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

Our plain-English summary of Relationship between 18F-FDG uptake on positron emission tomography and molecular biology in malignant pleural mesothelioma, by K. Kaira, M. Serizawa, Y. Koh, et al (European Journal of Cancer, 2012).

The study

• Authors: K. Kaira, M. Serizawa, Y. Koh, T. Takahashi, H. Hanaoka, N. Oriuchi, M. Endo, H. Kondo, T. Nakajima, N. Yamamoto
• Journal: European Journal of Cancer
• Published: 2012;48(8):1244-54
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The usefulness of 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-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 (18)F-FDG uptake.

Methods: Twenty-one patients with MPM who underwent (18)F-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 (18)F-FDG uptake in mesothelioma cell lines.

Results: (18)F-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 (18)F-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 (18)F-FDG uptake into mesothelioma cell, and mTOR inhibitor induced a decrease in Glut1 expression and (18)F-FDG uptake.

Conclusion: The amount of (18)F-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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

In plain English

This study, from the Shizuoka Cancer Center in Japan, asked why malignant pleural mesothelioma tumours take up different amounts of a radioactive sugar tracer (18F-FDG) on PET scans. It did not examine asbestos exposure. The authors studied 21 patients scanned between August 2003 and May 2009. They stained the patients' tumour tissue for markers of glucose handling, low oxygen, blood-vessel growth, cell growth and cell signalling. They also tested three mesothelioma cell lines in the laboratory. Tracer uptake was significantly correlated with Glut1, HIF-1a, hexokinase I, VEGF, CD34, Ki-67, p-mTOR and p53. Patients with high uptake had a median survival of 15.3 months, compared with 31.2 months for those with low uptake (p = 0.0048). High uptake was also more common in stage III to IV disease. In the cell lines, drugs blocking glucose transport or HIF-1a lowered tracer uptake. An mTOR inhibitor lowered uptake in two of the three lines. The authors concluded that glucose metabolism, hypoxia, blood-vessel growth, cell proliferation, cell-cycle control and mTOR signalling play a role in tracer uptake. They noted that their sample was small.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of PET scans and tumour tissue staining (immunohistochemistry) in patients, combined with laboratory experiments on mesothelioma cell lines
• Who was studied: 21 patients with malignant pleural mesothelioma who had 18F-FDG PET before treatment, between August 2003 and May 2009 (25 consecutive patients, 4 excluded because no tissue was available). Median age 66 years (range 19 to 79); 18 men and 3 women; 16 epithelial, 2 biphasic, 1 sarcomatous and 2 desmoplastic type. Also three mesothelioma cell lines: MSTO-211H, NCI-H28 and NCI-H2052.
• Exposure: Asbestos exposure was not studied. The study measured 18F-FDG uptake on PET (the ratio of tumour peak uptake to mediastinum mean uptake, called the T/M ratio, and SUVmax) against tumour tissue markers. In the cell lines, it tested glucose transporter inhibitors, a HIF-1a inhibitor (YC-1), a HIF-1a inducer (cobaltous chloride) and mTOR inhibitors (Ku-0063794 and temsirolimus).
• Main results:
  • Across all 21 patients, the median T/M ratio was 4.23 (range 0.95 to 9.43). A high T/M ratio was significantly more common in stage III to IV than in stage I to II disease (p = 0.0075).
  • Median survival for all patients was 21.0 months, and the 2-year survival rate was 39.2%.
  • Median survival was 31.2 months for patients with a low T/M ratio (4.23 or below) and 15.3 months for those with a high T/M ratio (above 4.23), p = 0.0048.
  • Using SUVmax instead (median 5.20 as the cutoff), median survival was 17.4 months for patients with high SUVmax versus 27.2 months for those with low SUVmax (p = 0.027).
  • By Spearman rank correlation, the T/M ratio was significantly correlated with: Glut1 (0.7765, p less than 0.0001); HIF-1a (0.5789, p = 0.0060); hexokinase I (0.7176, p = 0.0002); VEGF (0.6554, p = 0.0013); CD34 (0.7380, p = 0.0001); Ki-67 (0.5920, p = 0.0047); p-mTOR (0.4366, 95% confidence interval -0.0076 to 0.7370, p = 0.0478); and p53 (0.7032, p = 0.0004).
  • The T/M ratio was not significantly correlated with Glut3, EGFR, PTEN, p-Akt, pS6K, bcl-2 or Rb. There was also no significant difference in mean T/M ratio between epithelial type (3.93) and non-epithelial type (4.94) tumours (p = 0.4008).
  • In the cell lines, 18F-FDG uptake was significantly lower after treatment with Glut1 inhibitors or the HIF-1a inhibitor than in untreated controls. The HIF-1a inducer cobaltous chloride increased uptake.
  • The mTOR inhibitor Ku-0063794 significantly decreased 18F-FDG uptake in MSTO-211H and NCI-H2052 cells. No change was seen in NCI-H28 cells, which carry a VHL gene mutation.
• The authors' conclusion: The authors concluded that glucose metabolism, hypoxia, angiogenesis, cell proliferation, cell cycle control and the mTOR signalling pathway play an important role in 18F-FDG uptake in malignant mesothelioma cells. They also suggested, based on their laboratory data, that mTOR inhibition is a promising therapeutic option.
• Limitations the authors state:
  • The sample size was small; the authors said a larger, multicentre study is needed.
  • None of the 21 patients was treated with an mTOR inhibitor, so there are no clinical data linking 18F-FDG uptake and mTOR inhibition in patients.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunohistochemistry, GLUT1, Hypoxia, CD34, EGFR, Ki-67, Apoptosis.

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