Biological correlates of FDG uptake in non-small cell lung cancer
Introduction
Lung cancer is the leading cause of cancer related death in both men and women. About 3 million new cases a year are estimated to arise worldwide, of which more than 200 000 are in the European Union. An increase in incidence is to be expected until the first decades of the 21st century [1]. For the average patient with a diagnosis of lung cancer the overall 5-year survival rates have increased from 12% in the early 70s to 15% in 2001 [2]. Survival ranges from 75% for patients with pT1N0 disease to virtually nil for patients with stage IV non-small cell lung cancer (NSCLC) [3]. Surgery with curative intent represents the best chance for cure, but is only an option in patients with stages I, II, and selected cases of stage IIIA (T3N1M0) NSCLC. However, only 30% of NSCLC cases present at these early stages. Even if a complete curative resection can be performed, the majority of patients will relapse. The majority of these relapses occur at distant sites, indicating micrometastatic disease at presentation [4]. Progress is being made due to the introduction of novel treatment programs, like induction chemotherapy [5], concurrent chemo-radiation for stage III disease [6], [7], and more recently, adjuvant chemotherapy for earlier stages [8], [9]. It is of major importance to be able to predict the relapses and to prevent them with these active intensified treatment regimens. The tumor-node-metastasis (TNM) staging system, to date considered the most important tool in estimation of prognosis and guidance of treatment decisions [10], however, provides an incomplete biologic profile of NSCLC, does not always provide a satisfactory explanation for differences in relapse and survival and is thus far from perfect as a prognostic indicator [11], [12]. Each pathological stage consists of a heterogeneous population containing individuals at much higher risk of recurrence and death than others [11], [12], [13]. Therefore, there is a need for noninvasive quantitative measures of biological aggressiveness that could play a role in further characterization of NSCLCs. A better understanding of biological mechanisms in lung tumor cells could be helpful and finally might lead to a better selection of patients who may benefit from (neo)adjuvant therapy. Such noninvasive quantitative measures of biological aggressiveness may be of particular value in stratifying patients for clinical trials.
The introduction of the combined use of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) has had a great impact on the diagnosis and staging of lung cancer. FDG-PET provides noninvasive mediastinal staging and reduces the number of futile thoracotomies and mediastinoscopies [14], [15], [16]. Furthermore, FDG-PET detects unsuspected extrathoracic metastases in 14–16.9% of patients otherwise deemed potentially resectable [17]. The number of clinical applications for FDG-PET in NSCLC continues to increase. Recently, FDG-PET has also demonstrated its value in radiation treatment planning, detection of recurrent disease, in identifying tumor response to chemotherapy at an early phase of treatment and in identifying subsets of patients with poor outcome [18]. One of the great advantages of this technique is that it cannot only visualize but can also quantify FDG uptake to distinguish metabolically highly active from less active tumor tissues and therefore offers an opportunity for noninvasive, in vivo tissue characterization.
The biological basis of FDG-PET is the increased glucose metabolism of malignant cells as compared to noncancerous tissues. After administration of the glucose analog FDG, it will be transported into the tumor cell and will be phosphorylated by hexokinase. The intracellular FDG-6-phosphate is trapped in the malignant cells, as it will not be processed in the glycolytic pathway and can thus be visualized using PET. A variety of mechanisms have been proposed for accelerated glucose use in growing tumors and in transformed and malignant cells: passive diffusion, Na+-dependent glucose transport and via facilitative glucose transporters (GLUT). The latter is considered to be the most important mechanism for enhancing glucose influx into cells [19]. The glucose transporters GLUT-1 and GLUT-3, subtypes with a relatively high affinity for glucose, belong to the sugar transporter family, which currently includes 133 individual members [20]. Increased concentrations of the glucose phosphorylation enzyme, hexokinase, with decreased rates of glucose-6-phophatase are considered to accelerate glucose phosphorylation, which results in enhanced FDG intracellular trapping. Upregulation of hexokinase and glucose transporters, especially GLUT-1, and downregulation of glucose-6-phosphatase are frequently associated with malignant transformation. Glucose transport activity can be regulated by alterations in the expression of GLUT transporters and by post-translational mechanisms, including transporter translocation to plasma membranes [21]. Akhurst et al. recently reported that the use of chemotherapy could alter FDG uptake in tumors by altering the activity of hexokinase [22]. Moreover, the rate of FDG uptake in the primary site of NSCLC has been correlated with tumor doubling time [23] and proliferation rates [24] which, in turn, are known to correlate with tumor aggressiveness [25], [26], [27]. Furthermore, apoptosis plays a central role in the elimination of (the precursors of) tumor cells. Therapy resistance can be attributed, at least in part, to a disabled apoptotic program [28]. Sasaki et al. demonstrated that primary tumors showing high FDG uptake have the potential to be resistant to therapy and to metastasize [29]. It was recently reported that strong expression of the cysteine protease caspase-3, which is a key enzyme in apoptotic cell death, was a significant factor to predict poor prognosis [30]. Better understanding of a possible relationship between FDG uptake and apoptosis may provide insights into sensitivity or resistance of tumor cells. Furthermore, tumors that grow too rapidly or have a deficient vascular system are characterized by the formation of necrosis. Necrosis reflects cell death caused by hypoxia. Hypoxia results in enhanced anaerobic glycolysis and hence in increased FDG uptake [31]. Finally, the presence of inflammatory cells, might be confounding, since inflammatory cells may have a major impact on FDG uptake [32].
