1 5292 119 PROSTATIC INFLAMMATION ENHANCES BASAL-TO-LUMINAL DIFFERENTIATION AND ACCELERATES INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. CHRONIC INFLAMMATION HAS BEEN SHOWN TO PROMOTE THE INITIATION AND PROGRESSION OF DIVERSE MALIGNANCIES BY INDUCING GENETIC AND EPIGENETIC ALTERATIONS. IN THIS STUDY, WE INVESTIGATE AN ALTERNATIVE MECHANISM THROUGH WHICH INFLAMMATION PROMOTES THE INITIATION OF PROSTATE CANCER. ADULT MURINE PROSTATE EPITHELIA ARE COMPOSED PREDOMINANTLY OF BASAL AND LUMINAL CELLS. PREVIOUS STUDIES REVEALED THAT THE TWO LINEAGES ARE LARGELY SELF-SUSTAINED WHEN RESIDING IN THEIR NATIVE MICROENVIRONMENT. TO INTERROGATE WHETHER TISSUE INFLAMMATION ALTERS THE DIFFERENTIATION PROGRAM OF BASAL CELLS, WE CONDUCTED LINEAGE TRACING OF BASAL CELLS USING A K14-CREER;MTMG MODEL IN CONCERT WITH A MURINE MODEL OF PROSTATITIS INDUCED BY INFECTION FROM THE UROPATHOGENIC BACTERIA CP9. WE SHOW THAT ACUTE PROSTATITIS CAUSES TISSUE DAMAGE AND CREATES A TISSUE MICROENVIRONMENT THAT INDUCES THE DIFFERENTIATION OF BASAL CELLS INTO LUMINAL CELLS, AN ALTERATION THAT RARELY OCCURS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. PREVIOUSLY WE SHOWED THAT A MOUSE MODEL WITH PROSTATE BASAL CELL-SPECIFIC DELETION OF PHOSPHATASE AND TENSIN HOMOLOG (K14-CREER;PTEN(FL/FL)) DEVELOPS PROSTATE CANCER WITH A LONG LATENCY, BECAUSE DISEASE INITIATION IN THIS MODEL REQUIRES AND IS LIMITED BY THE DIFFERENTIATION OF TRANSFORMATION-RESISTANT BASAL CELLS INTO TRANSFORMATION-COMPETENT LUMINAL CELLS. HERE, WE SHOW THAT CP9-INDUCED PROSTATITIS SIGNIFICANTLY ACCELERATES THE INITIATION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA IN THIS MODEL. OUR RESULTS DEMONSTRATE THAT INFLAMMATION RESULTS IN A TISSUE MICROENVIRONMENT THAT ALTERS THE NORMAL PROSTATE EPITHELIAL CELL DIFFERENTIATION PROGRAM AND THAT THROUGH THIS CELLULAR PROCESS INFLAMMATION ACCELERATES THE INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. 2014 2 2926 28 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 3 6201 34 THE INFLAMMATORY MICROENVIRONMENT AND MICROBIOME IN PROSTATE CANCER DEVELOPMENT. CHRONIC INFLAMMATION PROMOTES THE DEVELOPMENT OF SEVERAL TYPES OF SOLID CANCERS AND MIGHT CONTRIBUTE TO PROSTATE CARCINOGENESIS. THIS HYPOTHESIS PARTLY ORIGINATES IN THE FREQUENT OBSERVATION OF INFLAMMATORY CELLS IN THE PROSTATE MICROENVIRONMENT OF ADULT MEN. INFLAMMATION IS ASSOCIATED WITH PUTATIVE PROSTATE CANCER PRECURSOR LESIONS, TERMED PROLIFERATIVE INFLAMMATORY ATROPHY. INFLAMMATION MIGHT DRIVE PROSTATE CARCINOGENESIS VIA OXIDATIVE STRESS AND GENERATION OF REACTIVE OXYGEN SPECIES THAT INDUCE MUTAGENESIS. ADDITIONALLY, INFLAMMATORY