Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance

Easwaran, Hariharan; Tsai, Hsing-Chen; Baylin, Stephen B.

doi:10.1016/j.molcel.2014.05.015

Cited by 797 publications

(657 citation statements)

References 98 publications

(149 reference statements)

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“…However, it is becoming increasingly clear that the impact of epigenetics on both the tumor cell and the tumor microenvironment plays a critical role in the development of drug resistance 9, 10, 11. Consistent with this hypothesis, previous laboratory and clinical data suggest that an epigenetic strategy may overcome chemotherapy resistance and mediate a return to a baseline state of treatment susceptibility in various cancers 11, 12, 13, 14, 15.…”

Section: Introductionmentioning

confidence: 76%

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

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The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease.

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Section: Introductionmentioning

confidence: 76%

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

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“…13,32,55 Phenotypic plasticity may allow non-CSCs to acquire CSC traits and replenish the CSC pool as has been reported in malignancies such as malignant melanomas 56,57 and prostate cancers. 58 Roesch et al 57 used the H3K4 demethylase JARID1B as a biomarker and characterized a small subpopulation of slow-cycling melanoma cells that cycled with doubling times of 44 weeks within the rapidly proliferating main population.…”

Section: Epigenetic Regulation In Cscsmentioning

confidence: 97%

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

Hardin

Zhang

Helein

et al. 2017

Laboratory Investigation

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The cancer stem-like cell (CSC) hypothesis postulates that a small population of cells in a cancer has self-renewal and clonal tumor initiation properties. These cells are responsible for tumor initiation, growth, recurrence and for resistance to chemotherapy and radiation therapy. CSCs can be characterized using markers such as SSEA-1, SSEA-4, CD44, CD24, ALDEFLUOR and others. CSCs form spheres when they are cultured in serum-free condition in low attachment plates and can generate tumors when injected into immune-deficient mice. During epithelial to mesenchymal transition (EMT), cells lose cellular adhesion and polarity and acquire an invasive phenotype. Recent studies have established a relationship between EMT and increased numbers of CSCs in some solid malignancies. Non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs) have been shown to have important roles during EMT and some of these molecules also have regulatory roles in the proliferation of CSCs. Specific lncRNAs enhanced cell migration and invasion in breast carcinomas, which was associated with the generation of stem cell properties. The tumor microenvironment of CSCs also has an important role in tumor progression. Recent studies have shown that the interaction between tumor cells and the local microenvironment at the metastatic site leads to the development of premetastatic niche(s) and allows for the proliferation of the metastatic cells during colonization. The role of exosomes in the microenvironment during the EMT program is currently a major area of research. This review examines CSCs and the relationship between EMT and CSCs in solid tumors with emphasis on thyroid CSCs. The role of non-coding RNAs and of the microenvironment in EMT and in tumor progression are also examined. This review also highlights the growing number of studies that show the close association of EMT and CSCs and the role of exosomes and other elements of the tissue microenvironment in CSC metastasis. A better understanding of these mechanisms will lead to more effective targeting of primary and metastatic malignancies.

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“…It is possible to analyze subgroups in TCGAbiolinks; however, the groups are mainly predefined and the user has less flexibility in choosing or making their own subgroups for analysis. Recent research has elucidated substantial heterogeneity in tumor genomes and epigenomes [18] and the importance of investigating cancer subgroups is becoming more evident [19]. Therefore, it is crucial to have tools and analysis pipelines that allow interrogation of tumor subgroups at multiple levels.…”

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confidence: 99%

Scan_Tcga Tools for Integrated Epigenomic and Transcriptomic Analysis of Tumor Subgroups

et al. 2016

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Aim:The Cancer Genome Atlas contains multiple levels of genomic data (mutation, gene expression, DNA methylation, copy number variation) for 33 cancer types for almost 11,000 patients. However, a dearth of appropriate software tools makes it difficult for bench scientists to use these data effectively. Materials & methods: Here, we present a suite of flexible, fast and command line-based scripts that will allow retrieval and analysis of DNA methylation (tool: scan_tcga_methylation.awk), mRNA (tool: scan_tcga_mRNA.awk) and miRNA expression (tool: scan_tcga_miRNAs.awk) from cancer genome atlas network level 3 data. Results: We demonstrate the utility of these tools by analyzing DNA methylation and mRNA expression signatures of 60 frequently deregulated cancer genes and also of 30 miRNAs in primary (n = 102) and metastatic melanoma patients (n = 367). Conclusion: Our analysis illustrates the validity of the scan_tcga tools and reveals the epigenomic signatures and importance of identifying smaller patient subgroups with distinct molecular profiles.

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Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance

Cited by 797 publications

References 98 publications

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

Scan_Tcga Tools for Integrated Epigenomic and Transcriptomic Analysis of Tumor Subgroups

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