Rationale
Tumor hypoxia is a well-characterized component of the solid tumor microenvironment and it has profound consequences on tumor growth characteristics and response to therapy. Hypoxic tumors are more resistant to radiotherapy and chemotherapy and patients with more hypoxic solid tumors fare worse compared to patients with better oxygenated tumors, irrespective of therapeutic modality (i.e., radiotherapy, chemotherapy or surgery) [1, 2]. At the cellular/molecular level, hypoxia promotes selection and clonal expansion of cells with mutated p53 pathways [3], increases metastatic potential [4, 5] and promotes genomic instability [6, 7]. These clinical and laboratory findings strongly suggest that hypoxia selects for a more aggressive tumor phenotype [7].
These detrimental effects of hypoxia have stimulated efforts to develop more accurate and tractable ways to image and quantify tumor hypoxia in human patients, but also to target tumor hypoxia (e.g., with hypoxic cell sensitizers) [8]. Such methods will ultimately enable clinicians to tailor specific antitumor therapies to the degree and localization of hypoxia tumor areas to produce a more favorable outcome [9]. Equally important, since tumor oxygenation inversely correlates with patient outcome (often irrespective of treatment modality), knowledge of the extent of tumor hypoxia in solid tumor patients will be a valuable tool in helping the oncologist to determine the best possible therapeutic approach. During the last few years, several hypoxia molecular “markers” have been identified and are currently being investigated as correlates of tumor hypoxia, but with mixed results [10, 11]. The lack of availability of reliable hypoxia markers seems to stem from (a) the great intra- and inter-tumoral heterogeneity of hypoxia, (b) the regulation of the expression of such genes by factors other than hypoxia (e.g., oncogenes) and (c) the disparity in hypoxic gene regulation in vitro vs. in vivo [9, 12]....