STRESS MIGHT CAUSE EPIGENETIC ALTERATIONS THAT PROMOTE NEOPLASTIC TRANSFORMATION. PROLIFERATIVE INFLAMMATORY ATROPHY IS ENRICHED FOR PROLIFERATIVE LUMINAL EPITHELIAL CELLS OF INTERMEDIATE PHENOTYPE THAT MIGHT BE PRONE TO GENOMIC ALTERATIONS LEADING TO PROSTATIC INTRAEPITHELIAL NEOPLASIA AND PROSTATE CANCER. STUDIES IN ANIMALS SUGGEST THAT INFLAMMATORY CHANGES IN THE PROSTATE MICROENVIRONMENT CONTRIBUTE TO REPROGRAMMING OF PROSTATE EPITHELIAL CELLS, A POSSIBLE STEP IN TUMOUR INITIATION. PROSTATIC INFECTION, CONCURRENT WITH EPITHELIAL BARRIER DISRUPTION, MIGHT BE A KEY DRIVER OF AN INFLAMMATORY MICROENVIRONMENT; THE DISCOVERY OF A URINARY MICROBIOME INDICATES A POTENTIAL SOURCE OF FREQUENT EXPOSURE OF THE PROSTATE TO A DIVERSE NUMBER OF MICROORGANISMS. HENCE, CURRENT EVIDENCE SUGGESTS THAT INFLAMMATION AND ATROPHY ARE INVOLVED IN PROSTATE CARCINOGENESIS AND SUGGESTS A ROLE FOR THE MICROBIOME IN ESTABLISHING AN INFLAMMATORY PROSTATE MICROENVIRONMENT THAT MIGHT PROMOTE PROSTATE CANCER DEVELOPMENT AND PROGRESSION. 2018 4 5785 33 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 5 5491 33 REVIEW ARTICLE: INFLAMMATION-RELATED PROMOTION OF GASTROINTESTINAL CARCINOGENESIS--A PERIGENETIC PATHWAY. CHRONIC INFLAMMATION HAS BEEN REPORTED TO ACCELERATE NEOPLASMAS IN GASTROINTESTINAL TRACT. CERTAIN BACTERIA INCLUDING HELICOBACTER PYLORI DIRECTLY INTERACT WITH HOST CELLS, INDUCE PROINFLAMMATORY CYTOKINES AND STIMULATE PRODUCTION OF FREE RADICALS. FREE RADICALS CAUSE MUTATIONS IN TARGET CELLS SO THAT NEOPLASTIC CLONES ARE ESTABLISHED. ACCUMULATION OF SUCH GENETIC ALTERATIONS MAY CAUSE MALIGNANT TRANSFORMATION OF SOME ESTABLISHED CLONES. IN ADDITION, INFLAMMATORY ALTERATIONS MAY PROMOTE GROWTH, EXPANSION AND INVASION OF GASTROINTESTINAL EPITHELIAL CELLS. THE LATTER CHANGES CAUSED BY INFLAMMATION MAY OCCUR EVEN WITHOUT FURTHER GENETIC MUTATIONS OR EPIGENETIC ALTERATIONS, AND THEREFORE MAY BE CATEGORIZED AS 'PERIGENETIC ALTERATIONS' OF NEOPLASTIC CELLS. FOR AN EXAMPLE, TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA) PLAYS PIVOTAL ROLES NOT ONLY IN THE REDUCTION BUT ALSO IN THE GROWTH, INVASION AND METASTASES OF CERTAIN NEOPLASMAS. OUR STUDIES SHOW THAT TNF-ALPHA INCREASES INTRACELLULAR RADICAL PRODUCTION, DEGRADATES E-CADHERIN / BETA-CATENIN COMPLEX AND PROMOTES DISPERSION AND MIGRATION IN EPITHELIAL CELLS TRANSFORMED WITH AN ACTIVATED SRC ONCOGENE (V-SRC). THESE DATA INDICATE THAT AN INFLAMMATORY CYTOKINE INDUCES THE MALIGNANT POTENTIAL OF SRC-ACTIVATED NEOPLASTIC CELLS. INTERESTINGLY, TNF-ALPHA ALSO INDUCED THESE PHENOTYPIC CHANGES IN NONMUTATED CELLS WHOSE C-SRC WAS ACTIVATED BY TGF-ALPHA, SUGGESTING THAT THE INVASIVE PROPERTIES OF THE CELL WERE NOT NECESSARILY RELATED TO GENE MUTATION. FURTHERMORE, CERTAIN RADICAL SCAVENGERS SUPPRESSED THE INVASIVE PHENOTYPE OF THE CELLS. THESE RESULTS INDICATE THAT PERIGENETIC ALTERATIONS ARE AN IMPORTANT TARGET OF PHARMACOLOGICAL INTERVENTION OF CARCINOGENESIS. 