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Radiation Treatment Effects on the Proteome of the Tumour Microenvironment

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Radiation Proteomics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 990))

Abstract

Exposure of tumourous tissue to ionizing radiation initiates a wound-healing response involving remodelling of the extracellular microenvironment. The initial reaction involves direct damage to the matrix proteins and the secretion and activation of proteolytic enzymes that lead to local destruction of the extracellular matrix. Subsequently the wounded area may undergo complete repair, may enter a prolonged period of heightened proteolysis, or may overproduce matrix proteins leading to fibrosis. The source of matrix degrading enzymatic activity may be the tumour cells and the tumour stroma. Additional complexity is provided by proteolytic activity released from tissue macrophages, mast cells and by invading inflammatory cells. The local production of growth factors, including VEGF and TGF-β play a key role in coordinating the response. It is anticipated that the application of modern proteomic technologies will reveal hitherto unrecognised levels of complexity in these processes. Hopefully this will lead to the development of new therapeutic strategies to prevent long-term health implications of radiation exposure.

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References

  1. Apetoh L et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059

    Article  PubMed  CAS  Google Scholar 

  2. Quesada V, Ordóñez GR, Sánchez LM, Puente XS, López-Otín C (2009) The degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res 37:D239–D243

    Article  PubMed  CAS  Google Scholar 

  3. Mason SD, Joyce JA (2011) Proteolytic networks in cancer. Trends Cell Biol 21:228–237

    Article  PubMed  CAS  Google Scholar 

  4. Wagner SN et al (1995) Modulation of urokinase and urokinase receptor gene expression in human renal cell carcinoma. Am J Pathol 147:183–192

    PubMed  CAS  Google Scholar 

  5. Lin Q, Yun Z (2010) Impact of the hypoxic tumor microenvironment on the regulation of cancer stem cell characteristics. Cancer Biol Ther 9:949–956

    Article  PubMed  CAS  Google Scholar 

  6. Miyazaki Y et al (2008) He effect of hypoxic microenvironment on matrix metalloproteinase expression in xenografts of human oral squamous cell carcinoma. Int J Oncol 32:145–151

    PubMed  CAS  Google Scholar 

  7. Erler JT et al (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44

    Article  PubMed  CAS  Google Scholar 

  8. Kakkad SM et al (2010) Hypoxic tumor microenvironments reduce collagen I fiber density. Neoplasia 8:608–617

    Google Scholar 

  9. Indovina P et al (2006) Hypoxia and ionizing radiation: changes in adhesive properties and cell adhesion molecule expression in MG-63 three-dimensional tumor spheroids. Cell Commun Adhes 13:185–198

    Article  PubMed  Google Scholar 

  10. Myllyharju J, Schipani E (2010) Extracellular matrix genes as hypoxia-inducible targets. Cell Tissue Res 339:19–29

    Article  PubMed  CAS  Google Scholar 

  11. Thiely JP (2002) Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2:442–454

    Article  Google Scholar 

  12. Jean C et al (2011) Influence of stress on extracellular matrix and integrin biology. Oncogene 30:2697–2706

    Article  PubMed  CAS  Google Scholar 

  13. Tibbs MK (1997) Wound healing following radiation therapy: a review. Radiother Oncol 42:99–106

    Article  PubMed  CAS  Google Scholar 

  14. Mueller CK, Schultze-Mosgau S (2009) Radiation-induced microenvironments–the molecular basis for free flap complications in the pre-irradiated field? Radiother Oncol 93:581–585

    Article  PubMed  CAS  Google Scholar 

  15. Kruegler WWO et al (1978) Fibroblast implantation enhances wound healing as indicated by breaking strength determinations. Otolaryngology 86:804–811

    Google Scholar 

  16. Penney DP, Rosenkrans WA (1984) Cell-cell matrix interactions in induced lung injury. I. The effects of X-irradiation on basal laminar proteoglycans. Radiat Res 99:410–419

    Article  PubMed  CAS  Google Scholar 

  17. Carnevali S et al (2003) Gamma radiation inhibits fibroblast-mediated collagen gel retraction. Tissue Cell 35:459–469

    Article  PubMed  CAS  Google Scholar 

  18. Wang J, Zheng H, Hauer-Jensen M (2001) Influence of short-term octreotide administration on chronic tissue injury, transforming growth factor β (TGF-β) overexpression, and collagen accumulation in irradiated rat intestine. J Pharmacol Exp Ther 297:35–42

