid: 1901624
references.citation: Cancer Cell. 2008 Feb;13(2):105-16
references.pmid: 18242511
references.citation: BMC Med. 2008 Jul 31;6:21
references.pmid: 18671844
references.citation: Science. 1987 May 29;236(4805):1100-2
references.pmid: 3107130
references.citation: Genes Dev. 2010 Oct 15;24(20):2317-29
references.pmid: 20876733
references.citation: Cell. 2008 Oct 31;135(3):549-60
references.pmid: 18984165
references.citation: Arch Neurol. 1965 Oct;13(4):372-82
references.pmid: 4953640
references.citation: J Exp Med. 2000 Jan 3;191(1):181-8
references.pmid: 10620616
references.citation: Nature. 1994 Oct 27;371(6500):796-9
references.pmid: 7935840
references.citation: J Neurosurg. 2007 May;106(5 Suppl):363-7
references.pmid: 17566202
references.citation: Am J Pathol. 1938 Jan;14(1):1-38.19
references.pmid: 19970371
references.citation: Genes Dev. 2001 Apr 1;15(7):859-76
references.pmid: 11297510
references.citation: Adv Neurol. 1981;29:259-75
references.pmid: 6798841
references.citation: Mol Syndromol. 2010 Sep;1(3):133-135
references.pmid: 21031083
references.citation: Hum Mol Genet. 2008 Aug 1;17(15):2336-44
references.pmid: 18442999
references.citation: Cell. 2008 Oct 31;135(3):437-48
references.pmid: 18984156
references.citation: J Invest Dermatol. 1994 May;102(5):812-8
references.pmid: 8176268
references.citation: J Med Genet. 1998 Oct;35(10):813-20
references.pmid: 9783703
references.citation: Humangenetik. 1975 Jun 19;28(2):129-38
references.pmid: 125227
references.citation: Cell. 1990 Jul 13;62(1):193-201
references.pmid: 2114220
references.citation: J Cell Biol. 1990 Aug;111(2):645-53
references.pmid: 1696266
references.citation: Cancer Res. 2006 Jan 15;66(2):605-12
references.pmid: 16423985
references.citation: Blood. 2010 Jul 15;116(2):157-64
references.pmid: 20233971
references.citation: Arch Dermatol. 1993 May;129(5):577-81
references.pmid: 8481017
references.citation: Hum Mol Genet. 2007 May 1;16(9):1098-112
references.pmid: 17400655
references.citation: Science. 1990 Jan 12;247(4939):209-12
references.pmid: 1688471
references.citation: Hum Mol Genet. 2008 Apr 1;17(7):936-48
references.pmid: 18089636
references.citation: J Clin Invest. 2003 Dec;112(12):1851-61
references.pmid: 14679180
references.citation: Curr Opin Genet Dev. 2003 Feb;13(1):20-7
references.pmid: 12573431
references.citation: J Pediatr Surg. 1972 Apr;7(2):144-51
references.pmid: 4623404
references.citation: J Neuropathol Exp Neurol. 2011 Jan;70(1):51-62
references.pmid: 21157378
references.citation: Cell. 1990 Aug 10;62(3):599-608
references.pmid: 2116237
references.citation: J Am Acad Dermatol. 1998 Jun;38(6 Pt 1):950-4
references.pmid: 9632003
references.citation: Mol Cell Biol. 2002 Jul;22(14):5100-13
references.pmid: 12077339
references.citation: EMBO J. 1990 Jun;9(6):1805-13
references.pmid: 1693331
references.citation: Cell. 1990 Nov 16;63(4):851-9
references.pmid: 2121371
references.citation: Cancer Cell. 2008 Feb;13(2):129-40
references.pmid: 18242513
references.citation: Nature. 2002 Dec 19-26;420(6917):860-7
references.pmid: 12490959
references.citation: Cell. 1992 May 1;69(3):389-91
references.pmid: 1316238
references.citation: J Clin Invest. 2006 Nov;116(11):2880-91
references.pmid: 17053831
references.citation: Am Surg. 2010 Apr;76(4):389-96
references.pmid: 20420249
