Skip to main content
SpringerLink
Log in

Cancer as an emergent phenomenon in systems radiation biology

  • Review
  • Published:
Radiation and Environmental Biophysics Aims and scope Submit manuscript

Abstract

Radiation-induced DNA damage elicits dramatic cell signaling transitions, some of which are directed towards deciding the fate of that particular cell, while others lead to signaling to other cells. Each irradiated cell type and tissue has a characteristic pattern of radiation-induced gene expression, distinct from that of the unirradiated tissue and different from that of other irradiated tissues. It is the sum of such events, highly modulated by genotype that sometimes leads to cancer. The challenge is to determine as to which of these phenomena have persistent effect that should be incorporated into models of how radiation increases the risk of developing cancer. The application of systems biology to radiation effects may help to identify which biological responses are significant players in radiation carcinogenesis. In contrast to the radiation biology paradigm that focuses on genomic changes, systems biology seeks to integrate responses at multiple scales (e.g. molecular, cellular, organ, and organism). A key property of a system is that some phenomenon emerges as a property of the system rather than of the parts. Here, the idea that cancer in an organism can be considered as an emergent phenomenon of a perturbed system is discussed. Given the current research goal to determine the consequences of high and low radiation exposures, broadening the scope of radiation studies to include systems biology concepts should benefit risk modeling of radiation carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. NAS/NRC (2006) Health risks from exposure to low levels of ionizing radiation: phase 2, in board on radiation effects research (BEIRVII). National Academy Press, Washington

    Google Scholar 

  2. Gudkov AV, Komarova EA (2003) The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 3:117–129

    Article  Google Scholar 

  3. Trosko JE (1998) Hierarchcal and cybernetic nature of biologic systems and their relevance to homeostatic adaptation to low-level exposures to oxidative stress-inducing agents. Environ Health Perspect 106:331–339

    Article  Google Scholar 

  4. Barcellos-Hoff MH (1998) How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res 150:S109–S120

    Article  Google Scholar 

  5. von Bertalanffy L (1951) General system theory; a new approach to unity of science. 1. Problems of general system theory. Hum Biol 23:302–312

    Google Scholar 

  6. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, Gudkov AV (1999) A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy [see comments]. Science 285:1733–1737

    Article  Google Scholar 

  7. Maj JG, Paris F, Haimovitz-Friedman A, Venkatraman E, Kolesnick R, Fuks Z (2003) Microvascular function regulates intestinal crypt response to radiation. Cancer Res 63:4338–4341

    Google Scholar 

  8. Barcellos-Hoff MH, Brooks AL (2001) Extracellular signaling via the microenvironment: a hypothesis relating carcinogenesis, bystander effects and genomic instability. Radiat Res 156:618–627

    Article  Google Scholar 

  9. Christophorou MA, Ringshausen I, Finch AJ, Swigart LB, Evan GI (2006) The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443:214–217

    Article  ADS  Google Scholar 

  10. Komarova EA, Kondratov RV, Wang K, Christov K, Golovkina TV, Goldblum JR, Gudkov AV (2004) Dual effect of p53 on radiation sensitivity in vivo: P53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23:3265–3271

    Article  Google Scholar 

  11. Dunker N, Krieglstein K (2000) Targeted mutations of transforming growth factor-β genes reveal important roles in mouse development and adult homeostasis. Eur J Biochem 267:6982–6988

    Article  Google Scholar 

  12. Massague J, Blain SW, Lo RS (2000) Tgf-β signaling in growth control, cancer, and heritable disorders. Cell 103:295–309

    Article  Google Scholar 

  13. Derynck R, Akhurst RJ, Balmain A (2001) Tgf-β signaling in tumor suppression and cancer progression. Nature Genet 29:117–129

    Article  Google Scholar 

  14. Lawrence DA, Pircher R, Jullien P (1985) Conversion of a high molecular weight latent beta-tgf from chicken embryo fibroblasts into a low molecular weight active beta-tgf under acidic conditions. Biochem Biophys Res Comm 133:1026–1034

    Article  Google Scholar 

  15. Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent tgf{beta} activation. J Cell Sci 116:217–224

    Article  Google Scholar 

  16. Barcellos-Hoff MH, Derynck R, Tsang ML-S, Weatherbee JA (1994) Transforming growth factor-β activation in irradiated murine mammary gland. J Clin Invest 93:892–899