    PubMed  CAS  Google Scholar 

  19. Rodemann HP, Bamberg M (1995) Cellular basis of radiation-induced fibrosis. Radiother Oncol 35:83–90

    Article  PubMed  CAS  Google Scholar 

  20. Riedel F et al (2005) Immunohistochemical analysis of radiation-induced non-healing dermal wounds of the head and neck. In Vivo 19:343–350

    PubMed  CAS  Google Scholar 

  21. Kim K, McBride WH (2010) Modifying radiation damage. Curr Drug Targets 11:1352–1365

    Article  PubMed  CAS  Google Scholar 

  22. Açil Y et al (2007) Proof of direct radiogenic destruction of collagen in vitro. Strahlenther Onko 183: 374–379

    Article  Google Scholar 

  23. Springer IN et al (2005) Radiation caries–radiogenic destruction of dental collagen. Oral Oncol 41: 723–728

    Article  PubMed  CAS  Google Scholar 

  24. Hübner W et al (2005) The influence of X-ray radiation on the mineral/organic matrix interaction of bone tissue: an FT-IR microscopic investigation. Int J Artif Organs 28:66–73

    PubMed  Google Scholar 

  25. Gouk SS et al (2008) Alterations of human acellular tissue matrix by gamma irradiation: histology, biomechanical property, stability, in vitro cell repopulation, and remodeling. J Biomed Mater Res B Appl Biomater 84:205–217

    PubMed  Google Scholar 

  26. Ehrhart EJ, Gillette EL, Barcellos-Hoff MH (1996) Immunohistochemical evidence of rapid extracellular matrix remodeling after iron-particle irradiation of mouse mammary gland. Radiat Res 145:157–162

    Article  PubMed  CAS  Google Scholar 

  27. Miller GG, Kenning JM, Dawson DT (1988) Radiation-induced changes in collagen isotypes I, III, and IV in the lung of LAF1 mouse: effects of time, dose, and WR-2721. Radiat Res 115:515–532

    Article  PubMed  CAS  Google Scholar 

  28. Rosenkrans W-A, Penney DP (1987) Cell-cell matrix interactions in induced lung injury. IV. Quantitative alterations in pulmonary fibronectin and laminin following X irradiation. Radiat Res 109:127–142

    Article  PubMed  CAS  Google Scholar 

  29. Giannopoulou E et al (2001) X-rays modulate extracellular matrix in vivo. Int J Cancer 94:690–698

    Article  PubMed  CAS  Google Scholar 

  30. Vozenin-Brotons MC et al (2004) Gene expression profile in human late radiation enteritis obtained by high-density cDNA array hybridization. Radiat Res 161:299–311

    Article  PubMed  CAS  Google Scholar 

  31. Bourgier C et al (2005) Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut 54:336–343

    Article  PubMed  CAS  Google Scholar 

  32. Haydont V et al (2007) Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats. Clin Cancer Res 13: 5331–5340

    Article  PubMed  CAS  Google Scholar 

  33. Williams JP et al (2004) Effect of administration of lovastatin on the development of late pulmonary effects after whole-lung irradiation in a murine model. Radiat Res 161:560–567

    Article  PubMed  CAS  Google Scholar 

  34. Angenete E et al (2009) Preoperative radiotherapy and extracellular matrix remodeling in rectal mucosa and tumour matrix metalloproteinases and plasminogen components. Acta Oncol 48:1144–1151

    Article  PubMed  CAS  Google Scholar 

  35. Zhao W et al (2001) Redox modulation of the pro-fibrogenic mediator plasminogen activator inhibitor-1 following ionizing radiation. Cancer Res 61: 5537–5543

    PubMed  CAS  Google Scholar 

  36. Zhao W et al (2000) Irradiation of rat tubule epithelial cells alters the expression of gene products associated with the synthesis and degradation of extracellular matrix. Int J Radiat Biol 76:391–402

    Article  PubMed  CAS  Google Scholar 

  37. Green N et al (1969) Radiation-induced delayed union of fractures. Radiology 93:635–641

    PubMed  CAS  Google Scholar 

  38. Arnold M, Kummermehr J, Trott K-R (1995) Radiation-induced impairment of osseous healing: quantitative studies using a standard drilling defect in rat femur. Radiat Res 143:77–84

