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Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.

ABSTRACT: Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe (P < 0.0001) and intraoperative Pe (P < 0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long-term surveillance indicated that presence of clusters in preoperative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence. Cancer Res; 77(18); 5194-206. ©2017 AACR.

SUBMITTER: Murlidhar V

PROVIDER: S-EPMC5600850 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.

Murlidhar Vasudha V Reddy Rishindra M RM Fouladdel Shamileh S Zhao Lili L Ishikawa Martin K MK Grabauskiene Svetlana S Zhang Zhuo Z Lin Jules J Chang Andrew C AC Carrott Philip P Lynch William R WR Orringer Mark B MB Kumar-Sinha Chandan C Palanisamy Nallasivam N Beer David G DG Wicha Max S MS Ramnath Nithya N Azizi Ebrahim E Nagrath Sunitha S

Cancer research 20170717 18

Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood s ...[more]

PMID: 28716896

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is a leading cause of cancer-related death with a 5-year survival of only 21%. Reliable prognostic and/or predictive biomarkers are needed to improve NSCLC patient stratification, particularly in curative disease stages. Since the endogenous cannabinoid system is involved in both carcinogenesis and anticancer immune defense, we hypothesized that tumor tissue expression of cannabinoid 1 and 2 receptors (CB1 and CB2) may affect survival.MethodsTumor tissue samples collected from 100 NSCLC patients undergoing radical surgery were analyzed for CB1 and CB2 gene and protein expression using the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The gene and protein expression data were correlated with disease stage, histology, tumor grading, application of chemotherapy, and survival. Additional paired tumor and normal tissue samples of 10 NSCLC patients were analyzed independently for comparative analysis of CB1 and CB2 gene expression.ResultsPatients with tumors expressing the CB2 gene had significantly longer overall survival (OS) (P<0.001), cancer specific survival (CSS) (P=0.002), and disease-free survival (DFS) (P<0.001). They also presented with fewer lymph node metastases at the time of surgery (P=0.011). A multivariate analysis identified CB2 tumor tissue gene expression as a positive prognostic factor for CSS [hazard ratio (HR) =0.274; P=0.013] and DFS (HR =0.322; P=0.009), and increased CSS. High CB2 gene and protein expression were detected in 79.6% and 31.5% of the tested tumor tissue samples, respectively. Neither CB1 gene nor CB1 or CB2 protein expression affected survival. When comparing paired tumor and tumor-free lung tissue samples, we observed reduced CB1 (P=0.008) and CB1 (P=0.056) gene expression in tumor tissues.ConclusionsIn NSCLC patients undergoing radical surgery, expression of the CB1 and CB2 receptor genes is significantly decreased in neoplastic versus tumor-free lung tissue. CB2 tumor tissue gene expression is strongly associated with longer survival (OS, CSS, DFS) and fewer lymph node metastases at the time of surgery. More studies are needed to evaluate its role as a biomarker in NSCLC and to investigate the potential use of CB2 modulators to treat or prevent lung cancers.

Project description:BackgroundThe pathogenesis and developmental mechanism of early-stage (FIGO 2009 IA2-IIA2) cervical cancer (CC) remain unclear. Seeking novel molecular biomarkers based on The Cancer Genome Atlas (TCGA) will facilitate the understanding of CC pathogenesis and help evaluate early-stage CC prognosis.MethodsTo identify prognosis-related genes in early-stage CC, we analyzed TCGA mRNA-seq data and clinical data by univariate Cox and Kaplan-Meier plotter analyses. Differential expression analysis identified upregulated genes in early-stage CC. Combined with the genes correlated with unfavorable prognosis, we selected desmoglein-2 (DSG2) for further investigation. To detect DSG2 expression in early-stage CC, we used immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blotting. The relationship between the expression of DSG2 and clinical features was analyzed by the Chi square test. Cox analysis was applied to assess the relationship between CC overall survival (OS) and risk factors. The correlations between DSG2 expression and CC cell line proliferation and migration were investigated with Cell Counting Kit-8 (CCK-8) and migration assays.ResultsThere were 416 prognosis-related genes in early-stage CC. DSG2, matrix metallopeptidase 1 (MMP1), carbonic anhydrase IX (CA9), homeobox A1 (HOXA1), and serine protease inhibitor B3 (SERPINB3) were upregulated in early-stage CC compared with adjacent noncancerous tissue (ANT) and correlated with unfavorable prognosis. Among them, DSG2 was most significantly correlated with patient survival. Coexpression analysis indicated that DSG2 was probably involved in cell division, positive regulation of transferase activity, positive regulation of cell migration, EGFR upregulation pathway and regulation of lymphangiogenesis. IHC, qRT-PCR and western blotting showed that DSG2 expression was higher in CC than in normal tissue. Significant correlations were identified between DSG2 expression and several aggressive clinical features, including pelvic lymph node metastasis (PLNM). Multivariate Cox analysis showed that DSG2 and PLNM were independent prognostic factors for OS. DSG2 knockdown inhibited CC cell proliferation and migration.ConclusionsDSG2 is a biomarker that promotes tumor proliferation and metastasis and is correlated with poor prognosis in early-stage CC.

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Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.

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Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.

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