Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cellular and Molecular Biology

Transiently hypoxic tumour cell turnover and radiation sensitivity in human tumour xenografts

British Journal of Cancer volume 126, pages 1616–1626 (2022)Cite this article

Subjects

Abstract

Background

Solid tumour perfusion can be unstable, creating transiently hypoxic cells that can contribute to radiation resistance. We investigated the in vivo lifetime of transiently hypoxic tumour cells and chronically hypoxic tumour cells during tumour growth and following irradiation.

Methods

Hypoxic cells in SiHa and WiDr human tumour xenografts were labelled using pimonidazole and EF5, and turnover was quantified as the loss of labelled cells over time. The perfusion-modifying drug pentoxifylline was used to reoxygenate transiently hypoxic cells prior to hypoxia marker administration or irradiation.

Results

Chronically hypoxic cells constantly turnover in SiHa and WiDr tumours, with half-lives ranging from 42–82 h and significant numbers surviving >96 h. Transiently hypoxic cells constitute 26% of the total hypoxic cells in WiDr tumours. These transiently hypoxic cells survive at least 24 h, but then rapidly turnover with a half-life of 34 h and are undetectable 72 h after labelling. Transiently hypoxic cells are radiation-resistant, although vascular dysfunction induced by 10 Gy of ionising radiation preferentially kills transiently hypoxic cells.

Conclusions

Transiently hypoxic tumour cells survive up to 72 h in WiDr tumours and are radiation-resistant, although transiently hypoxic cells are sensitive to vascular dysfunction induced by high doses of ionising radiation.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pimonidazole positive tumour area decreases with time.
Fig. 2: Pentoxifylline induces 2-nitroimidazole mismatch and reveals chronically and transiently hypoxic cell turnover.
Fig. 3: Hypoxia reduces tumour cell proliferation and loss of pimonidazole staining intensity.
Fig. 4: Hypoxic cell response to direct and indirect effects of ionising radiation.

Similar content being viewed by others

References

  1. Höckel M, Knoop C, Schlenger K, Vorndran B, Baußnann E, Mitze M, et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26:45–50.

    Article  PubMed  Google Scholar 

  2. Höckel M, Schlenger K, Aral B, Mitze M, Schäffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56:4509–15.

    PubMed  Google Scholar 

  3. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38:285–9.

    Article  CAS  PubMed  Google Scholar 

  4. Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996;41:31–39.

    Article  CAS  PubMed  Google Scholar 

  5. Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, et al. Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br J Cancer. 2001;84:1070–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, et al. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998;48:149–56.

    Article  CAS  PubMed  Google Scholar 

  7. Brizel DM, Dodge RK, Clough RW, Dewhirst MW. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol. 1999;53:113–7.

    Article  CAS  PubMed  Google Scholar 

  8. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996;56:941–3.

    CAS  PubMed  Google Scholar 

  9. Pitson G, Fyles A, Milosevic M, Wylie J, Pintilie M, Hill R. Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer. Int J Radiat Oncol Biol Phys. 2001;51:699–703.

    Article  CAS  PubMed  Google Scholar 

  10. Fyles A, Milosevic M, Hedley D, Pintilie M, Levin W, Manchul L, et al. Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol. 2002;20:680–7.

    Article  CAS  PubMed  Google Scholar 

  11. Bennewith KL, Dedhar S. Targeting hypoxic tumour cells to overcome metastasis. BMC Cancer. 2011;11:504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science. 2016;352:175–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dewhirst MW, Secomb TW, Ong ET, Hsu R, Gross JF. Determination of local oxygen consumption rates in tumors. Cancer Res. 1994;54:3333–6.

    CAS  PubMed  Google Scholar 

  14. Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol. 1995;34:313–6.

    Article  CAS  PubMed  Google Scholar 

  15. Tannock IF. Oxgen diffusion and the distribution of cellular radiosensitivity in tumours. Br J Radiol. 1972;45:515–24.

