Skip to main content

Advertisement

Log in

Stromal Mediation of Radiation Carcinogenesis

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Ionizing radiation is a well-established carcinogen in human breast and rodent mammary gland. This review addresses evidence that radiation elicits the critical stromal context for cancer, affecting not only frequency but the type of cancer. Recent data from the breast tumors of women treated with radiation therapy and the cellular mechanisms evident in experimental models suggest that radiation effects on stromal-epithelial interactions and tissue composition are a major determinant of cancer development.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

TGFβ:

Transforming growth factor β

ER:

estrogen receptor

PR:

progesterone receptor

EMT:

epithelial-mesenchymal transition

References

  1. Rubin H. Cancer as a dynamic developmental disorder. Cancer Res. 1985;45:2935–42.

    CAS  PubMed  Google Scholar 

  2. Barcellos-Hoff MH. The potential influence of radiation-induced microenvironments in neoplastic progression. J Mammary Gland Biol Neoplasia. 1998;3:165–75.

    Article  CAS  PubMed  Google Scholar 

  3. Sonnenschein C, Soto AM. Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog. 2000;29(4):205–11.

    Article  CAS  PubMed  Google Scholar 

  4. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):1–11.

    Article  Google Scholar 

  5. Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science. 2002;296(5570):1046–9.

    Article  CAS  PubMed  Google Scholar 

  6. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, et al. From the cover: reconstruction of functionally normal and malignant human breast tissues in mice. PNAS. 2004;101(14):4966–71.

    Article  CAS  PubMed  Google Scholar 

  7. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, et al. TGF-{beta} signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303(5659):848–51.

    Article  CAS  PubMed  Google Scholar 

  8. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci. 2004;117(8):1495–502.

    Article  CAS  PubMed  Google Scholar 

  9. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6(1):24–37.

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. NAS/NRC. Health risks from exposure to low levels of ionizing radiation: phase 2. Washington: National Academy Press; 2006.

    Google Scholar 

  12. Barcellos-Hoff MH. Cancer as an emergent phenomenon in systems radiation biology. Radiat Env Biophys. 2007;47(1):33–8.

    Article  Google Scholar 

  13. Herskind C, Rodemann HP. Spontaneous and radiation-induced differentiationof fibroblasts. Exp Gerontol. 2000;35(6-7):747–55.

    Article  CAS  PubMed  Google Scholar 

  14. Rave-Frank M, Virsik-Kopp P, Pradier O, Nitsche M, Grunefeld S. H. S. In vitro response of human dermal fibroblasts to X-irradiation: relationship between radiation-induced clonogenic cell death, chromosome aberrations and markers of proliferative senescence or differentiation. Int J Radiat Biol. 2001;77:1163–74.

    Article  CAS  PubMed  Google Scholar 

  15. Park CC, Henshall-Powell RL, Erickson AC, Talhouk R, Parvin B, Bissell MJ, et al. Ionizing radiation induces heritable disruption of epithelial cell interactions. Proc Natl Acad Sci USA. 2003;100(19):10728–33.

    Article  CAS  PubMed  Google Scholar 

  16. Tsai KK, Chuang EY, Little JB, Yuan ZM. Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res. 2005;65(15):6734–44.

    Article  CAS  PubMed  Google Scholar 

  17. Kadhim MA, Lorimore SA, Hepburn MD, Goodhead DT, Buckle VJ, Wright EG. Alpha-particle-induced chromosomal instability in human bone marrow cells. Lancet. 1994;344(8928):987–8.

    Article  CAS  PubMed  Google Scholar 

  18. Kadhim MA, Lorimore SA, Townsend KM, Goodhead DT, Buckle VJ, Wright EG. Radiation-induced genomic instability: delayed cytogenetic aberrations and apoptosis in primary human bone marrow cells. Int J Radiat Biol. 1995;67(3):287–93.

    Article  CAS  PubMed  Google Scholar 

  19. Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG. Transmission of chromosomal instability after plutonium alpha-particle irradiation [see comments]. Nature. 1992;355(6362):738–40.

