Role of Hypoxia in Solid Tumour Progression & Metastasis
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 our laboratory focuses on understanding how these factors influence tumour and normal tissue response to radiation treatment in individual patients. Our current work involves:
1) Examination of hypoxia and high interstitial fluid pressure (IFP) in animal models of human tumours with a focus on cancer of the cervix. In these studies we are collaborating with the clinical groups at the Princess Margaret Hospital in examining methods to exploit these factors to predict and improve treatment outcome.
2) Studies of the radiosensitivity of normal dermal fibroblasts in vivo. These studies are focusing on measuring DNA damage as a biological dosimeter for potential use in individuals who have been accidentally exposed to irradiation.
3) Examination of the sensitivity of lung tissue to different volumes of irradiation. These studies in rat and mouse lung are investigating mechanisms associated with the response of the lung to radiation damage and drugs that may be useful to mitigate the long term effects of this damage on lung function, when applied after the radiation exposure.
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 exposure to intermittent hypoxia in modifying the expression of genes likely to be associated with metastasis and tumour progression in xenograft models of human cervix carcinoma and pancreatic cancer. We are also initiating studies to examine the role of hypoxia in modifying or maintaining the aggressive phenotype of tumour stem cells.
- Para AE, Bezjak A, Yeung IW, Van Dyk J, Hill RP. Effects of genistein following fractionated lung irradiation in mice. Radiother Oncol. 2009 May 9. [Epub ahead of print]
- Hill RP, Marie-Egyptienne DT, Hedley DW. Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol. 2009 Apr;19(2):106-11.
- Lunt SJ, Chaudary N, Hill RP. The tumor microenvironment and metastatic disease. Clin Exp Metastasis. 2009;26(1):19-34.
- Kalliomäki 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. 2008 May 28;8:151.
- Subarsky P, Hill RP. Graded hypoxia modulates the invasive potential of HT1080 fibrosarcoma and MDA MB231 carcinoma cells. Clin Exp Metastasis. 2008;25(3):253-64.
- 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. 2007 Jul;84(1):75-83.