Review articleTumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers
Introduction
The tumor microenvironment plays a critical role in malignant tumor progression and treatment resistance. Microenvironmental parameters that have shown to be relevant for treatment outcome include tumor cell hypoxia and proliferation. Now treatment modifications and biological modifiers are becoming available that specifically target these individual compartments of the tumor microenvironment. Understanding the complexity and the dynamics of the microenvironment will allow better attuning of these different modalities and can provide tools for better selection of patients.
The introduction of new methods for qualitative and quantitative assessment of functional microenvironmental elements of tumors including vasculature, oxygenation and proliferation may allow selection of patients for the new treatment modalities by pre-treatment testing. A number of these tests have already demonstrated clinical relevance as prognostic indicators for survival and/or local and regional tumor control. The various aspects of tumor biology are often studied in isolation. However, the tumor, together with its microenvironment composes a dynamic system with complex structural and functional interactions. These interactions govern tumor growth and tumor aggressiveness and have great influence on the effect of radiotherapy and other cancer treatments. Co-registration of these elements at the micro-regional level and understanding the dynamics of the microenvironment may therefore provide important complementary information relevant for treatment strategy and design.
This article will give an overview of the currently available literature concerning the analysis of microenvironmental tumor parameters such as vasculature, hypoxia and proliferation. The main focus will be on endogenous and exogenous markers of tumor hypoxia and their role in patient selection based on treatment outcome. In radiation oncology the expected overall survival is an important parameter for treatment selection. However, local and regional tumor control is the most important parameter for the assessment of the efficacy of radiotherapy itself. Several of these aspects will be illustrated with results mainly originating from head and neck trials because in these tumors the negative effects of tumor cell proliferation and tumor cell hypoxia are shown most clearly.
Section snippets
Tumor vasculature
The vasculature can differ considerably among tumors of the same localization, histology, or even differentiation [8], [88], [146], [161]. The vascular bed is the feeding system of the tumor, supplying nutrients and oxygen. At the same time it provides a route for tumor cells to escape the primary tumor mass and metastasize. It is therefore not surprising that characteristics of the vascular architecture have attracted attention as putative markers of tumor progression but also as surrogate
Hypoxia: increased resistance to treatment
Hypoxic cells are more resistant to treatment than well-oxygenated cells. This is illustrated in head and neck cancer and in cancer of the uterine cervix where a correlation was found between tumor hypoxia and local control and survival after radiotherapy [15], [44], [58], [93]. It has been suggested that the abundance of cells at intermediate hypoxia, i.e. pO2 0.5–20 mmHg, causes the resistance of tumors to radiotherapy [155]. Others suggested that mainly acute hypoxia is the underlying cause
Exogenous and endogenous hypoxia markers
Exogenous hypoxia markers are drugs, chemicals or even bacteria that, after administration, specifically accumulate or are bio-reducible under hypoxic conditions. Endogenous hypoxia markers are genes or gene products that are specifically upregulated under hypoxic conditions. A registration of the distribution of hypoxia at the microregional level is obtained by immunohistochemical detection of exogenous and endogenous hypoxia markers. Endogenous hypoxia markers are mainly studied in
Dynamics of hypoxic cells
The tumor microenvironment is constantly changing due to tumor growth and temporal and spatial variations in blood supply. This is reflected by temporal and regional changes in hypoxia, apoptosis and proliferation rate within a tumor.
During pO2 measurements with polarographic needles, small amounts of oxygen are consumed excluding the possibility to measure continuously at the same position in a tumor [29]. The advantage of time-resolved luminescence pO2 measurements with the OxyLite system is
Proliferation and proliferative organization
The importance of proliferation for treatment outcome is clearly illustrated by the decrease in local control when radiation treatment periods are longer than 4–5 weeks [154]. The most likely mechanism is an increase in the effective net production of clonogenic tumor cells during treatment [154]. Attempts to use proliferation markers as indicators of treatment outcome have not been very successful thus far. Most studies rely on endogenous markers for proliferation such as Ki-67, proliferating
Conclusion
A number of functional microregional parameters, such as endogenous and exogenous markers of tumor hypoxia, have emerged that are good candidates for future use as indicators of tumor aggressiveness and treatment response. The key question to be addressed is whether integrated microregional marker profiles can be used as tools for selection of treatment strategies for individual patients. This requires testing of these markers in prospective randomized clinical trials comparing standard
Acknowledgments
We thank J.P.W. Peters for preparation of the photomicrographs. Supported by the Dutch Cancer Society.
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