    Article  CAS  PubMed  Google Scholar 

  16. Tannock IF. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer. 1968;22:258–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955;9:539–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hirst DG, Hirst VK, Joiner B, Prise V, Shaffi KM. Changes in tumour morphology with alterations in oxygen availability: further evidence for oxygen as a limiting substrate. Br J Cancer. 1991;64:54–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hirst DG, Denekamp J, Hobson B. Proliferation kinetics of endothelial and tumour cells in three mouse mammary carcinomas. Cell Prolif. 1982;15:251–61.

    Article  CAS  Google Scholar 

  20. Durand RE, Aquino-Parsons C. Non-constant tumour blood flow: Implications for therapy. Acta Oncol. 2001;40:862–9.

    Article  CAS  PubMed  Google Scholar 

  21. Harada H, Inoue M, Itasaka S, Hirota K, Morinibu A, Shinomiya K, et al. Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nat Commun. 2012;3:710–83.

    Article  CAS  Google Scholar 

  22. Ljungkvist ASE, Bussink J, Kaanders JHAM, Rijken PFJW, Begg AC, Raleigh JA, et al. Hypoxic cell turnover in different solid tumor lines. Int J Radiat Oncol Biol Phys. 2005;62:1157–68.

    Article  PubMed  Google Scholar 

  23. Durand RE, Sham E. The lifetime of hypoxic human tumor cells. Int J Radiat Oncol Biol Phys. 1998;42:711–5.

    Article  CAS  PubMed  Google Scholar 

  24. Lunt SJ, Kalliomaki TMK, Brown A, Yang VX, Milosevic M, Hill RP. Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours. BMC Cancer. 2008;8:1–14.

    Article  Google Scholar 

  25. Sen A, Capitano ML, Spernyak JA, Schueckler JT, Thomas S, Singh AK, et al. Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. Cancer Res. 2011;71:3872–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA. 2011;108:2909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516.

    Article  PubMed  CAS  Google Scholar 

  28. Kumar V, Boucher Y, Liu H, Ferreira D, Hooker J, Catana C, et al. Noninvasive assessment of losartan-induced increase in functional microvasculature and drug delivery in pancreatic ductal adenocarcinoma. Transl Oncol. 2016;9:431–7.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Stylianopoulos T, Munn LL, Jain RK. Reengineering the tumor vasculature: improving drug delivery and efficacy. Trends Cancer. 2018;4:258–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Secomb TW, Hsu R, Dewhirst MW, Klitzman B, Gross JF. Analysis of oxygen transport to tumor tissue by microvascular networks. Int J Radiat Oncol Biol Phys. 1993;25:481–9.

    Article  CAS  PubMed  Google Scholar 

  31. Baish JW, Gazit Y, Berk DA, Nozue M, Baxter LT, Jain RK. Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model. Microvasc Res. 1996;51:327–46.

    Article  CAS  PubMed  Google Scholar 

  32. Pogue BW, O’Hara JA, Wilmot CM, Paulsen KD, Swartz HM. Estimation of oxygen distribution in RIF-1 tumors by diffusion model-based interpretation of pimonidazole hypoxia and eppendorf measurements. Radiat Res. 2001;155:15–25.

    Article  CAS  PubMed  Google Scholar 

  33. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8:425–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jain RK. Determinants of tumor blood flow: a review. Cancer Res. 1988;48:2641–58.

    CAS  PubMed  Google Scholar 

  35. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49:6449–65.

    CAS  PubMed  Google Scholar 

  36. Brown JM. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol. 1979;52:650–6.

    Article  CAS  PubMed  Google Scholar 

  37. Trotter MJ, Chaplin DJ, Durand RE, Olive PL. The use of fluorescent probes to identify regions of transient perfusion in murine tumors. Int J Radiat Oncol Biol Phys. 1989;16:931–4.

    Article  CAS  PubMed  Google Scholar 

  38. Durand RE, Lepard NE. Contribution of transient blood flow to tumour hypoxia in mice. Acta Oncol. 1995;34:317–23.

    Article  CAS  PubMed  Google Scholar 

  39. Braun RD, Lanzen JL, Dewhirst MW. Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Physiol Heart Circ Physiol. 1999;277:H551–H568.

