title: Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.
abstract: Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-β pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.
authors.affiliation: Departments of Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Teitz
authors.forename: Madoka
authors.initials: M
authors.lastname: Inoue
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Valentine
authors.forename: Kejin
authors.initials: K
authors.lastname: Zhu
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Christopher
authors.initials: C
authors.lastname: Calabrese
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rubinstein
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
mesh_terms: D000818:Animals; D019046:Bone Marrow Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018305:Ganglioneuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D010524:Peripheral Nervous System Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D059467:Transcriptome
chemical_list: C571825:MYCN protein, mouse; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D011518:Proto-Oncogene Proteins; C505526:Casp8 protein, mouse; D053181:Caspase 8
references.citation: J Biol Chem. 2012 Mar 9;287(11):8092-100
references.pmid: 22267731
references.citation: J Biol Chem. 2000 Nov 10;275(45):35565-9
references.pmid: 10954721
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12664-9
references.pmid: 15314226
references.citation: Cancer Res. 2012 Sep 15;72(18):4714-23
references.pmid: 22815530
references.citation: BMC Cancer. 2009 Mar 30;9:97
references.pmid: 19331667
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: PLoS One. 2011 Apr 29;6(4):e19133
references.pmid: 21559450
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22249-54
references.pmid: 21135236
references.citation: J Am Soc Nephrol. 2012 Feb;23(2):252-65
references.pmid: 22095944
references.citation: Dev Biol. 2011 Nov 15;359(2):209-21
references.pmid: 21920357
references.citation: Crit Rev Clin Lab Sci. 2012 May-Jun;49(3):85-115
references.pmid: 22646747
references.citation: Cancer Biol Ther. 2010 Mar 15;9(6):446-52
references.pmid: 20147780
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):63-73
references.pmid: 19197333
references.citation: J Clin Oncol. 2009 Jan 10;27(2):289-97
references.pmid: 19047291
references.citation: Nat Neurosci. 2010 Jan;13(1):133-40
references.pmid: 20023653
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Oncogene. 2012 Feb 9;31(6):728-38
references.pmid: 21743496
references.citation: J Clin Oncol. 2010 Oct 1;28(28):4316-23
references.pmid: 20805453
references.citation: J Cancer Res Clin Oncol. 2008 Jun;134(6):705-14
references.pmid: 18084776
references.citation: Reprod Biol Endocrinol. 2004 Jan 07;2:2
references.pmid: 14711377
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4622-30
references.pmid: 18628477
references.citation: Am J Pathol. 2009 Aug;175(2):856-66
references.pmid: 19608868
references.citation: Mol Carcinog. 2011 Mar;50(3):153-62
references.pmid: 21104989
references.citation: Genes Dev. 2003 Apr 1;17(7):883-95
references.pmid: 12654726
references.citation: Genesis. 2003 Aug;36(4):196-202
references.pmid: 12929090
references.citation: Oncologist. 2010;15(4):350-9
references.pmid: 20413640
references.citation: Cancer Res. 2006 Jun 15;66(12):5981-4
references.pmid: 16778165
references.citation: Nature. 2006 Jan 5;439(7072):95-9
references.pmid: 16397500
references.citation: RNA. 2008 Jun;14(6):1012-7
references.pmid: 18426918
references.citation: Nat Rev Cancer. 2003 Mar;3(3):203-16
references.pmid: 12612655
references.citation: J Am Soc Nephrol. 2011 Aug;22(8):1462-74
references.pmid: 21784902
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18968-73
references.pmid: 16365299
references.citation: EMBO J. 1997 Jun 2;16(11):2985-95
references.pmid: 9214616
references.citation: Cancer Res. 2008 Feb 1;68(3):937-45
references.pmid: 18245497
references.citation: Nat Rev Cancer. 2009 Feb;9(2):108-22
references.pmid: 19165226
references.citation: Nature. 2009 Mar 26;458(7237):519-23
references.pmid: 19204729
references.citation: Curr Biol. 2011 Jun 7;21(11):933-41
references.pmid: 21600772
references.citation: Neoplasia. 2008 Dec;10(12):1350-61
references.pmid: 19048114
references.citation: Nat Cell Biol. 2009 Nov;11(11):1287-96
references.pmid: 19838175
references.citation: Oncogene. 2004 May 6;23(21):3737-48
references.pmid: 14990994
references.citation: Cell. 1996 Jun 14;85(6):817-27
references.pmid: 8681377
references.citation: Cell Death Differ. 2008 Sep;15(9):1350-5
references.pmid: 18566604
references.citation: J Clin Invest. 2008 Jan;118(1):100-10
references.pmid: 18079967
references.citation: J Cell Biol. 2012 Feb 20;196(4):395-406
references.pmid: 22351925
references.citation: Cancer Lett. 2009 Aug 28;281(2):128-33
references.pmid: 19111387
references.citation: N Engl J Med. 2010 Jun 10;362(23):2202-11
references.pmid: 20558371
references.citation: PLoS One. 2012;7(8):e41523
references.pmid: 22876288
references.citation: Cancer Res. 2004 Jul 1;64(13):4531-8
references.pmid: 15231663
references.citation: FEBS Lett. 2001 Jun 15;499(1-2):121-6
references.pmid: 11418125