    Article  PubMed  CAS  Google Scholar 

  39. Matsumura S et al (1998) Changes in phenotypic expression of osteoblasts after X irradiation. Radiat Res 149:463–471

    Article  PubMed  CAS  Google Scholar 

  40. Dudziak ME et al (2000) The effects of ionizing radiation on osteoblast-like cells in vitro. Plast Reconstr Surg 106:1049–1061

    Article  PubMed  CAS  Google Scholar 

  41. Narayan K, Cliff WJ (1982) Morphology of irradiated microvasculature: a combined in vivo and electron-microscopic study. Am J Pathol 106:47–62

    PubMed  CAS  Google Scholar 

  42. Neta R, Oppenheim JJ, Douches SD (1988) Interdependence of the radioprotective effects of human recombinant interleukin 1 alpha, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-stimulating factor. J Immunol 140:108–111

    PubMed  CAS  Google Scholar 

  43. Zhou Y et al (2010) Modulation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in RAW264.7 cells by irradiation. Mol Med Rep 3:809–813

    CAS  Google Scholar 

  44. Müller K, Meineke V (2011) Radiation-induced mast cell mediators differentially modulate chemokine release from dermal fibroblasts. J Dermatol Sci 61: 199–205

    Article  PubMed  Google Scholar 

  45. Steiner HH et al (2004) Autocrine pathways of the vascular endothelial growth factor (VEGF) in glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF levels. J Neurooncol 66:129–138

    Article  PubMed  Google Scholar 

  46. Polytarchou C et al (2004) X-rays affect the expression of genes involved in angiogenesis. Anticancer Res 24:2941–2945

    PubMed  CAS  Google Scholar 

  47. Brooks P, Roth JM, Lymberis SC, DeWyngaert K, Broek D, Formenti SC (2002) Ionizing radiation modulates the exposure of the HUIV26 cryptic epitope within collagen type IV during angiogenesis. Int J Radiat Oncol Biol Phys 54:1194–1201

    Article  PubMed  CAS  Google Scholar 

  48. Carmeliet P, Collen D (1998) Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res 91:255–258

    Article  PubMed  CAS  Google Scholar 

  49. Takeuchi H et al (2012) A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors. J Gastroenterol 47:56–64

    Article  PubMed  CAS  Google Scholar 

  50. Yang K et al (2007) Matrix-metallo-proteinases and their tissue inhibitors in radiation-induced lung injury. Int J Radiat Biol 83:665–676

    Article  PubMed  CAS  Google Scholar 

  51. Lee WH et al (2012) Irradiation alters MMP-2/TIMP-2 system and collagen type IV degradation in brain. Int J Radiat Oncol Biol Phys 82:1559–1566

    Article  PubMed  CAS  Google Scholar 

  52. Chang PY et al (2007) Particle radiation alters expression of matrix metalloproteases resulting in ECM remodeling in human lens cells. Radiat Environ Biophys 46:187–194

    Article  PubMed  CAS  Google Scholar 

  53. Abderrahmani R et al (2009) Effects of pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 in radiation-induced intestinal injury. Int J Radiat Oncol Biol Phys 74:941–948

    Article  Google Scholar 

  54. Gogineni VR et al (2009) RNAi-mediated downregulation of radiation-induced MMP-9 leads to apoptosis via activation of ERK and Akt in IOMM-Lee cells. Int J Oncol 34:209–218

    PubMed  CAS  Google Scholar 

  55. Cheng JC et al (2006) Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene 25:7009–7018

    Article  PubMed  CAS  Google Scholar 

  56. Park CM et al (2006) Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res 66:8511–8519

    Article  PubMed  CAS  Google Scholar 

  57. Schweigerer L et al (2005) Sublethal irradiation promotes invasiveness of neuroblastoma cells. Biochem Biophys Res Commun 330:982–988

    Article  PubMed  CAS  Google Scholar 

  58. Park CC et al (2003) Ionizing radiation induces heritable disruption of epithelial cell interactions. Proc Natl Acad Sci U S A 100:10728–10733

    Article  PubMed  CAS  Google Scholar 

  59. Tsukamoto H et al (2007) Irradiation-induced epithelial-mesenchymal transition (EMT) related to invasive potential in endometrial carcinoma cells. Gynecol Oncol 107:500–504

    Article  PubMed  Google Scholar 

  60. Wang M et al (2012) Heavy ions can enhance TGFβ mediated epithelial to mesenchymal transition. J Radiat Res 53:51–57

    Article  PubMed  CAS  Google Scholar 

  61. Cordes N et al (2006) Beta1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury. Oncogene 25:1378–1390

    Article  PubMed  CAS  Google Scholar 

  62. Fuks Z et al (1992) Effects of extracellular matrix on the response of endothelial cells to radiation in vitro. Eur J Cancer 28A:725–731

