Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery

Background Most cancer deaths are caused by metastases, resulting from circulating tumor cells (CTC) that detach from the primary cancer and survive in distant organs. The aim of the present study was to develop a CTC gene signature and to assess its prognostic relevance after surgery for pancreatic...

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Published in:	BMC cancer Vol. 12; no. 1; p. 527
Main Authors:	Sergeant, Gregory, van Eijsden, Rudy, Roskams, Tania, Van Duppen, Victor, Topal, Baki
Format:	Journal Article
Language:	English
Published:	London BioMed Central 16.11.2012 BioMed Central Ltd Springer Nature B.V
Subjects:	Adenocarcinoma - diagnosis Adenocarcinoma - metabolism Adenocarcinoma - mortality Adenocarcinoma - surgery Aged Analysis Biomarkers, Tumor - metabolism Biomedical and Life Sciences Biomedicine Bone morphogenetic proteins Cancer Cancer Research Cancer therapies Carcinoma, Pancreatic Ductal - diagnosis Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - mortality Carcinoma, Pancreatic Ductal - surgery Care and treatment Cell Line, Tumor DNA microarrays Female Fluorescence Gene expression Gene Expression Profiling Genes Genetic aspects Genomics Health Promotion and Disease Prevention Hematology Humans Information management Male Medical research Medicine/Public Health Metastasis Microarray Analysis Middle Aged Mitogens Motility Neoplastic Cells, Circulating - metabolism Oncology Oncology, Experimental Pancreas Pancreatic cancer Pancreatic Neoplasms - diagnosis Pancreatic Neoplasms - genetics Pancreatic Neoplasms - mortality Pancreatic Neoplasms - surgery Patient outcomes Predictive Value of Tests Prognosis Protein kinases Proteins Research Article RNA Statistical analysis Surgery Surgical Oncology Survival Analysis Transforming growth factors Translational oncology Cell motility Transforming growth factor - β1 Gene expression profiling Pancreatic ductal adenocarcinoma p38 – MAPK signaling Circulating tumour cells Cancer cell migration
ISSN:	1471-2407, 1471-2407
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Summary:	Background Most cancer deaths are caused by metastases, resulting from circulating tumor cells (CTC) that detach from the primary cancer and survive in distant organs. The aim of the present study was to develop a CTC gene signature and to assess its prognostic relevance after surgery for pancreatic ductal adenocarcinoma (PDAC). Methods Negative depletion fluorescence activated cell sorting (FACS) was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumour (T), and non-tumoural pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS). Results Using stringent statistical analysis, we retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway, TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were overexpressed in CTC. High co-expression of TGF-β1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 6 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR (95% CI) = 1.366 (1.004 – 1.861)). Conclusions Pancreatic CTC isolated from blood samples using FACS-based negative depletion, express a cell motility gene signature. Expression of this newly defined cell motility gene signature in the primary tumour can predict survival of patients undergoing surgical resection for pancreatic cancer. Trial Registration Clinical trials.gov NCT00495924
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ISSN:	1471-2407 1471-2407
DOI:	10.1186/1471-2407-12-527