At present it is still not fully elucidated which of these factors contribute to the variable levels of FDG uptake in NSCLC. Results from studies on other tumor types cannot be extrapolated to NSCLC, as different tumors have different glucose-regulating mechanisms and enzyme expression patterns in association with various oncogenic alterations [33]. The aim of the present study was to investigate the mechanisms that drive FDG in the primary site of early stage untreated NSCLC. The relationship among FDG uptake and the immunohistochemical expressions of the key glucose membrane transporters, GLUT-1 and GLUT-3; the isoforms of the glycolytic enzyme hexokinase, HK-I, HK-II and HK-III; the cysteine protease, caspase-3, and several histological parameters was evaluated.
Section snippets
Patient eligibility criteria
FDG uptake in early stage NSCLC was measured using PET in 19 patients (18 males, 1 female, mean age 62.4 years, range 38–76 years) who were subsequently treated with curative surgery. Patient characteristics are summarized in Table 1. Exclusion criteria were poorly regulated diabetes mellitus, preoperative chemotherapy or radiotherapy and metachronous lung cancers treated for at least 2 years before the study period. All patients underwent whole body FDG-PET as part of their routine
Results
All tumors accumulated FDG and were well-visualized by PET. The mean SUV of all tumors was 9.6 ± 5.0 (range 3.3–22.8). The diameter of the primary tumors as determined from the resected specimens, ranged from 1.0 to 7.5 cm, with a mean tumor size of 3.3 cm. FDG uptake was significantly higher in squamous cell carcinomas (mean SUV 13.4 ± 4.9, n = 8) compared to adenocarcinomas (7.1 ± 3.3, n = 8, p = 0.007) or large cell carcinomas (5.9 ± 1.9, n = 3, p = 0.02). There was no significant difference in FDG uptake
Discussion
The present study shows that the degree of FDG accumulation in the primary site of early stage NSCLC is mainly determined by tumor histology and the combination of the expression level of the glucose membrane transporters, GLUT-1 and GLUT-3 and tumor cell differentiation. This indicates that sufficient FDG uptake capability (reflected by GLUT-1 and GLUT-3) is relevant for detection of NSCLC by FDG-PET. Mamede et al. [32] and Higashi et al. [35] found a statistically significant correlation
Conclusion
The present study supports the hypothesis that overexpression of GLUT-1 in combination with overexpression of GLUT-3 and tumor cell differentiation determine the extent of FDG accumulation and that squamous cell carcinomas accumulate more FDG than adenocarcinomas or large cell carcinomas.
Acknowledgments
This study was funded with internal resources. The funding source had no involvement in study design and conduct, in the collection, management, analysis, and interpretation of data, in the writing of the report or in the decision to submit the paper for publication. The authors declare that none of them have a conflict of interest.
References (49)
- et al.
Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review
Lancet Oncol
(2004) - et al.
Outcome following lung resections for pT1 non-small cell lung cancer
Eur J Surg Oncol
(2006) Seeking improved outcome in the curative treatment of non-small-cell lung cancer
Lung Cancer
(2005)- et al.
Current perspectives on treatment strategies for locally advanced, unresectable stage III non-small cell lung cancer
Lung Cancer
(2005) Revisions in the international system for staging lung cancer
Chest
(1997)- et al.
Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II, and IIIA
Chest
(2000) - et al.
Stage IB nonsmall cell lung cancers: are they all the same?
Ann Thorac Surg
(2006) - et al.
FDG-PET in staging lung cancer: how does it change the algorithm?
Lung Cancer
(2004) - et al.
Lung tumor growth correlates with glucose metabolism measured by fluoride-18 fluorodeoxyglucose positron emission tomography
Ann Thorac Surg
(1995) - et al.
[18F]FDG uptake and PCNA, Glut-1, and Hexokinase-II expressions in cancers and inflammatory lesions of the lung
Neoplasia
(2005)
Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer
Lung Cancer
Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance
J Hepatol
Preoperative chemotherapy for cStage III-pN0 patients with non-small cell lung cancer
Jpn J Thorac Cardiovasc Surg
Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer
J Clin Oncol
Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer
N Engl J Med
Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer
N Engl J Med
TNM classification for lung cancer
Ann Thorac Cardiovasc Surg
Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial
Lancet
Preoperative staging of non-small-cell lung cancer with positron-emission tomography
N Engl J Med
Relationship between non-small cell lung cancer fluorodeoxyglucose uptake at positron emission tomography and surgical stage with relevance to patient prognosis
Clin Cancer Res
Positron-emission tomography and assessment of cancer therapy
N Engl J Med
Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival
Cancer
Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma
Cancer
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