Article

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: 22.15). 11/2011; 9(5):476-85. DOI: 10.1016/j.stem.2011.10.008
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Louis Vermeulen, Jul 07, 2015
1 Follower
 · 
213 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer stem cells (CSCs), which comprise a small fraction of cancer cells, are believed to constitute the origin of most human tumors. Considerable effort has been focused on identifying CSCs in multiple tumor types and identifying genetic signatures that distinguish CSCs from normal tissue stem cells. Many studies also suggest that CSCs serve as the basis of metastases. Yet, experimental evidence that CSCs are the basis of disseminated metastases has lagged behind the conceptual construct of CSCs. Recent work, however, has demonstrated that CSCs may directly or indirectly contribute to the generation of metastasis. Moreover, CSC heterogeneity may be largely responsible for the considerable complexity and organ specificity of metastases. In this review, we discuss the role of CSCs in metastasis and their potential as therapeutic targets.
    Pharmacology [?] Therapeutics 02/2013; DOI:10.1016/j.pharmthera.2013.01.014 · 7.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglia become activated in humans subsequent to infection with HIV, and uncontrolled brain inflammation plays a key role in neuronal injury and and cognitive dysfunction during HIV infection. Various studies have shown a deleterious role for the HIV regulatory protein Tat in the development and maintenance of HIV-associated neurocognitive disorders (HAND). One cell surface receptor implicated in inhibiting microglial activation is the protein-tyrosine phosphatase (PTP), CD45. It is especially effective at inhibiting microglial activation because its action takes place far upstream from proinflammatory intracellular signaling mediators. To investigate the possible role of CD45 in microglial responsiveness to HIV-1 Tat protein, we treated BV-2 microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1, 10-phenanthroline) oxovanadate (phen), 5 μM] and HIV-1 Tat protein (700ng/ml). We found a synergistic pro-inflammatory microglial activation as supported by tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β) release, both of which were dependent on p44/42 mitogen-activated protein kinase (MAPK) activation. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibited these Tat or Tat/Phen effects via attenuation of p44/42 MAPK, suggesting CD45 negatively regulates microglial activation. As a validation of these findings in vivo, brains from transgenic mice deficient for CD45 through complete genetic ablation, or by CNS delivery of CD45shRNA, demonstrate markedly increased production of TNF-α 24 hours after intracerebroventricular injection of HIV-Tat protein (5μg/mouse) compared to control mice. This increased microglial activation was accompanied by astrogliosis and a significant loss of cortical neurons due to apoptosis in CD45 deficient animals. These results suggest therapeutic agents that activate CD45 PTP signaling may be effective in suppressing microglial activation associated with HAND.
    American Journal of Translational Research 01/2012; 4(3):302-15. · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Morphological and clinical heterogeneity of advanced colorectal cancer is probably caused by genetic variability in putative cancer stem cell genes, including Lgr5. Here, we investigated 23 variants of the Lgr5 gene in normal tissue, primary tumors, lymph node metastases and distant metastases of stage III and stage IV colorectal cancer patients. These data were compared to results of immunohistochemical Lgr5 expression analysis and to prognostic clinical parameters. No differences were found comparing germline and somatic Lgr5 genotype in primary tumors, but additional Lgr5 gene alterations could be demonstrated in lymph node and distant metastases. Significant negative correlation was seen between Lgr5 allelic variation and Lgr5 protein expression (p=0.0394), which mainly can be attributed to the negative influence of non-coding Lgr5 gene variations on Lgr5 protein expression (p=0.0166). Lgr5 gene variants could be found more frequently in primary tumors of stage III patients with increased time to recurrence, in distant metastases of patients with better survival and in lymph node metastases of patients with poorer survival compared to patients with Lgr5 wild type in primary and metastatic tissues, respectively. However, the analytic power of these prognostic data was low due to small sample size in the investigated groups. In conclusion, our data indicate that Lgr5 allelic variation affect Lgr5 protein expression in colorectal carcinomas. The somatic Lgr5 genotype seems to be relatively stable in primary tumors, but becomes vulnerable during the metastatic process of colorectal cancer. This instability has possibly prognostic importance, which has to be further evaluated by large cohort studies.
    American Journal of Translational Research 01/2012; 4(3):279-90. · 3.23 Impact Factor