A common feature of solid tumours is a reduced oxygen supply, known as hypoxia, which occurs due to an inadequate tumour blood supply. Hypoxia encourages tumour growth and low oxygen levels within tumour tissue predict for poor patient survival. One way in which hypoxia encourages tumour growth is to increase the level of genes and proteins important for the survival of tumour cells in an oxygen-deficient environment. To do this hypoxia first increases the level of the protein Hypoxia-Inducible Factor which comes in 2 forms, HIF-1 and HIF-2. HIF then co-ordinates other proteins involved in processes such as new blood vessel formation, nutrient acquisition, cell survival and cell growth. The presence of HIF in tumours also predicts for poor patient survival.

Despite considerable evidence for the cancer-promoting functions of hypoxia and HIF in other solid tumours, little is known about their effect in primary bone sarcomas. Ewing's sarcoma is a highly aggressive tumour most common in childhood or adolescence. The presence of areas of hypoxia in primary Ewing's tumours, where HIF-1 is also present, has recently been associated with poor clinical outcome. Osteosarcoma is the most common malignant bone tumour in adolescents and young adults. The presence of HIF-1 in osteosarcoma has also been associated with poor prognosis. This suggests that hypoxia and HIF might contribute to the development of these primary bone tumours.

Experimental evidence for this is largely limited to the observation that Ewing's sarcoma (ES) and osteosarcoma (OS) cells increase levels of HIF-1 when exposed to hypoxia. We plan to study levels of both HIF-1 and HIF-2 in ES and OS cells in culture and also in tumour samples. We will then identify which form of HIF is the main regulator of other pro-tumourigenic proteins in each cell type.

We will then look in more detail at the cell functions affected by hypoxia and HIF. ES cells are resistant to hypoxia-induced cell death, but sensitive to death induced by glucose-deprivation. HIF-1 plays a role in both situations, although effects of HIF-2 have not been studied. We will investigate effects of HIF-1 and HIF-2 on cell death and cell growth due to hypoxia and glucose-deprivation in both ES and OS cells. Secondly, we will assess whether the ability of ES to form pseudo blood-vessels is affected by hypoxia. Endothelial cells, the cells normally responsible for blood vessel formation, migrate and form blood vessel-like ‘tubes’ in culture in response to hypoxia. We will investigate effects of hypoxia, HIF-1 and HIF-2 on these functions in ES cells.

Given the wealth of data describing critical functions for hypoxia and HIF in breast cancer and other tumour types, it is important to identify the role of hypoxia-regulated pathways in primary bone sarcomas. Many of these hypoxia-regulated genes and pathways are potential targets for the development of novel anticancer therapies.

Professor Nicholas Athanasou and Dr Helen Knowles, University of Oxford