The use of whole body irradiation to reduce tumour development in a mouse model of prostate cancer lawrence


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The use of whole body irradiation to reduce tumour development in a mouse model of prostate cancer lawrence

  1. 1. The use of whole body irradiation to reduce tumour development in a mouse model of prostate cancer Mark Lawrence Supervisors: Assoc. Prof. Pamela Sykes and Dr Rebecca Ormsby
  2. 2. The radiation adaptive response “…a conditioning radiation dose lowers the biological effect of a subsequent (usually higher) radiation exposure.” BEIR VII (2006). • (in vitro) i.e. cell death, DNA repair, mutation induction, chromosomal aberrations. • (in vivo) i.e. immune function, survival, cancer latency and frequency.
  3. 3. Low dose radiation increases latency of radiation-induced lymphoma in mice R.E.J. MITCHEL, J.S. JACKSON, D.P. MORRISON and S.M. CARLISLE “Low doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice” Radiation Research. 159 320 (2003). • Dose, dose-rate, and timing of irradiation. • Haematological cancer studied, almost exclusively.
  4. 4. Prostate cancer • Most common cancer in Australian men (>29% of all diagnoses). • High incidence in Western countries versus Asian countries. • Dietary and environmental factors. • Familial, early onset, prostate cancer is infrequent (<10% cases). • Age is most significant predictor of prostate cancer. Australian Institute of Health and Welfare:
  5. 5. The TRAMP mouse • Transgenic Adenocarcinoma of the Mouse Prostate. • 100% of mice will get prostate cancer. • Disease progression is reproducible. • Model mirrors disease in humans. PIN (prostatic intraepithelial neoplasia)well moderately poorly differentiated adenocarcinomas. • TRAMP tumours transiently regress following androgen withdrawal, but recur as androgen-independent prostate cancer (as observed in man).
  6. 6. Experiments High dose Adaptive response Castration Low dose Determine high dose inducing and promoting potential; in this model. Traditional experimental approach. Test low dose radiation tumour suppressing effect. Investigate phenomenon in conjunction with standard therapy.
  7. 7. Endpoints • Prostate/GUT weight and volume. • Time to palpable tumour. • Histopathological grade. • Cell proliferation. • Programmed cell death (apoptosis). • DNA damage and repair.
  8. 8. Immunofluorescence for Ki-67
  9. 9. Automated Image Analysis
  10. 10. Immunofluorescence γH2AX Large T-antigen
  11. 11. The mouse genitourinary tract
  12. 12. Light microscopy of whole mouse prostate sections
  13. 13. Figure: Mean proliferation frequency (±SE) in prostate lobes of 50 mGy and sham treated TRAMP mice, 3 days following treatment. n=10/group Proliferation pilot study on archival TRAMP prostate tissue •TRAMP mice treated with 50 mGy or sham and tissues taken 3 days following irradiation. • Proliferation rates are lobe specific. • Micro-dissection of prostate is vital. • Significant effect observed in ventral prostate lobes. - repeat experiment with micro-dissection and increased animal numbers required. • Pilot study determined how many cells/images are required for analysis. – optimised image analysis method. *
  14. 14. High dose experiment 6 weeks Remove prostate (and other tissues) Mice 6 weeks old (carcinogenic process beginning) 2 Gy or Sham irradiated Little is known regarding: • radiation-induced prostate cancer • radiation sensitivity of the TRAMP mouse
  15. 15. Figure: Prostate weight as a per cent of body weight in sham- and 2 Gy-irradiated TRAMP mice. P=0.05 Independent Samples T-test. n=10-11/group Prostate weight increase following 2 Gy whole body irradiation of TRAMP mice
  16. 16. Dorso-lateral prostate proliferation six weeks following 2 Gy irradiation N=10-11/treatment group Proliferationindex(+/-SE) • Still to analyse other lobes and histopathology. • Further high dose experiments with >6 weeks between irradiation and tissue collection.
  17. 17. Summary • Radiation adaptive response. – Can modulate a range of biological processes (including cancer) • Expand investigation of adaptive response to an epithelial cancer. – Prostate cancer • Explore a range of dose and timing parameters. • Through investigation of radiation adaptive response: – Increased knowledge of fundamental processes in prostate cancer. – New treatment strategies.
  18. 18. Acknowledgments Supervisors A/Prof Pamela Sykes Dr Rebecca Ormsby DOE lab Dr Benjamin Blyth Alex Staudacher Michelle Newman Ami-Louise Cochrane Monica Dreimanis Katrina Bexis Low Dose Radiation Research Program, Biological and Environmental Research, US Department of Energy Grant DE-FG02-05ER64104 and The Cancer Council of South Australia. Royal Adelaide Hospital A/Prof Eva Bezak Dame Roma Mitchell Cancer Research Laboratories Prof. Wayne Tilley Dr Lisa Butler