    Article  Google Scholar 

  17. Barcellos-Hoff MH, Dix TA (1996) Redox-mediated activation of latent transforming growth factor-β1. Mol Endocrinol 10:1077–1083

    Article  Google Scholar 

  18. Jobling MF, Mott JD, Finnegan M, Erickson AC, Taylor SE, Ledbetter S, Barcellos-Hoff MH (2006) Isoform specificity of redox-mediated tgf-β activation. Radiat Res 166:839–848

    Article  Google Scholar 

  19. Andarawewa KL, Kirshner J, Mott JD, Barcellos-Hoff MH (2007) Tgfβ: roles in DNA damage responses. In: Jakowlew S (ed) Transforming growth factor-beta in cancer therapy, volume 1 basic and clinical biology. Humana Press, Totowa (in press)

    Google Scholar 

  20. Ewan KB, Henshall-Powell RL, Ravani SA, Pajares MJ, Arteaga CL, Warters RL, Akhurst RJ, Barcellos-Hoff MH (2002) Transforming growth factor-β1 mediates cellular response to DNA damage in situ. Cancer Res 62:5627–5631

    Google Scholar 

  21. Meyn RE, Stephens LC, Mason KA, Medina D (1996) Radiation-induced apoptosis in normal and pre-neoplastic mammary glands in vivo: significance of gland differentiation and p53 status. Int J Cancer 65:466–472

    Article  Google Scholar 

  22. Kuperwasser C, Pinkas J, Hurlbut GD, Naber SP, Jerry DJ (2000) Cytoplasmic sequestration and functional repression of p53 in the mammary epithelium is reversed by hormonal treatment. Cancer Res 60:2723–2729

    Google Scholar 

  23. Jerry DJ, Kittrell FS, Kuperwasser C, Laucirica R, Dickinson ES, Bonilla PJ, Butel JS, Medina D (2000) A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene 19:1052–1058

    Article  Google Scholar 

  24. Cordenonsi M, Dupont S, Maretto S, Insinga A, Imbriano C, Piccolo S (2003) Links between tumor suppressors: P53 is required for tgf-beta gene responses by cooperating with smads. Cell 113:301–314

    Article  Google Scholar 

  25. Glick AB, Weinberg WC, Wu IH, Quan W, Yuspa SH (1996) Transforming growth factor beta 1 suppresses genomic instability independent of a g1 arrest, p53, and rb. Cancer Res 56:3645–3650

    Google Scholar 

  26. Tang B, Bottinger EP, Jakowlew SB, Bangall KM, Mariano J, Anver MR, Letterio JJ, Wakefield LM (1998) Transforming growth factor-beta1 is a new form of tumor supressor with true haploid insufficiency. Nat Med 4:802–807

    Article  Google Scholar 

  27. Abraham RT (2003) Checkpoint signaling: epigenetic events sound the DNA strand-breaks alarm to the atm protein kinase. Bioessays 25:627–630

    Article  Google Scholar 

  28. Kastan MB, Lim DS, Kim ST, Xu B, Canman C (2000) Multiple signaling pathways involving atm. Cold Spring Harb Symp Quant Biol 65:521–526

    Article  Google Scholar 

  29. Kirshner J, Jobling MF, Pajares MJ, Ravani SA, Glick A, Lavin M, Koslov S, Shiloh Y, Barcellos-Hoff MH (2006) Inhibition of tgfβ1 signaling attenuates atm activity in response to genotoxic stress. Cancer Res 66:10861–10868

    Article  Google Scholar 

  30. Barcellos-Hoff MH (2001) It takes a tissue to make a tumor: epigenetics, cancer and the microenvironment. J Mammary Gland Biol Neoplasia 6:213–221

    Article  Google Scholar 

  31. Rubin H (2001) Selected cell and selective microenvironment in neoplastic development. Cancer Res 61:799–807

    Google Scholar 

  32. Soto AM, Sonnenschein C (2005) Emergentism as a default: cancer as a problem of tissue organization. J Biosci 30:103–118

    Article  Google Scholar 

  33. Kenny PA, Bissell MJ (2003) Tumor reversion: correction of malignant behavior by microenvironmental cues. Int J Cancer 107:688–695

    Article  Google Scholar 

  34. Engelmann I, Bauer G (2000) How can tumor cells escape intercellular induction of apoptosis? Anticancer Res 20:2297–2306

