Targeting hypoxic tumour cells to overcome metastasis

The cellular environment within solid tumours is increasingly being appreciated as an important limitation to current cancer therapy. The vasculature within most solid tumours consists of abnormally formed, poorly functional blood vessels that are incapable of delivering sufficient oxygen and nutrients to properly support the growing tumour mass [1]. Available oxygen is consumed by rapidly proliferating tumour cells located within 70 to 150 μm of tumour vasculature, thereby limiting the amount of oxygen that is available to diffuse further into the tumour tissue. Thus, a proportion of cells in most tumours (ranging from < 1% to > 50%) are exposed to relatively low oxygen tensions (pO2 < 10 mmHg, equivalent to < 1.3% O2 in vitro). While reduced oxygen tensions can be lethal for some cells, many tumour cells are able to survive under poorly oxygenated (hypoxic) conditions. It is well-established that hypoxic tumour cells are resistant to radiation therapy, but the clinical impact of hypoxic tumour cells extends beyond the treatment of localized primary tumours with ionizing radiation. Hypoxic tumour cells promote tumour progression and metastasis through a variety of direct and indirect mechanisms, and hypoxic tumour cells, therefore, represent a significant impediment to successful cancer therapy.Patient survival rates are closely associated with the development of distant metastatic disease [2-4], with an estimated 90% of cancer-related deaths being attributed to the metastatic spread of cancer [5,6]. Patients with primary tumours that contain high proportions of hypoxic cells have decreased disease-free and overall survival rates after surgical resection of the primary tumour [7,8]. The decreased survival is due to the development of metastatic disease, suggesting that (undetected) disseminated tumour cells were present in the patient at the time of surgery. The strong association between the development of metastatic disease and the proportion of hypoxic cells in