CD133 Protein N-Glycosylation Processing Contributes to Cell Surface Recognition of the Primitive Cell Marker AC133 Epitope

Mak, Anthony B.; Blakely, Kim M.; Williams, Rashida; Penttilä, Pier-Andrée; Shukalyuk, Andrey I.; Osman, Khan Towhid; Kasimer, Dahlia; Ketela, Troy; Moffat, Jason

doi:10.1074/jbc.m111.261545

Cited by 82 publications

(80 citation statements)

References 43 publications

(51 reference statements)

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“…We hypothesized that this is due to differential folding of CD133 on the surface of CSCs, which may be influenced by glycosylation that affects accessibility of the AC133 epitope (27). A recent report confirmed that N-glycosylation of CD133 determines the recognition of the AC133 epitope (28). We therefore conclude that the level of CD133 mRNA or protein is not a reliable marker for the presence and enumeration of CSCs.…”

Section: Discussionmentioning

confidence: 44%

“…Previously, we found that the use of CD133 as a CSC marker depends on the availability of the AC133 epitope and is not determined by CD133 mRNA or protein expression, which remain unchanged during in vitro and in vivo differentiation of colon CSCs (27). Recently, it was confirmed that N-glycosylation of CD133 affects the cell surface recognition of AC133 (28). Altogether, this suggests that the prognostic value of CD133 in CRC is not due to an enumeration of CSCs.…”

Section: Introductionmentioning

confidence: 54%

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Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer

Kemper

Versloot

Cameron

et al. 2012

Clinical Cancer Research

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Purpose: High expression of cancer stem cell (CSC) marker CD133 has been used as a predictor for prognosis in colorectal cancer (CRC), suggesting that enumeration of CSCs, using CD133, is predictive for disease progression. However, we showed recently that both CD133 mRNA and protein are not downregulated during differentiation of colon CSCs, pointing to an alternative reason for the prognostic value of CD133. We therefore set out to delineate the relation between CD133 expression and prognosis.Experimental Design: A CRC patient series was studied for expression of CD133 and other CSC markers by microarray and quantitative PCR analysis. In addition, several common mutations were analyzed to determine the relation with CD133 expression.Results: CD133 mRNA expression predicted relapse-free survival in our patient series, whereas several other CSC markers could not. Moreover, no correlation was found between expression of other CSC markers and CD133. Interestingly, high CD133 expression was related to mutations in K-Ras and B-Raf, and inhibition of mutant K-Ras or downstream mitogen-activated protein kinase kinase (MEK) signaling decreases CD133 expression. In addition, an activated K-Ras gene expression signature could predict CD133 expression in our patient set as well as data sets of other tumor types.Conclusion: CD133 expression is upregulated in CRC tumors that have a hyperactivated RasRaf-MEK-ERK pathway and is therefore related to mutations in K-Ras or B-Raf. As mutations in either gene have been related to poor prognosis, we conclude that CD133 expression is not indicative for CSC numbers but rather related to the mutation or activity status of the Ras-Raf pathway. Clin Cancer Res; 18(11); 3132-41. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 44%

Section: Introductionmentioning

confidence: 54%

Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer

Kemper

Versloot

Cameron

et al. 2012

Clinical Cancer Research

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“…Among the candidate genes PPEF1, PTPN7, PPP4C and PPP2R5E were previously shown to be important regulators of CD133 level emphasising the validity of our screen. 31 Moreover, several genes are reported to be relevant for stem cells, such as PPP4C identified in a previous RNAi screen for stem cell self-renewal factors, 21 DUSP5 described as an antidifferentiation regulator in embryonic stem cells 19 and PPEF1 identified as a marker for CD133 þ GSCs. 7 The selected candidate genes were validated in a secondary screen in three patient-derived GSC lines, but at variable level, which is most likely because of the molecular heterogeneity of tumour-derived patient samples.…”

Section: Discussionmentioning

confidence: 99%

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

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Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside-nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state. Glioblastoma, classified by the WHO (World Health Organization) as grade IV astrocytoma, 1 is the most common primary malignant brain tumour in adults. Despite progress in surgical resection, radiation and chemotherapy, glioblastoma remains a deadly disease with a median survival time of about 1 year. 2 One particular therapeutic challenge for glioblastoma treatment is posed by their remarkable intratumoural cellular heterogeneity. Several studies indicate the existence of a highly tumourigenic, sub-population of cancer cells with stemlike characteristics. [3][4][5] There is substantial evidence that these so-called cancer stem cells have inherent chemotherapy and radiation resistance. 6,7 These findings suggest that cancer cells harbouring stem cell-like characteristics are responsible for ineffective therapy, explaining high recurrence rates despite significant reduction in tumour volume. Glioblastoma stem-like cells (GSCs) share properties with neural precursor cells, such as a capacity for self-renewal, differentiation and maintained proliferation, as well as stem cell marker expression. 4,5,8,9 GSCs were originally defined by expression of CD133 (Prominin-1) and its extracellular AC133 epitope. 4 Although recent...

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“…The nature of CD133's epitope is a main factor that influenced the antibody binding (14). Both micromilieu and drug treatment could affect CD133 stability and its transport to the cell surface (15,16). We speculate that the different prognostic value may be due to different stem cell characteristics in subtypes of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

CD133 mRNA may be a suitable prognostic marker for human breast cancer

2017

Stem Cell Investig.

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CD133 Protein N-Glycosylation Processing Contributes to Cell Surface Recognition of the Primitive Cell Marker AC133 Epitope

Cited by 82 publications

References 43 publications

Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer

Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

CD133 mRNA may be a suitable prognostic marker for human breast cancer

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