    Google Scholar 

  35. Hanusch J, Schwieger A, Sers C, Schafer R, Bauer G (2000) Oncogenic transformation increases the sensitivity for apoptosis induction by inhibitors of macromolecular synthesis. Int J Oncol 17:89–95

    Google Scholar 

  36. Portess DI, Bauer G, Hill MA, O’Neill P (2007) Low dose irradiation of non-transformed cells stimulates the selective removal of pre-cancerous cells via intercellular induction of apoptosis. Cancer Res 67:1246–1253

    Article  Google Scholar 

  37. Barcellos-Hoff MH, Ravani SA (2000) Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60:1254–1260

    Google Scholar 

  38. Barcellos-Hoff MH (1993) Radiation-induced transforming growth factor β and subsequent extracellular matrix reorganization in murine mammary gland. Cancer Res 53:3880–3886

    Google Scholar 

  39. 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  Google Scholar 

  40. Naparstek E, FitzGerald JJ, Sakakeeny MA, Klassen V, Pierce JH, Woda BA, Falco J, Fitzgerald S, Nizin P, Greenberger JS (1986) Induction of malignant transformation of cocultivated hematopoietic stem cells by x-irradiation of murine bone marrow stromal cells in vitro. Cancer Res 46:4677–4684

    Google Scholar 

  41. Naparstek E, Donnelly T, Kase K, Greenberger J (1985) Biologic effects of in vitro x-irradiation of murine long-term bone marrow cultures on the production of granulocyte-macrophage colony-stimulating factors. Exp Hematol 13:701–708

    Google Scholar 

  42. Park CC, Henshall-Powell R, Erickson AC, Talhouk R, Parvin B, Bissell MJ, Barcellos-Hoff MH (2003) Ionizing radiation induces heritable disruption of epithelial cell-microenvironment interactions. Proc Natl Acad Sci 100:10728–10733

    Article  ADS  Google Scholar 

  43. Andarawewa KL, Erickson AC, Chou WS, Costes SV, Gascard P, Mott JD, Bissell MJ, Barcellos-Hoff MH (2007) Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor {beta} induced epithelial to mesenchymal transition. Cancer Res 67:8662–8670

    Article  Google Scholar 

  44. Tsai KKC, Chuang EY-Y, Little JB, Yuan Z-M (2005) Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res 65:6734–6744

    Article  Google Scholar 

  45. Rosenkrans Jr. WA, Penney DP (1985) Cell-cell matrix interactions in induced lung injury ii. X-irradiation mediated changes in specific basal laminar glycosaminoglycans. Int J Radiat Oncol Biol Phys 11:1629–1637

    Google Scholar 

  46. Rosenkrans WA, 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  Google Scholar 

  47. Mott JD, Werb Z (2004) Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16:558–564

    Article  Google Scholar 

  48. McBride WH, Chiang C-S, Olson JL, Wang C-C, Hong J-H, Pajonk F, Dougherty GJ, Iwamoto KS, Pervan M, Liao Y-P (2004) A sense of danger from radiation. Radiat Res 162:1–19

    Article  Google Scholar 

  49. Stone HB, Coleman CN, Anscher MS, McBride WH (2003) Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol 4:529–536

    Article  Google Scholar 

Download references

Acknowledgments

The author acknowledges funding from NASA Specialized Center for Research in Radiation Health Effects and the Office of Biological and Environmental Research, of the U.S. Department of Energy Contract No. DE-AC-03-76SF00098 to Lawrence Berkeley National Laboratory and a grant from the Low Dose Radiation Program, Office of Biological and Environmental Research, of the U.S. Department of Energy.

Author information

Authors and Affiliations

  1. Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Bldg. 977, Berkeley, CA, 94720, USA

    Mary Helen Barcellos-Hoff

Authors
  1. Mary Helen Barcellos-Hoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary Helen Barcellos-Hoff.

Additional information

Presented at the First International Workshop on Systems Radiation Biology, February 14–16 2007, GSF-Research Centre, Neuherberg, Germany.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barcellos-Hoff, M.H. Cancer as an emergent phenomenon in systems radiation biology . Radiat Environ Biophys 47, 33–38 (2008). https://doi.org/10.1007/s00411-007-0141-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00411-007-0141-0

Keywords

Search

Navigation