OverviewThe Hypoxic Tumour Microenvironment, Patient Selection and Hypoxia-modifying Treatments
Introduction
The response to cancer treatment is largely influenced by the tumour microenvironment. One of the most important factors playing a crucial role in this process is the existence of hypoxia in solid tumours. It has been shown to decrease the therapeutic efficacy of radiation treatment, surgery and some forms of chemotherapy. In 1955 it was first recognised that human tumours contain regions of hypoxic cells and that the radiocurability of these tumours was limited by hypoxia [1]. With the introduction in the late 1980s of a computerised polarographic needle electrode system, it became possible to measure tumour oxygenation status [2]. It enabled the rapid identification and characterisation of tumour hypoxia and the assessment of its clinical relevance. Hypoxia was found to be a characteristic feature in about 50% of all locally advanced solid tumours, irrespective of their size and histology [3]. Furthermore, clinical studies in carcinomas of the uterine cervix 4, 5 and head and neck 6, 7 showed a correlation between hypoxia and a poor response to radiotherapy. Hypoxic tumours may also be less responsive to chemotherapeutic agents. This has been shown in vitro and in vivo in a variety of tumours 8, 9, 10. Oxygen deprivation induces changes in a variety of cellular processes, such as apoptosis, proliferation and repair, leading to treatment resistance [11].
The causes of hypoxia are multifactorial and include abnormal and chaotic tumour vasculature, impaired blood perfusion, rate of oxygen consumption and anaemia [3]. Severe tumour hypoxia ultimately leads to tissue necrosis, but non-lethal levels of hypoxia may have a strong effect on tumour cell biology. It elicits multiple cellular response pathways that alter gene expression and lead to proteomic changes. These effects, in turn, are capable of promoting increased metastasis, angiogenesis and the selection of cells with diminished apoptotic potential, leading to a worse outcome. Hypoxia may thus provide an overall positive advantage for malignant growth 12, 13.
Several therapeutic approaches have been developed to overcome hypoxia, some being successful and others not. The main focus has been on either eliminating hypoxia by breathing a high oxygen gas mixture such as carbogen [14] and the use of hyperbaric oxygen [15] or by sensitising hypoxic cells to radiation with hypoxic cell sensitisers [16]. Newer approaches, such as gene therapy or the inhibition of response pathways, are currently under investigation. For these treatments to be successful it is important to develop predictive assays reflecting the biological heterogeneity of individual tumours, thereby providing a tool to optimise and better select patients for those treatment strategies. This review summarises the approaches that have been undertaken to counteract tumour hypoxia and highlights the importance of understanding hypoxic response pathways.
Section snippets
Pathophysiology of Tumour Hypoxia
The presence of hypoxic regions is a characteristic pathophysiological property of many solid tumours and has been found in a wide range of human malignancies. It arises as a result of an imbalance between the supply and consumption of oxygen 17, 18, 19. Several major pathogenetic mechanisms are involved, such as abnormal tumour vasculature, limited tissue perfusion and tumour-associated or therapy-associated anaemia leading to a reduced oxygen transport capacity of the blood 3, 17.
Tumour
Hypoxia Modification in Radiotherapy
With the evidence that tumour hypoxia is a characteristic feature and of prognostic significance in patients with carcinoma of the head and neck and the uterine cervix, several treatment modifications have been tested in the clinic. Although a number of trials did not show any benefit, an overview analysis clearly showed that the modification of tumour hypoxia significantly improved radiotherapy outcome, especially in head and neck carcinomas [39]. However, despite these positive data, hypoxic
Patient Selection
Treatment strategies have been developed to counteract tumour resistance mechanisms, although usually at the cost of increased short- and long-term side-effects. To maximise the probability that patients benefit from treatments especially designed to modify tumour hypoxia and to provide the best attainable quality of life for individual patients, it is of great importance to develop tools allowing better selection of patients before treatment. It is known from experimental and human studies
Measurement of Tumour Hypoxia
The observations that linked the existence of hypoxia with a more malignant tumour behaviour have elicited numerous studies to establish the prognostic significance of hypoxia for treatment outcome. The ultimate aim of these studies was to provide a good basis for treatment selection dependent on tumour oxygenation. Therefore, the ability to determine the degree and extent of hypoxia in solid tumours is not only important prognostically but also in the selection of patients for
Conclusion
Tumour hypoxia has, for many years, been the subject of investigation, as it plays a critical role in treatment resistance. Successful approaches have been developed to counteract tumour hypoxia, although most of these treatments are accompanied by an increase in side-effects. Thus far, not one treatment targeting tumour hypoxia is widely accepted in clinical practice, but several phase III trials are currently investigating new strategies. For these treatments to be successful it is important
Acknowledgement
This study was supported by grant KUN 2003-2899 of the Dutch Cancer Society.
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