2003 6 3950 27 LNFLAMMATION-INDUCED EPIGENETIC SWITCHES IN CANCER. THE LINK BETWEEN INFLAMMATION AND CANCER IS WELL ESTABLISHED. CHRONIC INFLAMMATION PROMOTES CANCER INITIATION AND PROGRESSION. VARIOUS STUDIES SHOWED THAT THE UNDERLYING MECHANISMS INVOLVE EPIGENETIC ALTERATIONS. THESE EPIGENETIC ALTERATIONS MIGHT CULMINATE INTO AN EPIGENETIC SWITCH THAT TRANSFORMS PREMALIGNANT CELLS INTO TUMOR CELLS OR NON-INVASIVE INTO INVASIVE TUMOR CELLS, THEREBY PROMOTING METASTASIS. EPIGENETIC SWITCHES REQUIRE AN INITIATING EVENT, WHICH CAN BE INFLAMMATION, WHEREAS THE RESULTING PHENOTYPE IS INHERITED WITHOUT THE INITIATING SIGNAL. EPIGENETIC SWITCHES ARE INDUCED AND MAINTAINED BY DNA METHYLATION, HISTONE MODIFICATIONS, POLYCOMB GROUP (PCG)/TRITHORAX GROUP (TRXG) PROTEINS, AND FEEDBACK LOOPS CONSISTING OF TRANSCRIPTION FACTORS AND MICRORNAS. SINCE EPIGENETIC SWITCHES ARE REVERSIBLE, THEY MIGHT REPRESENT AN IMPORTANT BASIS FOR THE DESIGN OF NOVEL ANTICANCER THERAPEUTICS. THIS REVIEW SUMMARIZES PUBLISHED EVIDENCE OF EPIGENETIC SWITCHES IN CANCER DEVELOPMENT THAT ARE INDUCED BY INFLAMMATION. 2016 7 1326 23 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES. 2012 8 6154 36 THE GENE EXPRESSION PROGRAM OF PROSTATE FIBROBLAST SENESCENCE MODULATES NEOPLASTIC EPITHELIAL CELL PROLIFERATION THROUGH PARACRINE MECHANISMS. THE GREATEST RISK FACTOR FOR DEVELOPING CARCINOMA OF THE PROSTATE IS ADVANCED AGE. POTENTIAL MOLECULAR AND PHYSIOLOGIC CONTRIBUTORS TO THE FREQUENCY OF CANCER OCCURRENCE IN OLDER INDIVIDUALS INCLUDE THE ACCUMULATION OF SOMATIC MUTATIONS THROUGH DEFECTS IN GENOME MAINTENANCE, EPIGENETIC GENE SILENCING, OXIDATIVE STRESS, LOSS OF IMMUNE SURVEILLANCE, TELOMERE DYSFUNCTION, CHRONIC INFLAMMATION, AND ALTERATIONS IN TISSUE MICROENVIRONMENT. IN THIS CONTEXT, THE PROCESS OF PROSTATE CARCINOGENESIS CAN BE INFLUENCED THROUGH INTERACTIONS BETWEEN INTRINSIC CELLULAR ALTERATIONS AND THE EXTRINSIC MICROENVIRONMENT AND MACROENVIRONMENT, BOTH OF WHICH CHANGE SUBSTANTIALLY AS A CONSEQUENCE OF AGING. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE MOLECULAR ALTERATIONS THAT OCCUR DURING THE PROCESS OF PROSTATE FIBROBLAST SENESCENCE TO IDENTIFY FACTORS IN THE AGED TISSUE MICROENVIRONMENT CAPABLE OF PROMOTING THE PROLIFERATION AND POTENTIALLY THE NEOPLASTIC PROGRESSION OF PROSTATE EPITHELIUM. WE EVALUATED THREE MECHANISMS LEADING TO CELL SENESCENCE: OXIDATIVE STRESS, DNA DAMAGE, AND REPLICATIVE EXHAUSTION. WE IDENTIFIED A CONSISTENT PROGRAM OF GENE EXPRESSION THAT INCLUDES A SUBSET OF PARACRINE FACTORS CAPABLE OF INFLUENCING ADJACENT PROSTATE EPITHELIAL GROWTH. BOTH DIRECT COCULTURE AND CONDITIONED MEDIUM FROM SENESCENT PROSTATE FIBROBLASTS STIMULATED EPITHELIAL CELL PROLIFERATION, 3-FOLD AND 2-FOLD, RESPECTIVELY. THE PARACRINE-ACTING PROTEINS FIBROBLAST GROWTH FACTOR 7, HEPATOCYTE GROWTH FACTOR, AND AMPHIREGULIN (AREG) WERE ELEVATED IN THE EXTRACELLULAR ENVIRONMENT OF SENESCENT PROSTATE FIBROBLASTS. EXOGENOUS AREG ALONE STIMULATED PROSTATE EPITHELIAL CELL GROWTH, AND NEUTRALIZING ANTIBODIES AND SMALL INTERFERING RNA TARGETING AREG ATTENUATED, BUT DID NOT COMPLETELY ABROGATE THE GROWTH-PROMOTING EFFECTS OF SENESCENT FIBROBLAST CONDITIONED MEDIUM. THESE RESULTS SUPPORT THE CONCEPT THAT AGING-RELATED CHANGES IN THE PROSTATE MICROENVIRONMENT MAY CONTRIBUTE TO THE PROGRESSION OF PROSTATE NEOPLASIA. 2006 9 3659 33 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 10 2338 29 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER. 2022 11 5291 30 PROSTATE CARCINOGENESIS: INSIGHTS IN RELATION TO EPIGENETICS AND INFLAMMATION. PROSTATE CANCER IS A MULTIFACTORIAL DISEASE THAT MAINLY OCCURS DUE TO THE ACCUMULATION OF SOMATIC, GENETIC, AND EPIGENETIC CHANGES, RESULTING IN THE INACTIVATION OF TUMOR-SUPPRESSOR GENES AND ACTIVATION OF ONCOGENES. MUTATIONS IN GENES, SPECIFICALLY THOSE THAT CONTROL CELL GROWTH AND DIVISION OR THE REPAIR OF DAMAGED DNA, MAKE THE CELLS GROW AND DIVIDE UNCONTROLLABLY TO FORM A TUMOR. THE RISK OF DEVELOPING PROSTATE CANCER DEPENDS UPON THE GENE THAT HAS UNDERGONE THE MUTATION. IDENTIFYING SUCH GENETIC RISK FACTORS FOR PROSTATE CANCER POSES A CHALLENGE FOR THE RESEARCHERS. BESIDES GENETIC MUTATIONS, MANY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS (METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION) NUCLEOSOMAL REMODELING, AND CHROMOSOMAL LOOPING, HAVE SIGNIFICANTLY CONTRIBUTED TO THE ONSET OF PROSTATE CANCER AS WELL AS THE PROGNOSIS, DIAGNOSIS, AND TREATMENT OF PROSTATE CANCER. CHRONIC INFLAMMATION ALSO PLAYS A MAJOR ROLE IN THE ONSET AND PROGRESSION OF HUMAN CANCER, VIA MODIFICATIONS IN THE TUMOR MICROENVIRONMENT BY INITIATING EPITHELIALMESENCHYMAL TRANSITION AND REMODELING THE EXTRACELLULAR MATRIX. IN THIS ARTICLE, THE AUTHORS PRESENT A BRIEF HISTORY OF THE MECHANISMS AND POTENTIAL LINKS BETWEEN THE GENETIC ABERRATIONS, EPIGENETIC CHANGES, INFLAMMATION, AND INFLAMMASOMES THAT ARE KNOWN TO CONTRIBUTE TO THE PROGNOSIS OF PROSTATE CANCER. FURTHERMORE, THE AUTHORS EXAMINE AND DISCUSS THE CLINICAL POTENTIAL OF PROSTATE CARCINOGENESIS IN RELATION TO EPIGENETICS AND INFLAMMATION FOR ITS DIAGNOSIS AND TREATMENT.. 