    Article  CAS  Google Scholar 

  40. Brurberg KG, Skogmo HK, Graff BA, Olsen DR, Rofstad EK. Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy. Radiother Oncol. 2005;77:220–6.

    Article  PubMed  Google Scholar 

  41. Pigott KH, Hill SA, Chaplin DJ, Saunders MI. Microregional fluctuations in perfusion within human tumours detected using laser Doppler flowmetry. Radiother Oncol. 1996;40:45–50.

    Article  CAS  PubMed  Google Scholar 

  42. Simonsen TG, Gaustad JV, Leinaas MN, Rofstad EK. Vascular abnormalities associated with acute hypoxia in human melanoma xenografts. Radiother Oncol. 2012;105:72–78.

    Article  PubMed  Google Scholar 

  43. Gaustad JV, Simonsen TG, Hansem LMK, Rofstad EK. Intravital microscopy of tumor vessel morphology and function using a standard fluorescence microscope. Eur J Nucl Med Mol Imaging. 2021;48:3089–3100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Krishna MC, Matsumoto S, Yasui H, Saito K, Devasahayam N, Subramanian S, et al. Electron paramagnetic resonance imaging of tumor pO2. Radiat Res. 2012;177:376–86.

    Article  CAS  PubMed  Google Scholar 

  45. Baudelet C, Ansiaux R, Jordan BF, Havaux X, Macq B, Gallez B. Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia? Phys Med Biol. 2004;49:3389–411.

    Article  PubMed  Google Scholar 

  46. Magat J, Jordan BF, Cron GO, Gallez B. Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using 19F MRI. Med Phys. 2010;37:5434–41.

    Article  CAS  PubMed  Google Scholar 

  47. Ron A, Deán-Ben XL, Gottschalk S, Razansky D. Volumetric optoacoustic imaging unveils high-resolution patterns of acute and cyclic hypoxia in a murine model of breast cancer. Cancer Res. 2019;79:4767–75.

    Article  CAS  PubMed  Google Scholar 

  48. Bader SB, Dewhirst MW, Hammond EM. Review cyclic hypoxia: an update on its characteristics, methods to measure it and biological implications in cancer. Cancers. 2021;13:1–20.

    Google Scholar 

  49. Bennewith KL, Durand RE. Drug-induced alterations in tumour perfusion yield increases in tumour cell radiosensitivity. Br J Cancer. 2001;85:1577–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vordermark D, Horsman M. Hypoxia as a biomarker and for personalized radiation oncology. Recent Results Cancer Res. 2016;198:123–42.

    Article  CAS  PubMed  Google Scholar 

  51. Siemann DW, Horsman MR. Modulation of the tumor vasculature and oxygenation to improve therapy. Pharmacol Ther. 2015;153:107–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: Results of a phase III randomized trial. J Clin Oncol. 2012;30:1777–83.

    Article  CAS  PubMed  Google Scholar 

  53. Kaanders JHAM, Wijffels KIEM, Marres HAM, Ljungkvist ASE, Pop L, van den Hoogen F, et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002;62:7066–74.

    CAS  PubMed  Google Scholar 

  54. Lee I, Kim JH, Levitt SH, Song CW. Increases in tumor response by pentoxifylline alone or in combination with nicotinamide. Int J Radiat Oncol Biol Phys. 1992;22:425–9.

    Article  CAS  PubMed  Google Scholar 

  55. Chaudary N, Hill RP. Increased expression of metastasis-related genes in hypoxic cells sorted from cervical and lymph nodal xenograft tumors. Lab Invest. 2009;89:587–96.

    Article  CAS  PubMed  Google Scholar 

  56. Cairns RA, Kalliomaki T, Hill RP. Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res. 2001;61:8903–8.

    CAS  PubMed  Google Scholar 

  57. Cairns RA, Hill RP. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 2004;64:2054–61.

    Article  CAS  PubMed  Google Scholar 

  58. Arteel GE, Thurman RG, Yates JM, Raleigh JA. Evidence that hypoxia markers detect oxygen gradients in liver: Pimonidazole and retrograde perfusion of rat liver. Br J Cancer. 1995;72:889–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Koch CJ, Evans SM, Lord EM. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2, 2, 3, 3, 3-pentafluoropropyl)acetamide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br J Cancer. 1995;72:869–74.

