Advertisement

Mammalian Genome

, Volume 23, Issue 3–4, pp 277–285 | Cite as

Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse Chr 5

  • Jessica Amlin-Van Schaick
  • Sungjin Kim
  • Karl W. Broman
  • Karlyne M. Reilly
Article

Abstract

Tumor location can profoundly affect morbidity and patient prognosis, even for the same tumor type. Very little is known about whether tumor location is determined stochastically or whether genetic risk factors can affect where tumors arise within an organ system. We have taken advantage of the Nf1−/+;Trp53−/+cis mouse model of astrocytoma/glioblastoma to map genetic loci affecting whether astrocytomas are found in the spinal cord. We identify a locus on distal Chr 5, termed Scram1 for spinal cord resistance to astrocytoma modifier 1, with a LOD score of 5.0 and a genome-wide significance of P < 0.004. Mice heterozygous for C57BL/6J×129S4/SvJae at this locus show less astrocytoma in the spinal cord compared to 129S4/SvJae homozygous mice, although we have shown previously that 129S4/SvJae mice are more resistant to astrocytoma than C57BL/6J. Furthermore, the astrocytomas that are found in the spinal cord of Scram1 heterozygous mice arise in older mice. Because spinal cord astrocytomas are very rare and difficult to treat, a better understanding of the genetic factors that govern astrocytoma in the spine may lead to new targets of therapy or prevention.

Keywords

Spinal Cord Astrocytoma Spinal Cord Tumor Spinal Cord Section Backcross Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank M. Anvers, R. Tuskan, K. Smith, K. Fox, and E. Truffer for technical assistance and D. Louis and G. Jallo for helpful discussions. JCAVS is a predoctoral student in the Graduate Partnership Program of the NIH and the Institute for Biomedical Sciences at George Washington University. This work is from a dissertation to be prepared in partial fulfillment of the requirements for the PhD degree. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsements by the US Government. This work was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (ZIA BC 010539 to KMR), federal funds from the National Cancer Institute to SAIC Frederick (contract N01-CO-12400), federal contract from the National Institutes of Health to The Johns Hopkins University (contract HHSN268200782096C), and extramural funding from the National Institutes of Health (R01 GM074244 to KWB).