2021 12 2033 31 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 13 4539 30 MULTISTAGE CARCINOGENESIS IN MOUSE SKIN. THE MOUSE SKIN MODEL OF MULTISTAGE CARCINOGENESIS HAS FOR MANY YEARS PROVIDED A CONCEPTUAL FRAMEWORK FOR STUDYING CARCINOGENESIS MECHANISMS AND POTENTIAL MEANS FOR INHIBITING SPECIFIC STAGES OF CARCINOGENESIS. THE PROCESS OF SKIN CARCINOGENESIS INVOLVES THE STEPWISE ACCUMULATION OF GENETIC CHANGE ULTIMATELY LEADING TO MALIGNANCY. INITIATION, THE FIRST STEP IN MULTISTAGE SKIN CARCINOGENESIS INVOLVES CARCINOGEN-INDUCED GENETIC CHANGES. A TARGET GENE IDENTIFIED FOR SOME SKIN TUMOR INITIATORS IS C-HA-RAS. THE SECOND STEP, THE PROMOTION STAGE, INVOLVES PROCESSES WHEREBY INITIATED CELLS UNDERGO SELECTIVE CLONAL EXPANSION TO FORM VISIBLE PREMALIGNANT LESIONS TERMED PAPILLOMAS. THE PROCESS OF TUMOR PROMOTION INVOLVES THE PRODUCTION AND MAINTENANCE OF A SPECIFIC AND CHRONIC HYPERPLASIA CHARACTERIZED BY A SUSTAINED CELLULAR PROLIFERATION OF EPIDERMAL CELLS. THESE CHANGES ARE BELIEVED TO RESULT FROM EPIGENETIC MECHANISMS SUCH AS ACTIVATION OF THE CELLULAR RECEPTOR, PROTEIN KINASE C, BY SOME CLASSES OF TUMOR PROMOTERS. THE PROGRESSION STAGE INVOLVES THE CONVERSION OF PAPILLOMAS TO MALIGNANT TUMORS, SQUAMOUS CELL CARCINOMAS. THE ACCUMULATION OF ADDITIONAL GENETIC CHANGES IN CELLS COMPRISING PAPILLOMAS HAS BEEN CORRELATED WITH TUMOR PROGRESSION, INCLUDING TRISOMIES OF CHROMOSOMES 6 AND 7 AND LOSS OF HETEROZYGOSITY. THE CURRENT REVIEW FOCUSES ON THE MECHANISMS INVOLVED IN MULTISTAGE SKIN CARCINOGENESIS, A SUMMARY OF KNOWN INHIBITORS OF SPECIFIC STAGES AND THEIR PROPOSED MECHANISMS OF ACTION, AND THE RELEVANCE OF THIS MODEL SYSTEM TO HUMAN CANCER. 1992 14 3525 32 IL-1BETA, IL-8, AND MATRIX METALLOPROTEINASES-1, -2, AND -10 ARE ENRICHED UPON MONOCYTE-BREAST CANCER CELL COCULTIVATION IN A MATRIGEL-BASED THREE-DIMENSIONAL SYSTEM. BREAST CANCER REMAINS THE FIRST CANCER-RELATED CAUSE OF DEATH IN WOMEN WORLDWIDE, PARTICULARLY IN DEVELOPING COUNTRIES IN WHICH MOST CASES ARE DIAGNOSED IN LATE STAGES. ALTHOUGH MOST CANCER STUDIES ARE BASED IN THE GENETIC OR EPIGENETIC CHANGES OF THE TUMOR CELLS, IMMUNE CELLS WITHIN THE TUMOR STROMA OFTEN COOPERATE WITH CANCER PROGRESSION. PARTICULARLY, MONOCYTES ARE ATTRACTED TO THE TUMOR PRIMARY SITE IN WHICH THEY ARE DIFFERENTIATED INTO TUMOR-ASSOCIATED MACROPHAGES THAT FACILITATE TUMOR CELL INVASION AND METASTASIS. IN THIS STUDY, WE USED THREE-DIMENSIONAL CULTURES TO FORM ACINI-LIKE