Global Hypomethylation of Genomic DNA in Cancer-Associated Myofibroblasts

Jiang, Lei; Gonda, Tamas A.; Gamble, Mary V.; Salas, Martha; Seshan, Venkatraman; Tu, Shuiping; Twaddell, William S.; Hegyi, Péter; Lázár, György; Steele, Islay; Varró, Andrea; Wang, Yichen; Tycko, Benjamin

doi:10.1158/0008-5472.can-08-1319

Cited by 134 publications

(143 citation statements)

References 45 publications

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“…These libraries represented cell types sampled from one breast cancer patient, implicating the relationship between BCL6 and its antisense transcript in the biology of this individual breast cancer. While carcinoma-associated myofibroblasts are not necessarily cancer cells per se, they have epigenetic alterations similar to those seen in malignant carcinoma epithelium, and are globally hypomethylated (Jiang et al 2008). One plausible explanation for the increase in antisense expression at this locus is increased hypomethylation at CpG islands downstream from the BCL6 gene (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 98%

Next-generation tag sequencing for cancer gene expression profiling

Morrissy¹,

Morin²,

Delaney³

et al. 2009

Genome Res.

295

259

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We describe a new method, Tag-seq, which employs ultra high-throughput sequencing of 21 base pair cDNA tags for sensitive and cost-effective gene expression profiling. We compared Tag-seq data to LongSAGE data and observed improved representation of several classes of rare transcripts, including transcription factors, antisense transcripts, and intronic sequences, the latter possibly representing novel exons or genes. We observed increases in the diversity, abundance, and dynamic range of such rare transcripts and took advantage of the greater dynamic range of expression to identify, in cancers and normal libraries, altered expression ratios of alternative transcript isoforms. The strand-specific information of Tag-seq reads further allowed us to detect altered expression ratios of sense and antisense (S-AS) transcripts between cancer and normal libraries. S-AS transcripts were enriched in known cancer genes, while transcript isoforms were enriched in miRNA targeting sites. We found that transcript abundance had a stronger GC-bias in LongSAGE than Tagseq, such that AT-rich tags were less abundant than GC-rich tags in LongSAGE. Tag-seq also performed better in gene discovery, identifying >98% of genes detected by LongSAGE and profiling a distinct subset of the transcriptome characterized by AT-rich genes, which was expressed at levels below those detectable by LongSAGE. Overall, Tag-seq is sensitive to rare transcripts, has less sequence composition bias relative to LongSAGE, and allows differential expression analysis for a greater range of transcripts, including transcripts encoding important regulatory molecules.

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Section: Discussionmentioning

confidence: 98%

Next-generation tag sequencing for cancer gene expression profiling

Morrissy¹,

Morin²,

Delaney³

et al. 2009

Genome Res.

295

259

View full text Add to dashboard Cite

show abstract

“…Jiang et al detected global hypomethylation of genomic DNA by means of a methylation-sensitive SNP array analysis (MSNP), a restriction enzyme-based analysis, in the stromal myofibroblasts of gastric carcinomas (36). By contrast, when we focused on promoter CGIs in the current study, the results showed a higher number of hypermethylated genes than hypomethylated genes in CAFs (hypermethylated: 188 CGIs in Case 1 and 98 CGIs in Case 2; hypomethylated: 39 CGIs in Case 1 and 50 CGIs in Case 2).…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts associated with cancer cells keep enhanced migration activity after separation from cancer cells: A novel character of tumor educated fibroblasts

Ishii¹

2010

Int J Oncol

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Abstract.It is now clear that the association between cancer cells and recruited fibroblasts (cancer-associated fibroblasts; CAFs) leads to alteration of the biological properties of both types of cells and creates a specific microenvironment. Here we report a novel biological property of CAFs and its cellular mechanism using in vivo and in vitro model. Cultured CAFs derived from human lung cancer tissue displayed significantly higher migration activity in response to PDGF-BB than that of fibroblasts from corresponding non-cancerous tissue (NCAFs). Moreover, KM104GFP (GFP-labeled human fibroblast cell line) co-cultured with human cancer cell line Capan-1 showed significantly higher migration activity than KM104 GFP alone. No such phenomenon occurred when KM104 GFP and Capan-1 were cultured separately. Even after KM104 GFP were sorted from co-cultured Capan-1, KM104GFP retained their enhanced migration activity until passage-5 of culture in the absence of cancer cells. Despite a similar level of phosphorylation of ERK1/2 after exposure to PDGF-BB, the inhibitory effect of MEK inhibitor was significantly higher on migration of KM104 GFP that had been sorted from co-cultured Capan-1 than of KM104 GFP alone. This higher dependence on ERK1/2 signaling for cell migration was also seen in CAFs obtained from cancer tissue. The results of this study indicate that by association with cancer cells, CAFs can acquire enhanced migration activity which could be kept after separation from cancer cells and suggest the possibility that higher dependence on ERK1/2 signaling for enhanced migration activity would be one of the biological properties of CAFs.

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“…74,75 In our own SNP chip analysis of gastric cancer associated fibroblasts, we did not observe any evidence of genetic alterations. 76 Epigenetic alterations, on the other hand, do seem to be distinct from the epithelium and ubiquitous in the TME. Epigenetic changes, in particular methylation changes, may provide one explanation for how stromal cells maintain the expression differences even after removal from the tumor environment (as has been confirmed in multiple studies in breast, prostate and gastric cancer).…”

Section: Gastric Cancer As a Model Of Inflammation Driven Carcinogenesismentioning

confidence: 99%

Chronic inflammation, the tumor microenvironment and carcinogenesis

Gonda

Tu²,

Wang³

2009

Cell Cycle

Self Cite

225

161

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Chronic inflammation often precedes or accompanies a substantial number of cancers. Indeed, anti-inflammatory therapies have shown efficacy in cancer prevention and treatment. The exact mechanisms that turn a wound healing process into a cancer precursor are topics of intense research. A pathogenic link has been identified between inflammatory mediators, inflammation related gene polymorphisms and carcinogenesis. Animal models of cancer have been instrumental in demonstrating the diversity of mechanisms through which every tumor compartment and tumor stage may be affected by the underlying inflammatory process. In this review, we focus on the interaction between chronic inflammation, tumor stem cells and the tumor microenvironment. We summarize the proposed mechanisms that lead to the recruitment of bone marrow derived cells and explore the genetic and epigenetic alterations that may occur in inflammation associated cancers.

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Global Hypomethylation of Genomic DNA in Cancer-Associated Myofibroblasts

Cited by 134 publications

References 45 publications

Next-generation tag sequencing for cancer gene expression profiling

Next-generation tag sequencing for cancer gene expression profiling

Fibroblasts associated with cancer cells keep enhanced migration activity after separation from cancer cells: A novel character of tumor educated fibroblasts

Chronic inflammation, the tumor microenvironment and carcinogenesis

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