    Article  CAS  PubMed  Google Scholar 

  20. Clutton SM, Townsend KM, Goodhead DT, Ansell JD, Wright EG. Differentiation and delayed cell death in embryonal stem cells exposed to low doses of ionising radiation. Cell Death Differ. 1996;3(1):141–8.

    CAS  PubMed  Google Scholar 

  21. Limoli CL, Kaplan MI, Corcoran J, Meyers M, Boothman DA, Morgan WF. Chromosomal instability and its relationship to other end points of genomic instability. Cancer Res. 1997;57(24):5557–63.

    CAS  PubMed  Google Scholar 

  22. Preston DL, Pierce DA, Shimizu Y, Ron E, Mabuchi K. Dose response and temporal patterns of radiation-associated solid cancer risks. Health Phys. 2003;85(1):43–6.

    Article  CAS  PubMed  Google Scholar 

  23. Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, et al. Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res. 2007;168(1):1–64.

    Article  CAS  PubMed  Google Scholar 

  24. Preston DL, Mattsson A, Holmberg E, Shore R, Hildreth NG, Boice Jr JD. Radiation effects on breast cancer risk: a pooled analysis of eight cohorts. Radiat Res. 2002;158(2):220–35.

    Article  CAS  PubMed  Google Scholar 

  25. Castiglioni F, Terenziani M, Carcangiu ML, Miliano R, Aiello P, Bertola L, et al. Radiation effects on development of HER2-positive breast carcinomas. Clin Cancer Res. 2007;13(1):46–51.

    Article  CAS  PubMed  Google Scholar 

  26. Van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van’t Veer MB, Noordijk EM, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst. 2003;95(13):971–80.

    Article  PubMed  Google Scholar 

  27. Broeks A, Braaf LM, Wessels LF, Van de Vjver M, De Bruin ML, Stovall M, et al. Radiation-associated breast tumors display a distinct gene expression profile. Int J Radiat Oncol Biol Phys. 2010;76(2):540–7.

    Article  PubMed  Google Scholar 

  28. Barcellos-Hoff MH. Integrative radiation carcinogenesis: interactions between cell and tissue responses to DNA damage. Semin Cancer Biol. 2005;15(2):138–48.

    Article  CAS  PubMed  Google Scholar 

  29. Kaplan HS, Carnes WH, Brown MB, Hirsch BB. Indirect induction of lymphomas in irradiated mice: I. Tumor incidence and morphology in mice bearing nonirradiated thymic grafts. Cancer Res. 1956;16(5):422–5.

    CAS  PubMed  Google Scholar 

  30. Kaplan HS, Brown MB, Hirsch BB, Carnes WH. Indirect induction of lymphomas in irradiated mice: II. Factor of irradiation of the host. Cancer Res. 1956;16(5):426–8.

    CAS  PubMed  Google Scholar 

  31. Carnes WH, Kaplan HS, Brown MB, Hirsch BB. Indirect induction of lymphomas in irradiated mice: III. Role of the thymic graft. Cancer Res. 1956;16(5):429–33.

    CAS  PubMed  Google Scholar 

  32. Billingham RE, Orr JW, Woodhouse DL. Transplantation of skin components during chemical carcinogenesis with 20-methylcholanthrene. Br J Cancer. 1951;5:417–32.

    CAS  PubMed  Google Scholar 

  33. Morgan JE, Gross JG, Pagel CN, Beauchamp JR, Fassati A, Thrasher AJ, et al. Myogenic cell proliferation and generation of a reversible tumorigenic phenotype are triggered by preirradiation of the recipient site. J Cell Biol. 2002;157(4):693–702.

    Article  CAS  PubMed  Google Scholar 

  34. Ohuchida K, Mizumoto K, Murakami M, Qian L-W, Sato N, Nagai E, et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 2004;64(9):3215–22.

