Journal of Neuro-Oncology

, Volume 99, Issue 1, pp 13–24 | Cite as

Vascular gene expression patterns are conserved in primary and metastatic brain tumors

  • Yang Liu
  • Eleanor B. Carson-Walter
  • Anna Cooper
  • Bethany N. Winans
  • Mahlon D. Johnson
  • Kevin A. Walter
Laboratory Investigation - Human/Animal Tissue

Abstract

Malignant primary glial and secondary metastatic brain tumors represent distinct pathological entities. Nevertheless, both tumor types induce profound angiogenic responses in the host brain microvasculature that promote tumor growth. We hypothesized that primary and metastatic tumors induce similar microvascular changes that could function as conserved angiogenesis based therapeutic targets. We previously isolated glioma endothelial marker genes (GEMs) that were selectively upregulated in the microvasculature of proliferating glioblastomas. We sought to determine whether these genes were similarly induced in the microvasculature of metastatic brain tumors. RT-PCR and quantitative RT-PCR were used to screen expression levels of 20 candidate GEMs in primary and metastatic clinical brain tumor specimens. Differentially regulated GEMs were further evaluated by immunohistochemistry or in situ hybridization to localize gene expression using clinical tissue microarrays. Thirteen GEMs were upregulated to a similar degree in both primary and metastatic brain tumors. Most of these genes localize to the cell surface (CXCR7, PV1) or extracellular matrix (COL1A1, COL3A1, COL4A1, COL6A2, MMP14, PXDN) and were selectively expressed by the microvasculature. The shared expression profile between primary and metastatic brain tumors suggests that the molecular pathways driving the angiogenic response are conserved, despite differences in the tumor cells themselves. Anti-angiogenic therapies currently in development for primary brain tumors may prove beneficial for brain metastases and vice versa.

Keywords

Glioblastoma Metastatic brain tumor Angiogenesis Endothelial genes Vascular genes 

Notes

Acknowledgments

We thank Dr. Sumana Datta of Texas A&M University for advice regarding HSPG2 immunohistochemical staining. This work was supported by the National Institutes of Health (NINDS K08 NS046461 to K.A.W.), the American Brain Tumor Association (to K.A.W.), the Childhood Brain Tumor Foundation (to K.A.W.) and the Ronald Bittner Brain Tumor Research Fund (to K.A.W.).

Supplementary material

11060_2009_105_MOESM1_ESM.pdf (23 kb)
Supplementary material 1 (PDF 24 kb)