    Article  PubMed  CAS  Google Scholar 

  63. Simon EL et al (2005) High dose fractionated ionizing radiation inhibits prostate cancer cell adhesion and beta(1) integrin expression. Prostate 64:83–91

    Article  PubMed  CAS  Google Scholar 

  64. Park CC et al (2008) Beta1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res 68:4398–4405

    Article  PubMed  CAS  Google Scholar 

  65. Monferran S et al (2008) Alphavbeta3 and alphavbeta5 integrins control glioma cell response to ionising radiation through ILK and RhoB. Int J Cancer 123:357–364

    Article  PubMed  CAS  Google Scholar 

  66. Nam JM et al (2010) Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin alpha5beta1 and fibronectin. Cancer Res 70:5238–5248

    Article  PubMed  CAS  Google Scholar 

  67. Ise K et al (2004) Transforming growth factor-beta signaling is enhanced following mitomycin-C treatment of islet xenograft. Transplant Proc 36: 1183–1185

    Article  PubMed  CAS  Google Scholar 

  68. Hakenjos L, Bamberg M, Rodemann HP (2000) TGF-beta1-mediated alterations of rat lung fibroblast differentiation resulting in the radiation-induced fibrotic phenotype. Int J Radiat Biol 76:503–509

    Article  PubMed  CAS  Google Scholar 

  69. Yano H et al (2010) Smad, but not MAPK, pathway mediates the expression of type I collagen in radiation induced fibrosis. Biochem Biophys Res Commun 418:457–463

    Article  Google Scholar 

  70. Lee JW et al (2010) Regulators and mediators of radiation-induced fibrosis: gene expression profiles and a rationale for Smad3 inhibition. Otolaryngol Head Neck Surg 143:525–530

    Article  PubMed  Google Scholar 

  71. Zhao W, Goswami PC, Robbins ME (2004) Radiation-induced up-regulation of Mmp2 involves increased mRNA stability, redox modulation, and MAPK activation. Radiat Res 161:418–429

    Article  PubMed  CAS  Google Scholar 

  72. Kuhlmann UC et al (2009) Radiation-induced matrix production of lung fibroblasts is regulated by interleukin-8. Int J Radiat Biol 85:138–143

    Article  PubMed  Google Scholar 

  73. Fournier C et al (2001) Changes of fibrosis-related parameters after high- and low-LET irradiation of fibroblasts. Int J Radiat Biol 77:713–722

    Article  PubMed  CAS  Google Scholar 

  74. Jaggi JS et al (2005) Renal tubulointerstitial changes after internal irradiation with alpha-particle-emitting actinium daughters. J Am Soc Nephrol 16:2677–2689

    Article  PubMed  CAS  Google Scholar 

  75. Ogata T et al (2005) Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res 65:113–120

    PubMed  CAS  Google Scholar 

  76. Mullenders L et al (2009) Assessing cancer risks of low-dose radiation. Nat Rev Cancer 9:596–604

    Article  PubMed  CAS  Google Scholar 

  77. Ehrhart EJ et al (1997) Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. FASEB J 11:991–1002

    PubMed  CAS  Google Scholar 

  78. Romanenko A et al (2006) Aberrant expression of E-cadherin and beta-catenin in association with transforming growth factor-beta1 in urinary bladder lesions in humans after the Chernobyl accident. Cancer Sci 97:45–50

    Article  PubMed  CAS  Google Scholar 

  79. Romanenko A et al (2006) Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans. Virchows Arch 448:584–590

    Article  PubMed  CAS  Google Scholar 

  80. Tsai KK et al (2005) Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res 65:6734–6744

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Radiation Biology, Ingolstaedter Landstrasse 1, Neuherberg, 85764, Germany

    Michael J. Atkinson

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Correspondence to Michael J. Atkinson .

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  1. Radiation and Nuclear Safety Authority, STUK, Laippatie 4, Helsinki, 00880, Finland

    Dariusz Leszczynski

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Atkinson, M.J. (2013). Radiation Treatment Effects on the Proteome of the Tumour Microenvironment. In: Leszczynski, D. (eds) Radiation Proteomics. Advances in Experimental Medicine and Biology, vol 990. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5896-4_3

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