STRUCTURES TO ANALYZE THE INFLAMMATORY SECRETION PROFILE OF TUMOR CELLS INDIVIDUALLY OR IN CO-CULTURE WITH MONOCYTES. BREAST CANCER CELL LINES AND PRIMARY ISOLATES FROM EIGHT MEXICAN PATIENTS WITH BREAST CANCER WERE USED. WE FOUND HIGH LEVELS OF RANTES/CCL5, MCP-1/CCL2, AND G-CSF IN THE BREAST CANCER INDIVIDUAL CULTURES, SUPPORTING AN IMPORTANT RECRUITMENT CAPACITY OF MONOCYTES, BUT ALSO OF NEUTROPHILS. THE CO-CULTURES OF THE TUMOR CELLS AND MONOCYTES WERE SIGNIFICANTLY ENRICHED WITH THE POTENT PRO-INFLAMMATORY CYTOKINES INTERLEUKIN (IL)-1BETA AND IL-8, KNOWN TO SUPPORT MALIGNANT PROGRESSION. WE ALSO FOUND THAT THE INTERACTION OF TUMOR CELLS WITH MONOCYTES PROMOTED HIGH LEVELS OF MATRIX METALLOPROTEINASES (MMP)-1, MMP-2, AND MMP-10. OUR STUDY SUPPORTS THAT A KEY EVENT FOR MALIGNANT PROGRESSION IS THE RECRUITMENT OF DIFFERENT IMMUNE CELL POPULATIONS, WHICH HELP TO SUSTAIN AND ENHANCE A CHRONIC INFLAMMATORY MICROENVIRONMENT THAT HIGHLY FAVORS TUMOR MALIGNANCY. 2017 15 2055 23 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 16 6906 25 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 17 3799 22 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 18 2914 43 GENE REGULATORY NETWORK UNDERLYING THE IMMORTALIZATION OF EPITHELIAL CELLS. BACKGROUND: TUMORIGENIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS IN VITRO HAS BEEN DESCRIBED EXPERIMENTALLY AS THE POTENTIAL RESULT OF SPONTANEOUS IMMORTALIZATION. THIS PROCESS IS CHARACTERIZED BY A SERIES OF CELL-STATE TRANSITIONS, IN WHICH NORMAL EPITHELIAL CELLS ACQUIRE FIRST A SENESCENT STATE WHICH IS LATER SURPASSED TO ATTAIN A MESENCHYMAL STEM-LIKE PHENOTYPE WITH A POTENTIALLY TUMORIGENIC BEHAVIOR. IN THIS PAPER WE AIM TO PROVIDE A SYSTEM-LEVEL MECHANISTIC EXPLANATION TO THE EMERGENCE OF THESE CELL TYPES, AND TO THE TIME-ORDERED TRANSITION PATTERNS THAT ARE COMMON TO NEOPLASIAS OF EPITHELIAL ORIGIN. TO THIS END, WE FIRST INTEGRATE PUBLISHED FUNCTIONAL AND WELL-CURATED MOLECULAR DATA OF THE COMPONENTS AND INTERACTIONS THAT HAVE BEEN FOUND TO BE INVOLVED IN SUCH CELL STATES AND TRANSITIONS INTO A NETWORK OF 41 MOLECULAR COMPONENTS. WE THEN REDUCE THIS INITIAL NETWORK BY REMOVING SIMPLE MEDIATORS (I.E., LINEAR PATHWAYS), AND FORMALIZE THE RESULTING REGULATORY CORE INTO LOGICAL RULES THAT GOVERN THE DYNAMICS OF EACH OF THE NETWORK COMPONENTS AS A FUNCTION OF THE STATES OF ITS REGULATORS. RESULTS: COMPUTATIONAL DYNAMIC ANALYSIS SHOWS THAT OUR PROPOSED GENE REGULATORY NETWORK MODEL RECOVERS EXACTLY THREE ATTRACTORS, EACH OF THEM DEFINED BY A SPECIFIC GENE EXPRESSION PROFILE THAT CORRESPONDS TO THE EPITHELIAL, SENESCENT, AND MESENCHYMAL