Abstract
Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality. The goals of this study are to evaluate the association between levels of invasive circulating tumor cells (iCTCs) with CRC outcomes and to explore the molecular characteristics of iCTCs. Peripheral blood from 93 patients with Stage I–IV CRC was obtained and assessed for the detection and characterization of iCTCs using a functional collagen-based adhesion matrix (CAM) invasion assay. Patients were followed and assessed for overall survival. Tumor cells isolated by CAM were characterized using cell culture and microarray analyses. Of 93 patients, 88 (95%) had detectable iCTCs, ranging over 0–470 iCTCs/mL. Patients with Stage I–IV disease exhibited median counts of 0.0 iCTCs/mL (n = 6), 13.0 iCTCs/mL (n = 12), 41.0 iCTCs/mL (n = 12), and 133.0 iCTCs/mL (n = 58), respectively (p < 0.001). Kaplan–Meier curve analysis demonstrated a significant survival benefit in patients with low iCTC counts compared with in patients with high iCTC counts (log-rank p < 0.001). Multivariable Cox model analysis revealed that iCTC count was an independent prognostic factor of overall survival (p = 0.009). Disease stage (p = 0.01, hazard ratio 1.66; 95% confidence interval: 1.12–2.47) and surgical intervention (p = 0.03, HR 0.37; 95% CI: 0.15–0.92) were also independent prognostic factors. Gene expression analysis demonstrated the expression of both endothelial and tumor progenitor cell biomarkers in iCTCs. CAM-based invasion assay shows a high detection sensitivity of iCTCs that inversely correlated with overall survival in CRC patients. Functional and gene expression analyses showed the phenotypic mosaics of iCTCs, mimicking the survival capability of circulating endothelial cells in the blood stream.
Highlights
Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality in the UnitedStates with an incidence rate of 135,430 new cases and an estimated 50,260 deaths in 2017 [1].Patients with Stage IV disease have a 5-year survival rate under 10% [2]
We have developed a functional collagen-based adhesion matrix (CAM) enrichment assay for identifying com/journal/biomedicinesCirculating tumor cells (CTCs) that are positively expressing epithelial markers EpCAM and ESA/CD24 (Epi+), and for detecting the subpopulation that expresses CAM uptake (CAM+) or invasion marker seprase and stem cell marker CD44, termed invasive CTCs [9,10]
Of the 93 total patients, 88 patients (95%) had detectable invasive circulating tumor cells (iCTCs) and iCTC positives correlated with disease status: Stage I, 6 patients (7%); Stage II, 12 patients (14%); Stage III, 12 patients (14%); and Stage IV, 58 patients (65%)
Summary
States with an incidence rate of 135,430 new cases and an estimated 50,260 deaths in 2017 [1]. Patients with Stage IV disease have a 5-year survival rate under 10% [2]. II or III disease, 25–50% suffer from relapse, likely as a consequence of undetected spread of malignant cells, even after radical surgery and adjuvant therapy [3,4]. A prospective biomarker is needed to better predict disease recurrence, treatment response, and drug resistance, and to better understand the molecular mechanism of tumor cell invasion [5]. Circulating tumor cells (CTCs) have been isolated and have proven prognostic value in CRC patients [6,7,8]. We have developed a functional collagen-based adhesion matrix (CAM) enrichment assay for identifying CTCs that are positively expressing epithelial markers EpCAM and ESA/CD24
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