    Article  CAS  PubMed  Google Scholar 

  35. Terzaghi M, Little JB. X-radiation-induced transformation in C3H mouse embryo-derived cell line. Cancer Res. 1976;36:1367–74.

    CAS  PubMed  Google Scholar 

  36. Terzaghi M, Nettesheim P. Dynamics of neoplastic development in carcinogen-exposed tracheal mucosa. Cancer Res. 1979;39:3004–10.

    Google Scholar 

  37. Kennedy AR, Fox M, Murphy G, Little JB. Relationship between x-ray exposure and malignant transformation in C3H 10 T1/2 cells. Proc Natl Acad Sci USA. 1980;77(12):7262–6.

    Article  CAS  PubMed  Google Scholar 

  38. Bauer G. Elimination of transformed cells by normal cells: a novel concept for the control of carcinogenesis. Histol Histopathol. 1996;11(1):237–55.

    CAS  PubMed  Google Scholar 

  39. Engelmann I, Eichholtz-Wirth H, Bauer G. Ex vivo tumor cell lines are resistant to intercellular induction of apoptosis and independent of exogenous survival factors. Anticancer Res. 2000;20(4):2361–70.

    CAS  PubMed  Google Scholar 

  40. Terzaghi-Howe M. Inhibition of carcinogen-altered rat tracheal epithelial cell proliferation by normal epithelial cells in vivo. Carcinogenesis. 1986;8:145–50.

    Article  Google Scholar 

  41. Häufel T, Dormann S, Hanusch J, Schwieger A, Bauer G. Three distinct roles for TGF-beta during intercellular induction of apoptosis: a review. Anticancer Res. 1999;19(1A):105–11.

    PubMed  Google Scholar 

  42. Portess DI, Bauer G, Hill MA, O’Neill P. Low dose irradiation of non-transformed cells stimulates the selective removal of pre-cancerous cells via intercellular induction of apoptosis. Cancer Res. 2007;67(3):1246–53.

    Article  CAS  PubMed  Google Scholar 

  43. Barcellos-Hoff MH. Radiation-induced transforming growth factor β and subsequent extracellular matrix reorganization in murine mammary gland. Cancer Res. 1993;53:3880–6.

    CAS  PubMed  Google Scholar 

  44. Ehrhart EJ, Gillette EL, Barcellos-Hoff MH. Immunohistochemical evidence of rapid extracellular matrix remodeling after iron-particle irradiation of mouse mammary gland. Rad Res. 1996;145:157–62.

    Article  CAS  Google Scholar 

  45. Ehrhart EJ, Carroll A, Segarini P, Tsang ML-S, Barcellos-Hoff MH. Latent transforming growth factor-β activation in situ: quantitative and functional evidence following low dose irradiation. FASEB J. 1997;11:991–1002.

    CAS  PubMed  Google Scholar 

  46. Barcellos-Hoff MH, Derynck R, Tsang ML-S, Weatherbee JA. Transforming growth factor-β activation in irradiated murine mammary gland. J Clin Invest. 1994;93:892–9.

    Article  CAS  PubMed  Google Scholar 

  47. Barcellos-Hoff MH. How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res. 1998;150(5):S109–20.

    Article  CAS  PubMed  Google Scholar 

  48. Jerry DJ, Medina D, Butel JS. p53 mutations in COMMA-D cells. In Vitro Cell. Dev Biol. 1994;30A:87–9.

    CAS  Google Scholar 

  49. Medina D, Kittrell FS. Stroma is not a major target in 7, 12-dimethlybenzanthracene mediated tumorigenesis of mouse mammary preneoplasia. J Cell Sci. 2005;118:123–7.

    Article  CAS  PubMed  Google Scholar 

  50. Jerry DJ, Kittrell FS, Kuperwasser C, Laucirica R, Dickinson ES, Bonilla PJ, et al. A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene. 2000;19(8):1052–8.

    Article  CAS  PubMed  Google Scholar 

  51. Medina D, Kittrell FS, Shepard A, Stephens LC, Jiang C, Lu J, et al. Biological and genetic properties of the p53 null preneoplastic mammary epithelium. FASEB J. 2002;16(8):881–3.

