Radiation is one of the primary modalities for the treatment of localized cancer and a number of factors can influence the response of tumours and surrounding normal tissues to such treatment. These factors, which can be specific to the individual tumour or normal tissue and to their environment, can vary from patient to patient. One part of the research in my laboratory focuses on understanding how these factors control tumour and normal tissue response to radiation treatment in individual patients.

Our current work involves:

1) Examination of hypoxia in human tumours with a focus on cancer of the cervix and soft tissue sarcoma. In these studies we are collaborating with the clinical groups at the Princess Margaret Hospital in examining methods to measure hypoxia in tumours in relation to their value as predictors of treatment outcome.

2) Studies of the cellular radiosensitivity of normal human fibroblasts from skin in vivo. These studies are focusing on the use of assays of fibroblast response to irradiation as a possible local dosimeter following accidental exposure to irradiation.

3) Examination of the sensitivity of lung tissue to different volumes of irradiation. These studies in rat and mouse lungs are investigating mechanisms associated with the response of the lung to radiation damage (believed to be associated with the induction of a localized but prolonged inflammatory response), which can result in deleterious effects both inside and outside the radiation field.

The second major focus of our research is the spread of cancer from its initial site of growth to other locations in the body (metastasis), which is a major factor influencing the likelihood of successful treatment. The formation of metastasis by tumour cells is thought to be dependent on the expression of specific phenotypes by individual tumour cells. Our research is examining metastatic phenotypes that are expressed only transiently and that may be induced by exposure of tumour cells to conditions, such as hypoxia, which occur in the tumour microenvironment. Recent clinical results have suggested that tumours that contain substantial hypoxic regions may be more likely to form metastases. We have found in animal model systems that exposure to hypoxia, both in vitro and in vivo, can cause transient increases in the metastatic potential of tumour cells and that exposure to transient hypoxic episodes may be particularly important for this increased metastatic potential. We are examining the effect of hypoxic exposure in modifying the expression of genes likely to be associated with the cancer stem cell phenotype, metastasis and tumour progression. Recent studies by our clinical collaborators have identified elevated levels of interstitial fluid pressure, a characteristic of many tumours, as another factor that may affect metastasis. We are developing animal models to investigate the mechanisms responsible for this effect.

To contact Dr. Hill email his assistant Julie Owen.

• Baumann M, Krause M, Hill RP. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer. 8(7):545-54, 2008.

• Bristow RG and Hill RP. DNA repair and genetic instability. Nat Rev Cancer. 8(3):180-92, 2008.

• Kalliomaki TM, McCallum G, Lunt SJ, Wells PG, Hill RP. Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model. BMC Cancer, 8(1):151,2008.

• Subarsky P and Hill RP. Graded hypoxia modulates the invasive potential of HT1080 fibrosarcoma and MDA MB231 carcinoma cells. Clin Exp Metastasis. 25(3):253-64,2008.

• Maseide K, Pintilie M, Kandel R, Hill RP. Can sparsely and heterogeneously expressed proteins be detected using tissue microarrays? A simulation study of the hypoxia marker carbonic anhydrase IX (CA IX) in human soft tissue sarcoma. Pathol Res Pract. 204(3):175-83, 2008.

• Lunt S-J, Kalliomaki TM, Brown A, Yang VX, Milosevic M, Hill RP. Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours. BMC Cancer. 8:2, 2008.

• Iakovlev VV, Pintilie M, Morrison A, Fyles AW, Hill RP, Hedley DW. Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX. Lab Inves.87(12):1206-17, 2007.

• Hill RP, Perris R. ''Destemming'' cancer stem cells. J Natl Cancer Inst. 99(19):1435-40, 2007.

• Zhang L, Hill RP. Hypoxia enhances metastatic efficiency in HT1080 fibrosarcoma cells by increasing cell survival in lungs, not cell adhesion and invasion. Cancer Res. 67(16):7789-97, 2007.

• Hill RP, Kaspler P, Griffin AM, O'Sullivan B, Catton C, Alasti H, Abbas A, Heydarian M, Ferguson P, Wunder JS, Bell RS. Studies of the in vivo radiosensitivity of human skin fibroblasts. Radiother Oncol. Jul;84(1):75-83, 2007.

• Werier J, Ferguson P, Bell R, Hill R, Wunder J, O'Sullivan B, Kandel R. Model of radiation-impaired healing of a deep excisional wound. Wound Repair Regen. 14(4):498-505, 2006.

• Calveley VL, Khan MA, Yeung IWT, VanDyk J and Hill RP. Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation. Int J Radiat Biol 81(12):887-99: 2005.

• Langan AR, Khan MA, Yeung IWT, VanDyk J and Hill RP. The protective effects of Eukarion-189, a superoxide dismutase-catalase mimetic, on volume effects in radiation-induced lung damage. Radiother Oncol 79(2):231-8: 2006.

• Akudugu JM, Bell RS, Catton C, Davis AM, Griffin AM, O'Sullivan B, Waldron JN, Ferguson PC, Wunder JS, Hill RP. Wound healing morbidity in STS patients treated with preoperative radiotherapy in relation to in vitro skin fibroblast radiosensitivity, proliferative capacity and TGR-beta activity. Radiother Oncol. 78:17-26, 2006.

• Milosevic M, Fyles A, Hedley DW, Hill RP. The human tumor microenvironment: Invasive (needle) measurement of oxygen and interstitial fluid pressure (IFP). Seminars in Radiation Oncology 14; 249-258:2004.

The Tumour Microenvironment Group