References

  1. 1.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64(19):6892–6899CrossRefPubMedGoogle Scholar
  2. 2.
    Hall WA, Djalilian HR, Nussbaum ES, Cho KH (2000) Long-term survival with metastatic cancer to the brain. Med Oncol 17(4):279–286CrossRefPubMedGoogle Scholar
  3. 3.
    Kim WY, Lee HY (2009) Brain angiogenesis in developmental and pathological processes: mechanism and therapeutic intervention in brain tumors. FEBS J 276(17):4653–4664CrossRefPubMedGoogle Scholar
  4. 4.
    Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D (2005) Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 15(4):297–310PubMedCrossRefGoogle Scholar
  5. 5.
    Wong ML, Prawira A, Kaye AH, Hovens CM (2009) Tumour angiogenesis: its mechanism and therapeutic implications in malignant gliomas. J Clin Neurosci 16(9):1119–1130CrossRefPubMedGoogle Scholar
  6. 6.
    Jansen M, de Witt Hamer PC, Witmer AN, Troost D, van Noorden CJ (2004) Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas. Brain Res Brain Res Rev 45(3):143–163CrossRefPubMedGoogle Scholar
  7. 7.
    Charalambous C, Chen TC, Hofman FM (2006) Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme. Neurosurg Focus 20(4):E22CrossRefPubMedGoogle Scholar
  8. 8.
    Charalambous C, Hofman FM, Chen TC (2005) Functional and phenotypic differences between glioblastoma multiforme-derived and normal human brain endothelial cells. J Neurosurg 102(4):699–705CrossRefPubMedGoogle Scholar
  9. 9.
    Beaty RM, Edwards JB, Boon K, Siu IM, Conway JE, Riggins GJ (2007) PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium. J Neurooncol 81(3):241–248CrossRefPubMedGoogle Scholar
  10. 10.
    Madden SL, Cook BP, Nacht M, Weber WD, Callahan MR, Jiang Y, Dufault MR, Zhang X, Zhang W, Walter-Yohrling J, Rouleau C, Akmaev VR, Wang CJ, Cao X, St Martin TB, Roberts BL, Teicher BA, Klinger KW, Stan RV, Lucey B, Carson-Walter EB, Laterra J, Walter KA (2004) Vascular gene expression in nonneoplastic and malignant brain. Am J Pathol 165(2):601–608PubMedGoogle Scholar
  11. 11.
    Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3(1):53–57CrossRefPubMedGoogle Scholar
  12. 12.
    Carson-Walter EB, Hampton J, Shue E, Geynisman DM, Pillai PK, Sathanoori R, Madden SL, Hamilton RL, Walter KA (2005) Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis. Clin Cancer Res 11(21):7643–7650CrossRefPubMedGoogle Scholar
  13. 13.
    Shue EH, Carson-Walter EB, Liu Y, Winans BN, Ali ZS, Chen J, Walter KA (2008) Plasmalemmal vesicle associated protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models. BMC Neurosci 9:29CrossRefPubMedGoogle Scholar
  14. 14.
    Wegner M (1999) From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27(6):1409–1420CrossRefPubMedGoogle Scholar
  15. 15.
    Yokota N, Mainprize TG, Taylor MD, Kohata T, Loreto M, Ueda S, Dura W, Grajkowska W, Kuo JS, Rutka JT (2004) Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization. Oncogene 23(19):3444–3453CrossRefPubMedGoogle Scholar
  16. 16.
    Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ (2002) Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol 57(3):201–214CrossRefPubMedGoogle Scholar
  17. 17.
    de Bont JM, Kros JM, Passier MM, Reddingius RE, Sillevis Smitt PA, Luider TM, den Boer ML, Pieters R (2008) Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis. Neuro Oncol 10(5):648–660CrossRefPubMedGoogle Scholar
  18. 18.
    Neben K, Korshunov A, Benner A, Wrobel G, Hahn M, Kokocinski F, Golanov A, Joos S, Lichter P (2004) Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. Cancer Res 64(9):3103–3111CrossRefPubMedGoogle Scholar
  19. 19.
    Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451(7175):147–152CrossRefPubMedGoogle Scholar
  20. 20.
    Friedman RS, Bangur CS, Zasloff EJ, Fan L, Wang T, Watanabe Y, Kalos M (2004) Molecular and immunological evaluation of the transcription factor SOX-4 as a lung tumor vaccine antigen. J Immunol 172(5):3319–3327PubMedGoogle Scholar
  21. 21.
    Aaboe M, Birkenkamp-Demtroder K, Wiuf C, Sorensen FB, Thykjaer T, Sauter G, Jensen KM, Dyrskjot L, Orntoft T (2006) SOX4 expression in bladder carcinoma: clinical aspects and in vitro functional characterization. Cancer Res 66(7):3434–3442CrossRefPubMedGoogle Scholar
  22. 22.
    Schilham MW, Oosterwegel MA, Moerer P, Ya J, de Boer PA, van de Wetering M, Verbeek S, Lamers WH, Kruisbeek AM, Cumano A, Clevers H (1996) Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature 380(6576):711–714CrossRefPubMedGoogle Scholar
  23. 23.
    Hutchins JT, Deans RJ, Mitchell MS, Uchiyama C, Kan-Mitchell J (1991) Novel gene sequences expressed by human melanoma cells identified by molecular subtraction. Cancer Res 51(5):1418–1425PubMedGoogle Scholar
  24. 24.
    Mitchell MS, Kan-Mitchell J, Minev B, Edman C, Deans RJ (2000) A novel melanoma gene (MG50) encoding the interleukin 1 receptor antagonist and six epitopes recognized by human cytolytic T lymphocytes. Cancer Res 60(22):6448–6456PubMedGoogle Scholar