references.citation: Arch Dermatol Res. 2011 Jul;303(5):317-25
references.pmid: 21042801
references.citation: J Med Genet. 2002 May;39(5):311-4
references.pmid: 12011145
references.citation: Curr Opin Hematol. 2010 Jul;17(4):287-93
references.pmid: 20571392
references.citation: Development. 2005 Dec;132(24):5577-88
references.pmid: 16314489
references.citation: Science. 1990 Jul 13;249(4965):181-6
references.pmid: 2134734
references.citation: Acta Neurol Scand. 1971;47(3):357-68
references.pmid: 4999559
references.citation: Nat Rev Immunol. 2008 Jun;8(6):478-86
references.pmid: 18483499
references.citation: Pediatr Res. 2009 Jun;65(6):613-8
references.pmid: 19247213
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: J Orthop Sci. 2007 Jul;12(4):361-5
references.pmid: 17657556
references.citation: Am J Hum Genet. 2006 Jul;79(1):143-8
references.pmid: 16773574
references.citation: Arch Pathol Lab Med. 1993 Oct;117(10):996-9
references.pmid: 7692836
references.citation: J Clin Invest. 2010 Mar;120(3):859-70
references.pmid: 20160346
references.citation: J Exp Med. 2001 Jul 2;194(1):57-69
references.pmid: 11435472
references.citation: Science. 1999 Dec 10;286(5447):2172-6
references.pmid: 10591652
references.citation: Cancer Res. 2003 Dec 15;63(24):8573-7
references.pmid: 14695164
references.citation: Am J Hum Genet. 1989 Jan;44(1):58-67
references.pmid: 2491783
references.citation: J Immunol. 2007 Feb 15;178(4):2527-34
references.pmid: 17277161
references.citation: Am J Pathol. 2004 Apr;164(4):1471-9
references.pmid: 15039234
references.citation: Trends Mol Med. 2003 Jan;9(1):19-23
references.pmid: 12524206
references.citation: Am J Hum Genet. 2007 Jan;80(1):140-51
references.pmid: 17160901
references.citation: Blood. 2008 Dec 1;112(12):4646-54
references.pmid: 18768391
references.citation: Oncogene. 2011 Mar 10;30(10):1135-46
references.pmid: 21076468
references.citation: Cell Stem Cell. 2010 Apr 2;6(4):361-368
references.pmid: 20362540
references.citation: Hum Mutat. 2000;15(6):541-55
references.pmid: 10862084
references.citation: Nat Genet. 1996 Feb;12(2):144-8
references.pmid: 8563751
references.citation: Cancer Res. 2010 Jul 15;70(14):5717-27
references.pmid: 20551058
references.citation: Neurology. 2011 Jan 18;76(3):265-72
references.pmid: 21242495
references.citation: Hum Mol Genet. 2000 Apr 12;9(7):1059-66
references.pmid: 10767330
references.citation: Glia. 2008 Nov 1;56(14):1590-1605
references.pmid: 18803326
references.citation: J Dermatol Sci. 2008 Jan;49(1):7-19
references.pmid: 18024086
references.citation: Arch Dermatol. 1987 Aug;123(8):1011-6
references.pmid: 3115189
references.citation: Birth Defects Orig Artic Ser. 1981;17(2):129-45
references.pmid: 6802200
references.citation: Am J Pathol. 2010 Dec;177(6):3125-32
references.pmid: 21037083
references.citation: Hum Mutat. 2003 Dec;22(6):423-7
references.pmid: 14635100
references.citation: J Med Genet. 2007 Jul;44(7):463-6
references.pmid: 17327286
references.citation: J Neurooncol. 2010 May;98(1):11-9
references.pmid: 19921098
references.citation: J Invest Dermatol. 2008 Apr;128(4):1050-3
references.pmid: 17914445
references.citation: Arch Neurol. 1999 Mar;56(3):364-5
references.pmid: 10190829
references.citation: Science. 2006 Jul 28;313(5786):526-30
references.pmid: 16873664