Relationship between 18F-FDG uptake on positron emission tomography and molecular biology in malignant pleural mesothelioma

https://doi.org/10.1016/j.ejca.2012.01.016Get rights and content

Abstract

Background

The usefulness of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) can help for predicting the therapeutic response and outcome in malignant pleural mesothelioma (MPM). However, no satisfactory biologic explanation exists for this phenomenon. The aim of this study is to investigate the underlying biologic mechanisms of 18F-FDG uptake.

Methods

Twenty-one patients with MPM who underwent 18F-FDG PET before treatment were included in this study. Tumour sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); hexokinase I; vascular endothelial growth factor (VEGF); microvessels (CD34); epidermal growth factor receptor (EGFR); cell proliferation (Ki-67 labelling index); Akt/mTOR signalling pathway (PTEN, p-Akt, p-mTOR and p-S6K); cell cycle control (p53 and pRb); apoptosis marker (bcl-2). We also conducted an in vitro study of 18F-FDG uptake in mesothelioma cell lines.

Results

18F-FDG uptake was significantly correlated with Glut1 (p < 0.0001), HIF-1α (p = 0.006), hexokinase I (p = 0.0002), VEGF (p = 0.0013), CD34 (p = 0.0001), Ki-67(p = 0.0047), mTOR (p = 0.00478) and p53 (p = 0.0004). High uptake of 18F-FDG was significantly associated with poor outcome in MPM. Our in vitro study showed that upregulation of Glut1 and HIF-1α was closely related with 18F-FDG uptake into mesothelioma cell, and mTOR inhibitor induced a decrease in Glut1 expression and 18F-FDG uptake.

Conclusion

The amount of 18F-FDG uptake in MPM is determined by the presence of glucose metabolism, phosphorylation of glucose, hypoxia, angiogenesis, cell proliferation (Ki-67), cell cycle regulator, and mTOR signalling pathway.

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.

Section snippets

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.

References (38)

  • A. Klabatsa et al.

    Expression and prognostic significance of hypoxia-inducible 1α (HIF-1α) in malignant pleural mesothelioma (MPM)

    Lung Cancer

    (2006)
  • M.A. Hoda et al.

    Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo

    J Thorac Oncology

    (2011)
  • F. Benard et al.

    Prognostic value of FDG PET imaging in malignant pleural mesothelioma

    J Nucl Med

    (1999)
  • G.L. Ceresoli et al.

    Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose

    J Clin Oncol

    (2008)
  • A. Carretta et al.

    18-F FDG positron emission tomography in the evaluation of malignant pleural diseases: a pilot study

    Eur J Cardiothorac Surg

    (2000)
  • K. Higashi et al.

    Correlation of Glut-1 glucose transporter expression with [18F] FDG uptake in non-small cell lung cancer

    Eur J Nucl Med

    (2000)
  • J.H. Chung et al.

    Over expression of Glut 1 in lymphoid follicles correlates with false-positive 18F-FDG PET results in lung cancer staging

    J Nucl Med

    (2004)
  • M.M. Vleugel et al.

    Differential prognostic impact of hypoxia induced and diffuse HIF-1 alpha expression in invasive breast cancer

    J Clin Pathol

    (2005)
  • D.A. Elson et al.

    Coordinate up-regulation of hypoxia inducible factor (HIF)-1a and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing 1

    Cancer Res

    (2000)
  • Cited by (47)

    • Histology of the pleural rind at [<sup>18</sup>F]FDG PET/CT hot and cold spots in mesothelioma patients after talc pleurodesis and neoadjuvant chemotherapy

      2021, Pathology Research and Practice
      Citation Excerpt :

      The PM pleural rind is histologically a complex tissue and cell biological fundamentals for high SUVmax or enhanced glucose uptake, respectively, are scarce. In chemo-naïve patients, the amount of [18F]FDG uptake in PM was determined by the presence of various pathways, including glucose metabolism and phosphorylation, hypoxia, angiogenesis, cell proliferation, cell cycle regulation and mTOR signaling [9]. Few data are available on the value of [18F]FDG PET/CT after talc pleurodesis and neo-adjuvant chemotherapy (NAC) prior to surgery.

    • The correlation between FDG uptake and biological molecular markers in pancreatic cancer patients

      2016, European Journal of Radiology
      Citation Excerpt :

      Our data suggest that FDG uptake in pancreatic cancer may not be determined by mTOR and S6. However, the FDG uptake in lung cancer and that in malignant pleural mesothelioma has been reported to correlate with mTOR [4,8]. Further studies are needed to clarify the relationship between FDG uptake and the mTOR signal pathway.

    View all citing articles on Scopus
    View full text