Newly Identified Biomarkers for Detecting Circulating Tumor Cells in Lung Adenocarcinoma

Abstract

Circulating tumor cells (CTCs) have been implicated in cancer prognosis and follow up. Detection of CTCs was considered significant in cancer evaluation. However, due to the heterogeneity and rareness of CTCs, detecting them with a single maker is usually challenged with low specificity and sensitivity. Previous studies concerning CTCs detection in lung cancer mainly focused on non-small cell lung carcinoma. Currently, there is no report yet describing the CTC detection with multiple markers in lung adenocarcinoma. In this study, by employing quantitative real-time PCR, we identified four candidate genes (mRNA) that were significantly elevated in peripheral blood mononuclear cells and biopsy tissue samples from patients with lung adenocarcinoma: cytokeratin 7 (CK7), Ca 2+ -activated chloride channel-2 (CLCA2), hyaluronanmediated motility receptor (HMMR), and human telomerase catalytic subunit (hTERT). Then, the four markers were used for CTC detection; namely, positive detection was defined if at least one of the four markers was elevated. The positive CTC detection rate was 74.0% in patients with lung adenocarcinoma while 2.2% for healthy controls, 6.3% for benign lung disease, and 48.0% for non-adenocarcinoma non-small cell lung carcinoma. Furthermore, in a three-year follow-up study, patients with an increase in the detection markers of CTCs (CK7, CLCA2, HMMR or hTERT) on day 90 after first detection had shorter survival time compared to those with a decrease. These results demonstrate that the combination of the four markers with specificity and sensitivity is of great value in lung adenocarcinoma prognosis and follow up.

Carcinoma Cell Hyaluronan as a “Portable” Cancerized Prometastatic Microenvironment

“…RHAMM hyperexpression in breast primary tumor cell subpopulations is linked to increased peripheral metastases [46] while increased RHAMM expression in colorectal tumor budding cells at the invasive front of primary tumors is linked to frequent lymphatic invasion, high tumor grade and nodal metastasis [47]. RHAMM is also one of 4 genes elevated in circulating lung adenocarcinoma cells, and patients exhibiting an increase in these markers at 3 months after their first detection had a significantly shorter survival time than patients exhibiting a decrease in these markers [41]. These results predict that aggressive RHAMM positive subpopulations emerge early in the development of primary tumors and contribute to metastasis.…”

“…Furthermore, synthetic peptides, antibodies or small HA oligomers that that inhibit CD44 and RHAMM function have also proven effective for inhibiting tumor metastasis in multiple model systems. Given recent studies identifying the importance of RHAMM (in contrast to CD44) in mediating HA binding by suspended mesenchymal cells [62], it is worth considering that agents which specifically interfere with RHAMM/HA functions may be particularly effective at disrupting metastasis of circulating tumor cells that overexpress RHAMM [41]. These inhibitors have the potential to be adopted as either single or neoadjuvant therapies to improve patient outcome by limiting metastasis recurrence and relapse, which remain major clinical challenges in cancer treatment.…”

Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas

“…The hyaluronan-mediated motility receptor (HMMR) encodes a cell surface oncogenic protein that is widely upregulated in human cancers and plays a role in promoting cell motility and invasion. HMMR was detectable in the majority of lung ADC samples and was significantly elevated in patient plasma compared with controls and thus was considered as a biomarker for circulating tumor cells (37). The glucagon receptor is important in controlling blood glucose levels and was reported as a prognostic biomarker for lung SCC (38).…”

Circulating Plasma MicroRNAs As Diagnostic Markers for NSCLC

“…However, Hanssen A et al reported that the expression Ep-CAM may be downregulated in CTCs experiencing epithelial-to-mesenchymal transition (EMT), which raises the concern that this Ep-CAM based CTCs enrichment method may lose EMT-associated CTCs (Hanssen et al, 2016). Additionally, another group, Yingchun Man et.al have developed four CTCs markers (CK7, CLCA2, HMMR and hTERT) to detect CTCs, which significantly improves the specificity and sensitivity of CTC detection (Man et al, 2014). Intriguingly, by miRNA in situ hybridization, Francisco G. Ortega et al have identified miR-21 within CTCs as a marker used for detecting CTCs displaying an EMT phenotype (Ortega et al, 2015).…”