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Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers-CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin-by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24+/CD44+/EpCAM+/CD133+ cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24+/CD44+/EpCAM+/CD133+ cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24+/CD44+/EpCAM+/CD133+ cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile.

SUBMITTER: Skoda J

PROVIDER: S-EPMC4945008 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma.

Skoda Jan J Hermanova Marketa M Loja Tomas T Nemec Pavel P Neradil Jakub J Karasek Petr P Veselska Renata R

PloS one 20160714 7

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of ...[more]

PMID: 27414409

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Project description:BackgroundOne of the main reasons for the unsuccessful treatment of pancreatic cancer is the intense desmoplastic pancreatic microenvironment. In the literature, the effects of mesenchymal stem cells (MSCs) and their inflammatory phenotypes on cancer cells have been a subject of controversy. Therefore, it is crucial to elucidate the underlying mechanisms of this interaction, especially in the context of pancreatic cancer. We aimed to investigate the effects of naive, TLR4-activated, and TLR4-inhibited phenotypes of adipose-derived MSCs (ADMSC) on pancreatic ductal cell line (Panc-1).Methods and materialsAdipose-derived MSCs were induced into a proinflammatory phenotype using a 0.5 μg/mL dose of TLR4 agonist, while an anti-inflammatory phenotype was generated in ADMSCs using a 25 μg/mL dose of TLR4 antagonist. We observed that the proliferation of Panc-1 cells was inhibited when naive ADMSCs:Panc-1(10:1) and proinflammatory ADMSCs:Panc-1(10:1) were directly cocultured.ResultsIn indirect coculture, both naive and proinflammatory ADMSCs exhibited a significant 10-fold increase in their inhibitory effect on the proliferation and colony forming capacity of Panc-1 cells, with the added benefit of inducing apoptosis. In our study, both naive and proinflammatory ADMSCs were found to regulate the expression of genes associated with metastasis (MMP2, KDR, MMP9, TIMP1, IGF2R, and COL1A1) and EMT (CDH1, VIM, ZEB1, and CLDN1) in Panc-1 cells. Remarkably, both naive and proinflammatory ADMSCs demonstrated antitumor effects on Panc-1 cells. However, it was observed that anti-inflammatory ADMSCs showed tumor-promoting effects instead. Furthermore, we observed a reciprocal influence between ADMSCs and Panc-1 cells on each other's proinflammatory cytokine expressions, suggesting a dynamic interplay within the tumor microenvironment.ConclusionsThese findings underscore the significance of both the naive state and different inflammatory phenotypes of MSCs in the microenvironment and represent a pivotal step toward the development of novel therapeutic approaches for pancreatic cancer. Understanding the intricate interactions between MSCs and cancer cells may open new avenues for targeted interventions in cancer therapy.

Project description:BackgroundSpecific populations of highly tumorigenic cells are thought to exist in many human tumors, including pancreatic adenocarcinoma. However, the clinical significance of these tumor-initiating (ie, cancer stem) cells remains unclear. Aldehyde dehydrogenase (ALDH) activity can identify tumor-initiating cells and normal stem cells from several human tissues. We examined the prognostic significance and functional features of ALDH expression in pancreatic adenocarcinoma.MethodsALDH expression was analyzed by immunohistochemistry in 269 primary surgical specimens of pancreatic adenocarcinoma and examined for association with clinical outcomes and in paired primary tumors and metastatic lesions from eight pancreatic cancer patients who had participated in a rapid autopsy program. The clonogenic growth potential of ALDH-positive pancreatic adenocarcinoma cells was assessed in vitro by a colony formation assay and by tumor growth in immunodeficient mice (10-14 mice per group). Mesenchymal features of ALDH-positive pancreatic tumor cells were examined by using quantitative reverse transcription-polymerase chain reaction and an in vitro cell invasion assay. Gene expression levels and the invasive potential of ADLH-positive pancreatic cancer cells relative to the bulk cell population were examined by reverse transcription-polymerase chain reaction and an in vitro invasion assays, respectively. All statistical tests were two-sided.ResultsALDH-positive tumor cells were detected in 90 of the 269 primary surgical specimens, and their presence was associated with worse survival (median survival for patients with ALDH-positive vs ALDH-negative tumors: 14 vs 18 months, hazard ratio of death = 1.28, 95% confidence interval = 1.02 to 1.68, P = .05). Six (75%) of the eight patients with matched primary and metastatic tumor samples had ALDH-negative primary tumors, and in four (67%) of these six patients, the matched metastatic lesions (located in liver and lung) contained ALDH-positive cells. ALDH-positive cells were approximately five- to 11-fold more clonogenic in vitro and in vivo compared with unsorted or ALHD-negative cells, expressed genes consistent with a mesenchymal state, and had in vitro migratory and invasive potentials that were threefold greater than those of unsorted cells.ConclusionsALDH expression marks pancreatic cancer cells that have stem cell and mesenchymal features. The enhanced clonogenic growth and migratory properties of ALDH-positive pancreatic cancer cells suggest that they play a key role in the development of metastatic disease that negatively affects the overall survival of patients with pancreatic adenocarcinoma.

Dataset Information

Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma.

Publications

Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma.

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