    CAS  PubMed  Google Scholar 

  52. Tokunaga M, Land CE, Aoki Y, Yamamoto T, Asano M, Sato E, et al. Proliferative and nonproliferative breast disease in atomic bomb survivors. Results of a histopathologic review of autopsy breast tissue. Cancer. 1993;72(5):1657–65.

    Article  CAS  PubMed  Google Scholar 

  53. Boice JD Jr, Preston D, Davis FG, Monson RR. Frequent chest x-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts. Radiat Res. 1991;125:214–22.

    Google Scholar 

  54. Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst. 1993;85(1):25–31.

    Article  CAS  PubMed  Google Scholar 

  55. Howe GR, McLaughlin J. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivor study. Radiat Res. 1996;145:694–707.

    Article  CAS  PubMed  Google Scholar 

  56. Booth C, Potten CS. Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest. 2000;105(11):1493–9.

    Article  CAS  PubMed  Google Scholar 

  57. Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990;110(4):1001–20.

    CAS  PubMed  Google Scholar 

  58. Gyorki D, Asselin-Labat M-L, van Rooijen N, Lindeman G, Visvader J. Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res. 2009;11(4):R62.

    Article  PubMed  Google Scholar 

  59. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9(4):285–93.

    Article  CAS  PubMed  Google Scholar 

  60. Hatsell S, Rowlands T, Hiremath M, Cowin P. beta-Catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia. 2003;8:145–58.

    Article  PubMed  Google Scholar 

  61. Liu BY, McDermott SP, Khwaja SS, Alexander CM. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. PNAS. 2004;101(12):4158–63.

    Article  CAS  PubMed  Google Scholar 

  62. Teissedre B, Pinderhughes A, Incassati A, Hatsell S, Hiremath M, Cowin P. MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors. PLoS ONE. 2009;4:e4537.

    Article  PubMed  Google Scholar 

  63. Incassati A, Pinderhughes A, Eelkema R, Cowin P. Links between transforming growth factor-beta and canonical Wnt signaling yield new insights into breast cancer susceptibility, suppression and tumor heterogeneity. Breast Cancer Res. 2009;11(3):103.

    Article  PubMed  Google Scholar 

  64. Booth BW, Mack DL, Androutsellis-Theotokis A, McKay RDG, Boulanger CA, Smith GH. The mammary microenvironment alters the differentiation repertoire of neural stem cells. Proc Natl Acad Sci. 2008;105(39):14891–6.

    Article  CAS  PubMed  Google Scholar 

  65. Boulanger CA, Mack DL, Booth BW, Smith GH. Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo 10.1073/pnas.0611637104. PNAS. 2007;104(10):3871–6.

    Article  CAS  PubMed  Google Scholar 

  66. Smith G, Medina D. Re-evaluation of mammary stem cell biology based on in vivo transplantation. Breast Cancer Res. 2008;10(1):203.

    Article  PubMed  Google Scholar 

  67. Andarawewa KL, Erickson AC, Chou WS, Costes SV, Gascard P, Mott JD, et al. Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor beta Induced epithelial to mesenchymal transition. Cancer Res. 2007;67:8662–70.

    Article  CAS  PubMed  Google Scholar 

  68. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author wishes to acknowledge funding from NASA Specialized Center for Research in Radiation Health Effects, the Low Dose Radiation Program of the Office of Biological and Environmental Research, United States Department of Energy DE AC03 76SF00098, and the Bay Area Breast Cancer and the Environment Research Center grant number U01 ES012801 from the National Institute of Environmental Health Sciences, NIH and the National Cancer Institute, NIH.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mary Helen Barcellos-Hoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barcellos-Hoff, M.H. Stromal Mediation of Radiation Carcinogenesis. J Mammary Gland Biol Neoplasia 15, 381–387 (2010). https://doi.org/10.1007/s10911-010-9197-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-010-9197-6

Keywords

Navigation