Metabolic Signatures of Lung Cancer in Biofluids: NMR-Based Metabonomics of Blood Plasma

Abstract

Lung cancer is one of the most prevalent and fatal types of cancer, with average 5-year survival rates lower than 15%, 1,2 which is mainly due to the advanced stage at which lung tumors are usually diagnosed. Indeed, when lung cancer is detected before metastasizing to lymph nodes or distant sites, the 5-year survival rates increase drastically to 60À80%, thus stressing the importance of early diagnosis. However, the majority of patients show no signs or symptoms during the initial phases of neoplastic growth, hindering early detection and the possibility of curative surgical treatment. Moreover, radiological tests, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), which would allow the detection of initial cancer lesions, are not suitable for general screening of the population, mainly due to their high costs. Therefore, new methods that can aid in the early detection of lung cancer and contribute to improved prognosis are greatly needed.The search for metabolic markers of cancer in human tissues and biofluids has been the focus of a number of metabonomic studies in recent years. 3,4 In particular, metabolic profiling of blood plasma or serum has been increasingly used to unveil metabolic alterations associated with different cancer types, such as breast, 5À7 kidney, 8À10 liver, 11À13 prostate, 14À16 colorectal, 17À20 oral, 21,22 pancreatic, 23,24 esophageal, 25 and bone 26 cancers. In the case of lung cancer, only a few studies focusing on plasma or serum metabolic profiling have been recently reported. Maeda and co-workers proposed that the differences in the plasma amino acid profiles between healthy controls and non-small-cell lung cancer (NSCLC) patients, as assessed by targeted liquid chromatography coupled to mass spectrometry (LCÀMS), could potentially be useful for screening NSCLC. 27 In another MS study of specific compounds, namely, lysophosphatidylcholines (lysoPC), abnormal levels of lysoPC isomers with different fatty acyl positions were found in the plasma of lung cancer patients compared to controls. 28 Using a more global profiling approach, Jordan and colleagues reported the NMR analysis of paired tissue and serum samples from 14 subjects with two different lung cancer histological types (adenocarcinoma and squamous cell

1H NMR metabolic profiling of human serum associated with benign and malignant gallstone diseases

“…Significant difference was observed for LDL/VLDL signals in GBC samples as compared to control; LDL/VLDL was depleted in GBC samples. These results are consistent with the earlier published reports on various other studies on cancers (Garcia et al 2011;Rocha et al 2011). Cholesterol and cholesterol precursor molecules are required during cell division as the constituent of cell membrane and a regulated synthetic pathway of cholesterol synthesis is present.…”

Metabolomics provide new insights on lung cancer staging and discrimination from chronic obstructive pulmonary disease

“…Interestingly, in our study reduced levels of acetate, citrate, and methanol were observed in NSCLC patients compared with COPD patients. Rocha et al reported similar results for lung cancer patients compared with healthy controls [19]. Using 13 C stable isotope-resolved metabolomic experiments in human lung cancer tissues, increased citrate levels were observed in tumors compared with healthy tissues, suggesting that the Krebs cycle is more active in tumor tissues [58].…”

“…These studies indicate that lung cancer patients exhibit perturbed metabolism of amino acids, lipids, fatty acids, glycol, and steroids [44]. The authors of a study using NMR spectroscopy of human blood plasma to detect early lung cancer stages (mainly stages I and II) reported decreased concentrations of glucose, citrate, formate, acetate, alanine, glutamine, histidine, tyrosine, valine, and methanol and elevated levels of lactate and pyruvate [19]. In addition to metabolic profiling, studies that exclusively focus on amino acid profiles using Aminoindex technology are available in the literature [45].…”

“…Therefore, metabolomic-based studies have been extensively used for disease recognition, prognosis, predicting response to treatment and recovery monitoring. Recently, numerous COPD and lung cancer studies have revealed the great potential of metabolomic-based approaches in disease diagnostics and stratification [19][20][21][22][23][24][25]. Moreover this molecular technique, based on laboratory analysis of small blood sample, is minimally invasive for patient.…”

Polyphenols as mitochondria-targeted anticancer drugs

“…Succinate dehydrogenase links the TCA cycle and oxidative phosphorylation; its deficiency causes the development of highly metastatic extra-adrenal tumors (pheochromocytomas and paragangliomas) [68]. Suppression of the TCA cycle is recognized as one of the hallmarks of cancer [69] and its impairment is implicated as critical in the mechanism of, among others, colorectal tumorigenesis [70].…”