  60. Walton MI, Bleehen NM, Workman P. Effects of localised tumour hyperthermia on pimonidazole (Ro 03-8799) pharmacokinetics in mice. Br J Cancer. 1989;59:667–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Laughlin KM, Tracy M, Chan CY, Lord EM. Biodistribution of the Nitroimidazole EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide) in Mice Bearing Subcutaneous. J Pharmacol Exp Ther. 1996;277:1049–57.

  62. Bennewith KL, Durand RE. Quantifying transient hypoxia in human tumor xenografts by flow cytometry. Cancer Res. 2004;64:6183–9.

    Article  CAS  PubMed  Google Scholar 

  63. Wadsworth BJ, Cederberg RA, Lee C-M, Firmino NS, Franks SE, Pan J, et al. Angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation. Cancer Lett. 2020;493:31–40.

    Article  CAS  PubMed  Google Scholar 

  64. Ehrly AM. The effect of pentoxifylline on the flow properties of human blood. Curr Med Res Opin. 1978;5:608–13.

    Article  CAS  PubMed  Google Scholar 

  65. Price MJ, Li LT, Tward JD, Bublik I, Mcbride WH, Lavey RS. Effect of nicotinamide and pentoxifylline on normal tissue and fsa tumor oxygenation. Acta Oncol. 1995;34:391–5.

    Article  CAS  PubMed  Google Scholar 

  66. Zywietz F, Böhm L, Sagowski C, Kehrl W. Pentoxifylline enhances tumor oxygenation and radiosensitivity in rat rhabdomyosarcomas during continuous hyperfractionated irradiation. Strahlenther Onkol. 2004;180:306–14.

    Article  PubMed  Google Scholar 

  67. Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–9.

    Article  CAS  PubMed  Google Scholar 

  68. Song CW, Griffin RJ, Lee Y-J, Cho H, Seo J, Park I, et al. Reoxygenation and repopulation of tumor cells after ablative hypofractionated radiotherapy (SBRT and SRS) in murine tumors. Radiat Res. 2019;192:159–68.

    Article  CAS  PubMed  Google Scholar 

  69. Noguchi P, Wallace R, Johnson J, Earley EM, O’Brien S, Ferrone S, et al. Characterization of WiDr: a human colon carcinoma cell line. In Vitro. 1979;15:401–8.

    Article  CAS  PubMed  Google Scholar 

  70. Friedl F, Kimura I, Osato T, Ito Y. Studies on a new human cell line (SiHa) derived from carcinoma of uterus. I. Its establishment and morphology. Proc Soc Exp Biol Med. 1970;135:543–5.

    Article  CAS  PubMed  Google Scholar 

  71. Trotter MJ, Chaplin DJ, Olive PL. Use of a carbocyanine dye as a marker of functional vasculature in murine tumours. Br J Cancer. 1989;59:706–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Durand RE, Aquino-Parsons C. Clinical relevance of intermittent tumour blood flow. Acta Oncol. 2001;40:929–36.

    Article  CAS  PubMed  Google Scholar 

  73. Mahy P, De Bast M, Gallez B, Gueulette J, Koch CJ, Scalliet P, et al. In vivo colocalization of 2-nitroimidazole EF5 fluorescence intensity and electron paramagnetic resonance oximetry in mouse tumors. Radiother Oncol. 2003;67:53–61.

    Article  CAS  PubMed  Google Scholar 

  74. Koch CJ. Measurement of absolute oxygen levels in cells and tissues using oxygen sensors and 2-nitroimidazole EF5. Methods Enzymol. 2002;352:3–31.

    Article  CAS  PubMed  Google Scholar 

  75. Chaplin DJ, Hill SA. Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumours. Br J Cancer. 1995;71:1210–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 1996;56:5522–8.

