Abstract
Purpose: Monocarboxylate transporter 4 (MCT4) can influence the amount of lactate in the tumor microenvironment and further control cancer cell proliferation, migration, and angiogenesis. We investigated for the first time the expression of MCT4 in circulating tumor cells (CTCs) derived from early stage Non-Small Cell Lung Cancer patients (NSCLC) and whether this is associated with clinical outcome.Experimental Design: A highly sensitive RT-qPCR assay for quantification of MCT4 transcripts was developed and validated and applied to study MCT4 expression in CTC isolated through the Parsortix size-dependent microfluidic device from 53 and 9 peripheral blood (PB) samples of NSCLC patients at baseline (pre-surgery) and at relapse, respectively, as well as the “background noise” was evaluated using peripheral blood samples from 10 healthy donors (HD) in exactly the same way as patients.Results: MCT4 was differentially expressed between HD and NSCLC patients. Overexpression of MCT4 was detected in 14/53 (26.4%) and 3/9 (33.3%) patients at baseline and at progression disease (PD), respectively. The expression levels of MCT4 was found to increase in CTCs at the time of relapse. Kaplan-Meier analysis showed that the overexpression of MCT4 was significantly (P = 0.045) associated with progression-free survival (median: 12.5 months, range 5–31 months).Conclusion: MCT4 overexpression was observed at a high frequency in CTCs from early NSCLC patients supporting its role in metastatic process. MCT4 investigated as clinically relevant tumor biomarker characterizing tumor aggressiveness and its potential value as target for cancer therapy. We are totally convinced that MCT4 overexpression in CTCs merits further evaluation as a non-invasive circulating tumor biomarker in a large and well-defined cohort of patients with NSCLC.
Highlights
Lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer death globally
Clinical samples were collected from 32 men and 21 women and all patients were diagnosed with operable Non-Small Cell Lung Cancer (NSCLC). 23 patients were diagnosed with adenocarcinoma (ADC), 26 with Squamous Cell Carcinoma (SCC) and 4 with undifferentiated (NOS) NSCLC
We evaluated for the first time MCT4 expression in Circulating Tumor Cells (CTCs) fractions isolated by a size- based EpCAM independent technology (Parsortix) from early stage NSCLC patients using a highly sensitive and specific room temperature (RT)-qPCR
Summary
Lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer death globally. Non-Small Cell Lung Cancer (NSCLC) is the common histological subtype of the disease, accounting for 85% of all lung cancer diagnoses (Molina et al, 2008). Almost 45% of patients with operable early stage NSCLC relapse within the first 18 months and the probability of patients’ survival depends on the possibility of early detection of relapse (Siegel et al, 2015). The use of therapeutic modalities against the Minimal Residual Disease (MRD) and before the development of clinically detectable metastatic lesions seems to be emerged as an important advancement in the management of early stage NSCLC. The FDA has approved the use of ctDNA for the response prediction and monitoring development resistance to EGFR TKI therapy in NSCLC patients (Wang et al, 2017; Zhang et al, 2017)
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