STEM-LIKE CELLULAR PHENOTYPES, RESPECTIVELY. WE SHOW THAT ALTHOUGH A MESENCHYMAL STEM-LIKE STATE CAN BE ATTAINED EVEN UNDER UNPERTURBED PHYSIOLOGICAL CONDITIONS, THE LIKELIHOOD OF CONVERGING TO THIS STATE IS INCREASED WHEN PRO-INFLAMMATORY CONDITIONS ARE SIMULATED, PROVIDING A SYSTEMS-LEVEL MECHANISTIC EXPLANATION FOR THE CARCINOGENIC ROLE OF CHRONIC INFLAMMATORY CONDITIONS OBSERVED IN THE CLINIC. WE ALSO FOUND THAT THE REGULATORY CORE YIELDS AN EPIGENETIC LANDSCAPE THAT RESTRICTS TEMPORAL PATTERNS OF PROGRESSION BETWEEN THE STEADY STATES, SUCH THAT RECOVERED PATTERNS RESEMBLE THE TIME-ORDERED TRANSITIONS OBSERVED DURING THE SPONTANEOUS IMMORTALIZATION OF EPITHELIAL CELLS, BOTH IN VIVO AND IN VITRO. CONCLUSION: OUR STUDY STRONGLY SUGGESTS THAT THE IN VITRO TUMORIGENIC TRANSFORMATION OF EPITHELIAL CELLS, WHICH STRONGLY CORRELATES WITH THE PATTERNS OBSERVED DURING THE PATHOLOGICAL PROGRESSION OF EPITHELIAL CARCINOGENESIS IN VIVO, EMERGES FROM UNDERLYING REGULATORY NETWORKS INVOLVED IN EPITHELIAL TRANS-DIFFERENTIATION DURING DEVELOPMENT. 2017 19 45 28 A COMPREHENSIVE REVIEW ON RNA INTERFERENCE-MEDIATED TARGETING OF INTERLEUKINS AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN COLON CANCER. COLON CANCER IS THE WORLD'S FOURTH LEADING CAUSE OF DEATH. IT IS CANCER OF THE LATTER PART OF THE LARGE INTESTINE, I.E. THE COLON. CHRONIC INFLAMMATION OVER A LONG PERIOD ALSO LEADS TO THE DEVELOPMENT OF CANCER. CANCER IN THE COLON REGION IS ARDUOUS TO DIAGNOSE AND IS DETECTED AT A LATER STAGE WHEN IT METASTASIZES TO OTHER PARTS OF THE BODY LIKE THE LIVER, LUNGS, PERITONEUM, ETC. COLON CANCER IS A GREAT EXAMPLE OF SOLID TUMOURS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH CONVENTIONAL THERAPIES ARE EFFECTIVE, THEY LOSE THEIR EFFECTIVENESS BEYOND A CERTAIN POINT. RELAPSE OF THE DISEASE OCCURS FREQUENTLY. RNA INTERFERENCE (RNAI) IS EMERGING AS A GREAT TOOL TO SPECIFICALLY ATTACK THE CANCER CELLS OF A TARGET SITE LIKE THE COLON. RNAI DEALS WITH EPIGENETIC CHANGES MADE IN THE DEFECTIVE CELLS WHICH ULTIMATELY LEADS TO THEIR DEATH WITHOUT HARMING THE HEALTHY CELLS. IN THIS REVIEW, TWO TYPES OF EPIGENETIC MODULATORS HAVE BEEN CONSIDERED, NAMELY SIRNA AND MIRNA, AND THEIR EFFECT ON INTERLEUKINS. INTERLEUKINS, A CLASS OF CYTOKINES, ARE MAJOR INFLAMMATORY RESPONSES OF THE BODY THAT ARE RELEASED BY IMMUNE CELLS LIKE LEUKOCYTES AND MACROPHAGES. SOME OF THESE INTERLEUKINS ARE PRO-INFLAMMATORY, THEREBY PROMOTING INFLAMMATION WHICH EVENTUALLY CAUSES CANCER. RNAI CAN PREVENT COLON CANCER BY INHIBITING PRO-INFLAMMATORY INTERLEUKINS. 2023 20 925 30 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015