Methylation of Cancer-Stem-Cell-Associated Wnt Target Genes Predicts Poor Prognosis in Colorectal Cancer Patients

Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Cell stem cell (Impact Factor: 22.27). 11/2011; 9(5):476-85. DOI: 10.1016/j.stem.2011.10.008
Source: PubMed


Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including ASCL2 and LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue.

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    • "Random genomic hypomethylation alone may be sufficient to deregulate transcription factor activation, leading to ectopic gene expression and increased CSC characteristics such as poor differentiation, increased motility, and invasiveness [25] [26]. Recent reports demonstrate DNA methylation regulates expression of colon CSC surface proteins as well as targets downstream of Wnt signaling [27] [28], a vital pathway involved in the maintenance of normal intestinal stem cells and the growth of CSC in vitro [29]. "
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    ABSTRACT: Folate and its synthetic form, folic acid (FA), are essential vitamins for the regeneration of S-adenosyl methionine molecules, thereby maintaining adequate cellular methylation. The deregulation of DNA methylation is a contributing factor to carcinogenesis, as alterations in genetic methylation may contribute to stem cell reprogramming and dedifferentiation processes that lead to a cancer stem cell (CSC) phenotype. Here, we investigate the potential effects of FA exposure on DNA methylation and colonosphere formation in cultured human colorectal cancer (CRC) cell lines. We show for the first time that HCT116, LS174T, and SW480 cells grown without adequate FA demonstrate significantly impaired colonosphere forming ability with limited changes in CD133, CD166, and EpCAM surface expression. These differences were accompanied by concomitant changes to DNA methyltransferase (DNMT) enzyme expression and DNA methylation levels, which varied depending on cell line. Taken together, these results demonstrate an interaction between FA metabolism and CSC phenotype in vitro and help elucidate a connection between supplemental FA intake and CRC development. Copyright © 2015. Published by Elsevier Inc.
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    • "About 608,000 deaths from CRC are estimated worldwide, accounting for 8% of all cancer deaths [2, 3]. Surgery is the most common treatment for CRC, yet prognosis remains poor [4]. As a result, considerable interest has concentrated on chemotherapy after surgery, such as oxaliplatin or 5-fluorouracil (5-FU)-based adjuvant chemotherapy [5, 6]. "
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    ABSTRACT: Background Aim was to explore the association of ERCC1 and TS mRNA levels with the disease free survival (DFS) in Chinese colorectal cancer (CRC) patients receiving oxaliplatin and 5-FU based adjuvant chemotherapy. Methods Total 112 Chinese stage II-III CRC patients were respectively treated by four different chemotherapy regimens after curative operation. The TS and ERCC1 mRNA levels in primary tumor were measured by real-time RT-PCR. Kaplan–Meier curves and log-rank tests were used for DFS analysis. The Cox proportional hazards model was used for prognostic analysis. Results In univariate analysis, the hazard ratio (HR) for the mRNA expression levels of TS and ERCC1 (logTS: HR = 0.820, 95% CI = 0.600 - 1.117, P = 0.210; logERCC1: HR = 1.054, 95% CI = 0.852 - 1.304, P = 0.638) indicated no significant association of DFS with the TS and ERCC1 mRNA levels. In multivariate analyses, tumor stage (IIIc: reference, P = 0.083; IIb: HR = 0.240, 95% CI = 0.080 - 0.724, P = 0.011; IIc: HR < 0.0001, P = 0.977; IIIa: HR = 0.179, 95% CI = 0.012 - 2.593, P = 0.207) was confirmed to be the independent prognostic factor for DFS. Moreover, the Kaplan-Meier DFS curves showed that TS and ERCC1 mRNA levels were not significantly associated with the DFS (TS: P = 0.264; ERCC1: P = 0.484). Conclusion The mRNA expression of ERCC1 and TS were not applicable to predict the DFS of Chinese stage II-III CRC patients receiving 5-FU and oxaliplatin based adjuvant chemotherapy.
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    • "The inverse relationship was demonstrated for Short (Figure 3C). This association between DFS and TLR4 expression was not supported by other GSE series examining the endpoints of OS, DFS (GSE12945) [26], relapse-free survival (GSE8671) [18] and recurrence-free survival (GSE33113) [27]. In a separate series of 48 sporadic colon cancer samples, no association between TLR4 expression and survival was observed (exp (coef) = 1.13, "
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    ABSTRACT: Background Inflammation increases the risk of colorectal cancer (CRC). We and others have described a role for TLR4, the receptor for LPS, in colon cancer. To explore the relationships between TLR4 expression and CRC, we combined the strength of transcriptome array data and immunohistochemical (IHC) staining. Methods TLR4 signal intensity was scored in the stromal and epithelial compartments. Detection of differential expression between conditions of interest was performed using linear models, Cox proportional hazards models, and empirical Bayes methods. Results A strong association between TLR4 expression and survival was noted, though a dichotomous relationship between survival and specific TLR4 transcripts was observed. Increasing TLR4 expression was seen with advancing tumor stage and was also over-expressed in some adenomas. IHC staining confirmed the positive relationship between TLR4 staining score in the CRC tumor stroma and epithelium with tumor stage, with up to 47% of colon cancer stroma positive for TLR4 staining. Increased TLR4 expression by IHC was also marginally associated with decreased survival. We now also describe that pericryptal myofibroblasts are responsible for a portion of the TLR4 stromal staining. Conclusions Increased TLR4 expression occurs early in colonic neoplasia. TLR4 is associated with the important cancer-related outcomes of survival and stage.
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