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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; human ; IN-VIVO ; MODEL ; MODELS ; VIVO ; CLASSIFICATION ; COMMON ; DISEASE ; DISTINCT ; GENE ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TUMORS ; DNA ; MECHANISM ; mechanisms ; T cell ; T-CELL ; BIOLOGY ; SEQUENCE ; SEQUENCES ; SUSCEPTIBILITY ; BREAST-CANCER ; culture ; MOUSE ; STAGE ; PROGRESSION ; LYMPHOMA ; PATTERNS ; PROMOTER ; TUMOR PROGRESSION ; genetics ; COLORECTAL-CANCER ; DNA methylation ; inactivation ; p53 ; EVOLUTION ; PHENOTYPE ; MOUSE MODEL ; SELECTION ; specificity ; OVEREXPRESSION ; METHYLATION ; TUMOR CELLS ; heredity ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HYPERMETHYLATION ; HETEROGENEITY ; EPIGENETIC INACTIVATION ; targeting ; PROGRAM ; PATTERN ; TUMOR-SUPPRESSOR ; HUMAN CANCER ; ACUTE MYELOID-LEUKEMIA ; LIBRARIES ; CELL LYMPHOMA ; CPG ISLANDS ; GENE-TRANSCRIPTION ; development ; TUMOR-CELL ; SUPPRESSOR ; PROFILES ; EVENTS ; SIGNATURE ; DISEASE PROGRESSION ; USA ; CPG ISLAND HYPERMETHYLATION ; HUMAN CANCERS ; PROMOTER METHYLATION ; CANCERS ; in vivo ; genomic ; GENETIC ALTERATION ; RARE ; PREDICT ; CpG island ; MYC ; TUMOR-DEVELOPMENT ; DNA-METHYLATION ; scanning ; CELL LYMPHOMAS ; evidence ; TUMOR SUPPRESSORS ; CAUSAL ROLE ; DNA HYPOMETHYLATION
    Abstract: Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Global patterns of hypermethylation are tumor-type specific and nonrandom. The biological significance and the underlying mechanisms of tumor-specific aberrant promoter methylation remain unclear, but some evidence suggests that this specificity involves differential sequence susceptibilities, the targeting of DNA methylation activity to specific promoter sequences, or the selection of rare DNA methylation events during disease progression. Using restriction landmark genomic scanning on samples derived from tissue culture and in vivo models of T cell lymphomas, we found that MYC overexpression gave rise to a specific signature of CpG island hypermethylation. This signature reflected gene transcription profiles and was detected only in advanced stages of disease. The further inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic CpG island methylation signatures. Our data suggest that tumor-specific DNA methylation in lymphomas arises as a result of the selection of rare DNA methylation events during the course of tumor development. This selection appears to be driven by the genetic configuration of tumor cells, providing experimental evidence for a causal role of DNA hypermethylation in tumor progression and an explanation for the tremendous epigenetic heterogeneity observed in the evolution of human cancers. The ability to predict genome-wide epigenetic silencing based on relatively few genetic alterations will allow for a more complete classification of tumors and understanding of tumor cell biology
    Type of Publication: Journal article published
    PubMed ID: 17907813
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  • 2
    Publication Date: 2018-04-14
    Description: Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy. Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro . Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent. Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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