  25. 25.
    Horikoshi N, Cong J, Kley N, Shenk T (1999) Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene. Biochem Biophys Res Commun 261(3):864–869CrossRefPubMedGoogle Scholar
  26. 26.
    Castronovo V, Waltregny D, Kischel P, Roesli C, Elia G, Rybak JN, Neri D (2006) A chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer. Mol Cell Proteomics 5(11):2083–2091CrossRefPubMedGoogle Scholar
  27. 27.
    Wang D, Anderson JC, Gladson CL (2005) The role of the extracellular matrix in angiogenesis in malignant glioma tumors. Brain Pathol 15(4):318–326PubMedGoogle Scholar
  28. 28.
    Pen A, Moreno MJ, Martin J, Stanimirovic DB (2007) Molecular markers of extracellular matrix remodeling in glioblastoma vessels: microarray study of laser-captured glioblastoma vessels. Glia 55(6):559–572CrossRefPubMedGoogle Scholar
  29. 29.
    Ljubimova JY, Lakhter AJ, Loksh A, Yong WH, Riedinger MS, Miner JH, Sorokin LM, Ljubimov AV, Black KL (2001) Overexpression of alpha4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Cancer Res 61(14):5601–5610PubMedGoogle Scholar
  30. 30.
    Kalluri R (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3(6):422–433CrossRefPubMedGoogle Scholar
  31. 31.
    Bellon G, Caulet T, Cam Y, Pluot M, Poulin G, Pytlinska M, Bernard MH (1985) Immunohistochemical localisation of macromolecules of the basement membrane and extracellular matrix of human gliomas and meningiomas. Acta Neuropathol 66(3):245–252CrossRefPubMedGoogle Scholar
  32. 32.
    Virgintino D, Girolamo F, Errede M, Capobianco C, Robertson D, Stallcup WB, Perris R, Roncali L (2007) An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10(1):35–45CrossRefPubMedGoogle Scholar
  33. 33.
    Haralabopoulos GC, Grant DS, Kleinman HK, Lelkes PI, Papaioannou SP, Maragoudakis ME (1994) Inhibitors of basement membrane collagen synthesis prevent endothelial cell alignment in matrigel in vitro and angiogenesis in vivo. Lab Invest 71(4):575–582PubMedGoogle Scholar
  34. 34.
    Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163(5):1801–1815PubMedGoogle Scholar
  35. 35.
    Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116(10):2610–2621CrossRefPubMedGoogle Scholar
  36. 36.
    Ayers M, Fargnoli J, Lewin A, Wu Q, Platero JS (2007) Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res 67(14):6899–6906CrossRefPubMedGoogle Scholar
  37. 37.
    Lampert K, Machein U, Machein MR, Conca W, Peter HH, Volk B (1998) Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. Am J Pathol 153(2):429–437PubMedGoogle Scholar
  38. 38.
    Munaut C, Noel A, Hougrand O, Foidart JM, Boniver J, Deprez M (2003) Vascular endothelial growth factor expression correlates with matrix metalloproteinases MT1-MMP, MMP-2 and MMP-9 in human glioblastomas. Int J Cancer 106(6):848–855CrossRefPubMedGoogle Scholar
  39. 39.
    Guo P, Imanishi Y, Cackowski FC, Jarzynka MJ, Tao HQ, Nishikawa R, Hirose T, Hu B, Cheng SY (2005) Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma. Am J Pathol 166(3):877–890PubMedGoogle Scholar
  40. 40.
    Genis L, Galvez BG, Gonzalo P, Arroyo AG (2006) MT1-MMP: universal or particular player in angiogenesis? Cancer Metastasis Rev 25(1):77–86CrossRefPubMedGoogle Scholar
  41. 41.
    Sounni NE, Baramova EN, Munaut C, Maquoi E, Frankenne F, Foidart JM, Noel A (2002) Expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization. Int J Cancer 98(1):23–28CrossRefPubMedGoogle Scholar
  42. 42.
    Sounni NE, Devy L, Hajitou A, Frankenne F, Munaut C, Gilles C, Deroanne C, Thompson EW, Foidart JM, Noel A (2002) MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 16(6):555–564CrossRefPubMedGoogle Scholar
  43. 43.
    Deryugina EI, Soroceanu L, Strongin AY (2002) Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Cancer Res 62(2):580–588PubMedGoogle Scholar
  44. 44.
    Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG (2004) Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 36(6):1046–1069CrossRefPubMedGoogle Scholar
  45. 45.
    Kikuchi T, Daigo Y, Ishikawa N, Katagiri T, Tsunoda T, Yoshida S, Nakamura Y (2006) Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray. Int J Oncol 28(4):799–805PubMedGoogle Scholar
  46. 46.
    Zohrabian VM, Nandu H, Gulati N, Khitrov G, Zhao C, Mohan A, Demattia J, Braun A, Das K, Murali R, Jhanwar-Uniyal M (2007) Gene expression profiling of metastatic brain cancer. Oncol Rep 18(2):321–328PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Yang Liu
    • 1
  • Eleanor B. Carson-Walter
    • 1
  • Anna Cooper
    • 1
  • Bethany N. Winans
    • 1
  • Mahlon D. Johnson
    • 2
  • Kevin A. Walter
    • 1
    • 3
  1. 1.Department of NeurosurgeryUniversity of RochesterRochesterUSA
  2. 2.Department of NeuropathologyUniversity of RochesterRochesterUSA
  3. 3.James P. Wilmot Cancer CenterUniversity of RochesterRochesterUSA

Personalised recommendations