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CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype.

ABSTRACT: The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells.

SUBMITTER: Paschall AV

PROVIDER: S-EPMC5346671 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype.

Paschall Amy V AV Yang Dafeng D Lu Chunwan C Redd Priscilla S PS Choi Jeong-Hyeon JH Heaton Christopher M CM Lee Jeffrey R JR Nayak-Kapoor Asha A Liu Kebin K

Oncotarget 20161101 48

The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment ...[more]

PMID: 27659530

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Project description:Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.

Project description:Cancer stem cells (CSCs) exhibit intrinsic therapy/stress resistance, which often cause cancer recurrence after therapy. In this study, we investigated the potential relationship between the cluster of differentiation (CD)-133, a CSC marker of colon cancer, and nuclear factor erythroid 2-like 2 (NFE2L2; NRF2), a master transcription factor for the regulation of multiple antioxidant genes. In the first model of CSC, a sphere culture of the colorectal cell line HCT116, showed increased levels of CD133 and NRF2. Silencing of CD133 reduced the levels of CSC markers, such as Kruppel-like factor 4 (KLF4) and ATP-binding cassette subfamily G member 2 (ABCG2), and further suppressed the expression levels of NRF2 and its target genes. As a potential molecular link, CD133-mediated activation of phosphoinositide 3-kinase/serine-threonine kinase (PI3K/AKT) signaling appears to increase the NRF2 protein levels via phosphorylation and the consequent inhibition of glycogen synthase kinase (GSK)-3β. Additionally, NRF2-silenced HCT116 cells showed attenuated sphere formation capacity and reduced CSC markers expression, indicating the critical role of the NRF2 pathway in the development of CSC-like properties. As a second model of CSC, the CD133high cell population was isolated from HCT116 cells. CSC-like properties, including sphere formation, motility, migration, colony formation, and anticancer resistance, were enhanced in the CD133high population compared to CD133low HCT116 cells. Levels of NRF2, which were elevated in CD133high HCT116, were suppressed by CD133-silencing. In line with these, the analysis of The Cancer Genome Atlas (TCGA) database showed that high levels of CD133 expression are correlated with increased NRF2 signaling, and alterations in CD133 gene or expression are associated with unfavorable clinical outcome in colorectal carcinoma patients. These results indicate that the CD133/NRF2 axis contributes to the development of CSC-like properties in colon cancer cells, and that PI3K/AKT signaling activation is involved in CD133-mediated NRF2 activation.

Project description:BackgroundIsolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures.MethodsWe characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo.ResultsAll five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.In vivo growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones.ConclusionsOur data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.

Dataset Information

CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype.

Publications

CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype.

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