References

  1. Bailey JS, Grabowski-Boase L, Steffy BM, Wiltshire T, Churchill GA, Tarantino LM (2008) Identification of quantitative trait loci for locomotor activation and anxiety using closely related inbred strains. Genes Brain Behav 7:761–769PubMedCrossRefGoogle Scholar
  2. Benes V 3rd, Barsa P, Benes V Jr, Suchomel P (2009) Prognostic factors in intramedullary astrocytomas: a literature review. Eur Spine J 18:1397–1422PubMedCrossRefGoogle Scholar
  3. Binder BR, Mihaly J (2008) The plasminogen activator inhibitor “paradox” in cancer. Immunol Lett 118:116–124PubMedCrossRefGoogle Scholar
  4. Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890PubMedCrossRefGoogle Scholar
  5. Calzolari F, Malatesta P (2010) Recent insights into PDGF-induced gliomagenesis. Brain Pathol 20:527–538PubMedCrossRefGoogle Scholar
  6. Cao Y, Lathia JD, Eyler CE, Wu Q, Li Z, Wang H, McLendon RE, Hjelmeland AB, Rich JN (2010) Erythropoietin receptor signaling through STAT3 is required for glioma stem cell maintenance. Genes Cancer 1:50–61PubMedCrossRefGoogle Scholar
  7. Caplan J, Pradilla G, Hdeib A, Tyler BM, Legnani FG, Bagley CA, Brem H, Jallo G (2006) A novel model of intramedullary spinal cord tumors in rats: functional progression and histopathological characterization. Neurosurgery 59:193–200 discussion 193–200PubMedCrossRefGoogle Scholar
  8. Chastre E, Abdessamad M, Kruglov A, Bruyneel E, Bracke M, Di Gioia Y, Beckerle MC, van Roy F, Kotelevets L (2009) TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness. FASEB J 23:916–928PubMedCrossRefGoogle Scholar
  9. Chen TC, Hinton DR, Zidovetzki R, Hofman FM (1998) Up-regulation of the cAMP/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas. Lab Invest 78:165–174PubMedGoogle Scholar
  10. Ellis JA, Canoll P, McCormick PC 2nd, Feldstein NA, Anderson RC, Angevine PD, Kaiser MG, McCormick PC, Bruce JN, Ogden AT (2011) Platelet-derived growth factor receptor (PDGFR) expression in primary spinal cord gliomas. J Neurooncol. doi: 10.1007/s11060-011-0666-6
  11. Han X, Stewart JE Jr, Bellis SL, Benveniste EN, Ding Q, Tachibana K, Grammer JR, Gladson CL (2001) TGF-beta1 up-regulates paxillin protein expression in malignant astrocytoma cells: requirement for a fibronectin substrate. Oncogene 20:7976–7986PubMedCrossRefGoogle Scholar
  12. Harrop JS, Ganju A, Groff M, Bilsky M (2009) Primary intramedullary tumors of the spinal cord. Spine (Phila Pa 1976) 34:S69–S77CrossRefGoogle Scholar
  13. Hitoshi Y, Harris BT, Liu H, Popko B, Israel MA (2008) Spinal glioma: platelet-derived growth factor B-mediated oncogenesis in the spinal cord. Cancer Res 68:8507–8515PubMedCrossRefGoogle Scholar
  14. Hsu S, Quattrone M, Ostrom Q, Ryken TC, Sloan AE, Barnholtz-Sloan JS (2011) Incidence patterns for primary malignant spinal cord gliomas: a Surveillance, Epidemiology, and End Results study. J Neurosurg Spine 14:742–747PubMedCrossRefGoogle Scholar
  15. Huang CH, Yang WH, Chang SY, Tai SK, Tzeng CH, Kao JY, Wu KJ, Yang MH (2009) Regulation of membrane-type 4 matrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis. Neoplasia 11:1371–1382PubMedGoogle Scholar
  16. Kawa S, Fujimoto J, Tezuka T, Nakazawa T, Yamamoto T (2004) Involvement of BREK, a serine/threonine kinase enriched in brain, in NGF signalling. Genes Cells 9:219–232PubMedCrossRefGoogle Scholar
  17. Lucci-Cordisco E, Zito I, Gensini F, Genuardi M (2003) Hereditary nonpolyposis colorectal cancer and related conditions. Am J Med Genet A 122A:325–334PubMedCrossRefGoogle Scholar
  18. Milano MT, Johnson MD, Sul J, Mohile NA, Korones DN, Okunieff P, Walter KA (2010) Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study. J Neurooncol 98:83–92PubMedCrossRefGoogle Scholar
  19. Mock BA, Krall MM, Dosik JK (1993) Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis. Proc Natl Acad Sci USA 90:9499–9503PubMedCrossRefGoogle Scholar
  20. Mohyeldin A, Dalgard CL, Lu H, McFate T, Tait AS, Patel VC, Wong K, Rushing E, Roy S, Acs G, Verma A (2007) Survival and invasiveness of astrocytomas promoted by erythropoietin. J Neurosurg 106:338–350PubMedCrossRefGoogle Scholar
  21. Noren NK, Pasquale EB (2007) Paradoxes of the EphB4 receptor in cancer. Cancer Res 67:3994–3997PubMedCrossRefGoogle Scholar
  22. Peres EA, Valable S, Guillamo JS, Marteau L, Bernaudin JF, Roussel S, Lechapt-Zalcman E, Bernaudin M, Petit E (2011) Targeting the erythropoietin receptor on glioma cells reduces tumour growth. Exp Cell Res 317(16):2321–2332PubMedCrossRefGoogle Scholar
  23. Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T (2000) Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26:109–113PubMedCrossRefGoogle Scholar
  24. Reilly KM, Tuskan RG, Christy E, Loisel DA, Ledger J, Bronson RT, Smith CD, Tsang S, Munroe DJ, Jacks T (2004) Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects. Proc Natl Acad Sci USA 101:13008–13013PubMedCrossRefGoogle Scholar
  25. Ridley AJ (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16:522–529PubMedCrossRefGoogle Scholar
  26. Sharma S, Free A, Mei Y, Peiper SC, Wang Z, Cowell JK (2010) Distinct molecular signatures in pediatric infratentorial glioblastomas defined by aCGH. Exp Mol Pathol 89:169–174PubMedCrossRefGoogle Scholar
  27. Smith R, Sheppard K, DiPetrillo K, Churchill G (2009) Quantitative trait locus analysis using J/qtl. Methods Mol Biol 573:175–188PubMedCrossRefGoogle Scholar
  28. Stratton MR, Ford D, Neuhasen S, Seal S, Wooster R, Friedman LS, King MC, Egilsson V, Devilee P, McManus R et al (1994) Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet 7:103–107PubMedCrossRefGoogle Scholar
  29. Walrath JC, Fox K, Truffer E, Gregory Alvord W, Quinones OA, Reilly KM (2009) Chr 19(A/J) modifies tumor resistance in a sex- and parent-of-origin-specific manner. Mamm Genome 20:214–223PubMedCrossRefGoogle Scholar
  30. Wang Y, Yao M, Zhou C, Dong D, Jiang Y, Wei G, Cui X (2010) Erythropoietin promotes spinal cord-derived neural progenitor cell proliferation by regulating cell cycle. Neuroscience 167:750–757PubMedCrossRefGoogle Scholar
  31. Zhang K, Kagan D, DuBois W, Robinson R, Bliskovsky V, Vass WC, Zhang S, Mock BA (2009) Mndal, a new interferon-inducible family member, is highly polymorphic, suppresses cell growth, and may modify plasmacytoma susceptibility. Blood 114:2952–2960PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2011

Authors and Affiliations

  • Jessica Amlin-Van Schaick
    • 1
    • 2
  • Sungjin Kim
    • 3
  • Karl W. Broman
    • 3
  • Karlyne M. Reilly
    • 1
  1. 1.Mouse Cancer Genetics ProgramNational Cancer InstituteFrederickUSA
  2. 2.Institute for Biomedical SciencesGeorge Washington UniversityWashingtonUSA
  3. 3.Department of Biostatistics and Medical Informatics, School of Medicine and Public HealthUniversity of WisconsinMadisonUSA

Personalised recommendations