Relationship between 18F-FDG uptake on positron emission tomography and molecular biology in malignant pleural mesothelioma
Introduction
Malignant pleural mesothelioma (MPM) is an aggressive tumour with a poor prognosis and an increasing incidence in many countries. Recently, the usefulness of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) for the diagnosis of MPM has been investigated in some studies.1, 2, 3, 4 18F-FDG PET has proved useful in detecting malignant pleural lesions5 and assessing treatment efficacy in MPM.4 Moreover, 18F-FDG PET is also described to help predicting the prognosis of MPM.6 However, there is still no data about the possible mechanisms for 18F-FDG uptake in MPM.
Determination of malignant lesions with 18F-FDG PET is based on the glucose metabolism.7, 8 The overexpression of glucose transporter 1 (Glut1) has been shown to be closely related to 18F-FDG uptake in human cancer.7, 8 Glut 1 is thought to be a possible intrinsic marker of hypoxia, and the expression of Glut 1 has been found to be regulated by hypoxia in a hypoxia inducible factor (HIF)-1-dependent way.9, 10 Previous studies suggest that hypoxic conditions correspond to a higher 18F-FDG uptake.11, 12 In addition, several researchers described the relationship between 18F-FDG uptake and the expression of vascular endothelial growth factor (VEGF) or micro-vessel density (MVD).13, 14 HIF-1α is considered to support tumour growth by the induction of angiogenesis via the expression of the VEGF and also by high and anaerobic metabolic mechanisms.15 Recent preliminary report demonstrated that 18F-FDG PET could be a valuable tool for assessing the effects of the mammalian target of rapamycin (mTOR) inhibition in lung cancer patients.16 mTOR is a downstream component of the PI3K/AKT pathway involved in the regulation of cell proliferation, angiogenesis, and metabolism. However, there is no report about the relationship between 18F-FDG uptake within tumour cells and PI3K/AKT/mTOR signalling pathway in human neoplasms. As many factors can influence the extent of 18F-FDG uptake, the underlying mechanisms for 18F-FDG accumulation are still a matter of debate in various human neoplasms. Defining a correlation between these biomarkers and 18F-FDG uptake may lead to a better understanding and interpretation of 18F-FDG PET scanning in MPM. Moreover, the molecular biology including epidermal growth factor receptor (EGFR), cell cycle control (p53 and Rb) and apoptosis (bcl-2), has been described to play an important role in the pathogenesis of MPM.17 We conducted 18F-FDG PET studies and immunohistochemical analyses in patients with MPM. In vitro studies were also performed to investigate the possible mechanisms of 18F-FDG uptake.
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Patients
Between August 2003 and May 2009, 25 consecutive patients with MPM who underwent 18F-FDG PET were analysed in this study. Of these patients, four patients were excluded for further studies because the tissue specimen was not available. Thus, a total of 21 patients were analysed in the study. The study protocol was approved by the institutional review board.
The median age of the patients was 66 years (range, 19–79 years). Eighteen patients were men and three were women. Eleven of the 21 patients
18F-FDG PET findings and survival analysis
The median value of T/M ratio was 4.23 (range, 0.95–9.43). A median value of 4.23 was used as the cutoff T/M ratio in the following analyses, and the T/M ratio in more than 4.23 was defined as high expression. The incidence of patients with a high T/M ratio was significantly higher in stage III–IV than stage I–II (p = 0.0075). The mean of T/M ratio demonstrated no significant difference between patients with a histology of epithelial type (3.93 ± 0.52) and those with non-epithelial type (4.94 ± 1.33)
Discussion
This is the first study to evaluate the biological correlation of 18F-FDG uptake on PET in MPM. There was a statistically significant relationship between 18F-FDG activity and the expression of Glut1, HIF-1α, hexokinase I, VEGF, CD34, Ki-67, mTOR and p53. 18F-FDG uptake is useful for predicting disease staging and poor outcome in MPM. In vitro study with malignant mesothelioma cell lines demonstrated that the uptake of 18F-FDG was markedly decreased by the inhibition of Glut1 or HIF-1α, whereas
Conflict of interest statement
None declared.
Acknowledgements
This work was supported in part by Grant 21790793 (K.K) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and National Hospital Organisation Policy Based Medical Services. We thank Mrs. Akane Naruoka for her technical assistance of in vitro analysis and all staffs of pathology department in Shizuoka Cancer Center for their technical assistance of immunohistochemical analysis.
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