    CAS  PubMed  Google Scholar 

  77. Chaplin DJ, Horsman MR, Trotter MJ. Effect of nicotinamide on the microregional heterogeneity of oxygen delivery within a murine tumor. J Natl Cancer Inst. 1990;82:672–6.

    Article  CAS  PubMed  Google Scholar 

  78. Minchinton AI, Durand RE, Chaplin DJ. Intermittent blood flow in the KHT sarcoma-flow cytometry studies using hoechst 33342. Br J Cancer. 1990;62:195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Moore JV, Hasleton PS, Buckley CH. Tumour cords in 52 human bronchial and cervical squamous cell carcinomas: Inferences for their cellular kinetics and radiobiology. Br J Cancer. 1985;51:407–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ljungkvist ASE, Bussink J, Kaanders JHAM, van der Kogel AJ. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res. 2007;167:127–45.

    Article  CAS  PubMed  Google Scholar 

  81. Wittenborn TR, Horsman MR. Targeting tumour hypoxia to improve outcome of stereotactic radiotherapy. Acta Oncol. 2015;54:1385–92.

    Article  CAS  PubMed  Google Scholar 

  82. Zhou H, Hallac RR, Lopez R, Denney R, MacDonough MT, Li L, et al. Evaluation of tumor ischemia in response to an indole-based vascular disrupting agent using BLI and (19)F MRI. Am J Nucl Med Mol Imaging. 2015;5:143–53.

    PubMed  PubMed Central  Google Scholar 

  83. Liu L, O’Kelly D, Schuetze R, Carlson G, Zhou H, Trawick ML, et al. Non-invasive evaluation of acute effects of tubulin binding agents: a review of imaging vascular disruption in tumors. Molecules. 2021;26:2551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Iversen AB, Busk M, Bertelsen LB, Laustsen C, Munk OL, Nielsen T, et al. The potential of hyperpolarized 13-C magnetic resonance spectroscopy to monitor the effect of combretastatin based vascular disrupting agents. Acta Oncol. 2017;56:1626–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Drs. Andrew Minchinton and Alastair Kyle for use of their fluorescent microscope slide scanner and associated custom image processing programs.

Funding

This work was supported by the Canadian Institutes of Health Research (CIHR; MOP-126138 and PJT-159513). BJW was supported by a CIHR Doctoral Research Award. BJW and CML were scholars in the Strategic Training in Transdisciplinary Radiation Science for the 21st Century (STARS21) program. KLB was a Michael Smith Foundation of Health Research Biomedical Research Scholar.

Author information

Authors and Affiliations

  1. Integrative Oncology, BC Cancer, Vancouver, BC, Canada

    Brennan J. Wadsworth, Che-Min Lee & Kevin L. Bennewith

  2. Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Brennan J. Wadsworth & Kevin L. Bennewith

  3. Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada

    Che-Min Lee & Kevin L. Bennewith

Authors
  1. Brennan J. Wadsworth
    View author publications

    Search author on:PubMed Google Scholar

  2. Che-Min Lee
    View author publications

    Search author on:PubMed Google Scholar

  3. Kevin L. Bennewith
    View author publications

    Search author on:PubMed Google Scholar

Contributions

BJW contributed to project conceptualisation and experimental design, data collection, data analysis and interpretation and writing of the manuscript. CML contributed to data collection and analysis. KLB contributed to project conceptualisation, experimental design, data interpretation and writing of the manuscript.

Corresponding author

Correspondence to Kevin L. Bennewith.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

All animal experiments were approved by the University of British Columbia Animal Care Committee in accordance with Canadian Council on Animal Care guidelines.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wadsworth, B.J., Lee, CM. & Bennewith, K.L. Transiently hypoxic tumour cell turnover and radiation sensitivity in human tumour xenografts. Br J Cancer 126, 1616–1626 (2022). https://doi.org/10.1038/s41416-021-01691-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01691-5

This article is cited by

Search

Advanced search

Quick links