Unknown,Transcriptomics,Genomics,Proteomics

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The side population of human pancreatic cancer expresses cancer stem cell-associated genes

ABSTRACT: Purpose: To explore the side population (SP) in pancreatic ductal adenocarcinoma (PDAC) for its gene expression profile and its association to cancer stem cells (CSC) and to evaluate the value of genes from its gene signature on patient survival. Experimental design: Side and main population (MP) cells were isolated from 11 human PDAC resection specimens using fluorescence-activated cell sorting (FACS) after Hoechst incubation. Total RNA was extracted for whole-genome analysis. A gene signature for the purified SP (pSP; depleted from immune/endothelial CD45+/CD31+ cells) was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analyses for disease-free and overall survival. Results: An SP was identified in all PDAC samples. Whole-genome expression profiling of pSP revealed upregulation of genes related to therapy-resistance and of CSC-associated genes and pathways. A pSP signature of 32 up- or downregulated genes was capable of discriminating SP from MP in an independent set of 10 PDAC samples, and some contributing genes had a prognostic value in a separate series of 78 patients who underwent surgery for PDAC. Conclusion: Pancreatic cancer contains an SP with chemo-resistant and CSC-associated molecular characteristics. Genes from a newly defined pSP gene signature are related to survival of patients who undergo surgical resection for pancreatic cancer, and might therefore represent potential therapeutic targets. Microarray analysis was performed on SP and MP samples from 11 different human PDAC samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Wouter Van Delm

PROVIDER: E-GEOD-42404 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Human pancreatic cancer contains a side population expressing cancer stem cell-associated and prognostic genes.

Van den Broeck Anke A Vankelecom Hugo H Van Delm Wouter W Gremeaux Lies L Wouters Jasper J Allemeersch Joke J Govaere Olivier O Roskams Tania T Topal Baki B

PloS one 20130917 9

In many types of cancers, a side population (SP) has been identified based on high efflux capacity, thereby enriching for chemoresistant cells as well as for candidate cancer stem cells (CSC). Here, we explored whether human pancreatic ductal adenocarcinoma (PDAC) contains a SP, and whether its gene expression profile is associated with chemoresistance, CSC and prognosis. After dispersion into single cells and incubation with Hoechst dye, we analyzed human PDAC resections specimens using flow cy ...[more]

PMID: 24069258

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Project description:Pituitary adenomas cause significant endocrine and mass-related morbidity. Not much is known about mechanisms underlying pituitary tumor pathogenesis.We searched for a side population (SP) in pituitary tumor, representing cells with high efflux capacity and potentially enriching for cancer/tumor stem cells (CSC/TSC). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the further purified SP (pSP) depleted from endothelial and immune cells, enriches for cells that express ‘tumor stemness’ markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. The adenomas were found to contain self-renewing sphere-forming cells, considered a property of TSC. The sphere-initiating cells were retrieved in the pSP.Because benign pituitary adenomas do not grow in vitro and failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it more tumorigenic than the main population (MP). Of the two EMT-regulatory pathways tested, inhibition of Cxcr4 signaling reduced EMT-linked cell motility in vitro as well as xenograft tumor growth, whereas activation of TGFβ had no effect.The tumor pSP showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2-/-) mice bearing prolactinomas, contain more pSP, Sox2+ and colony-forming cells than wildtype glands.In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. Our study may contribute to a better understanding of pituitary tumor pathogenesis and lead to new therapeutic targets. We determined gene expression profiles for 9 human pituitary adenoma samples (5 x NF-A; 4 x GH-A). The samples were obtained immediately after transsphenoidal resection (by the neurosurgeon Dr. van Loon, Division Neurosurgery, University Hospitals Leuven). Informed consent was received from the patients. Hormonal phenotype was determined by the Department of Imaging and Pathology (University Hospitals Leuven). For each sample, total SP and MP cells were sorted by FACS. Separate assays were run subsequently for the two fractions. As such we present data from 18 microarrays.

Project description:Pituitary adenomas cause significant endocrine and mass-related morbidity. Not much is known about mechanisms underlying pituitary tumor pathogenesis. We searched for a side population (SP) in pituitary tumor, representing cells with high efflux capacity and potentially enriching for cancer/tumor stem cells (CSC/TSC). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the further purified SP (pSP) depleted from endothelial and immune cells, enriches for cells that express ‘tumor stemness’ markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. The adenomas were found to contain self-renewing sphere-forming cells, considered a property of TSC. The sphere-initiating cells were retrieved in the pSP. Because benign pituitary adenomas do not grow in vitro and failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it more tumorigenic than the main population (MP). Of the two EMT-regulatory pathways tested, inhibition of Cxcr4 signaling reduced EMT-linked cell motility in vitro as well as xenograft tumor growth, whereas activation of TGFβ had no effect. The tumor pSP showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2-/-) mice bearing prolactinomas, contain more pSP, Sox2+ and colony-forming cells than wildtype glands. In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. Our study may contribute to a better understanding of pituitary tumor pathogenesis and lead to new therapeutic targets. We determined gene expression profiles for 5 human pituitary adenoma samples (all NF-A type). The samples were obtained immediately after transsphenoidal resection (by the neurosurgeon Dr. van Loon, Division Neurosurgery, University Hospitals Leuven). Informed consent was received from the patients. Hormonal phenotype was determined by the Department of Imaging and Pathology (University Hospitals Leuven). For each sample, CD31¯/CD45¯ SP (purified SP or pSP) and pMP cells were sorted by FACS. Separate assays were run subsequently for the two fractions. As such we present data from 10 microarrays.

Dataset Information

The side population of human pancreatic cancer expresses cancer stem cell-associated genes

Publications

Human pancreatic cancer contains a side population expressing cancer stem cell-associated and prognostic genes.

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