1 5602 114 RORGAMMAT(+) HEMATOPOIETIC CELLS ARE NECESSARY FOR TUMOR CELL PROLIFERATION DURING COLITIS-ASSOCIATED TUMORIGENESIS IN MICE. COLORECTAL CANCER (CRC) IS ONE OF THE MOST COMMON TUMOR ENTITIES. IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES, THE DEVELOPMENT OF COLITIS-ASSOCIATED COLON CANCER IS CONSIDERED A DANGEROUS LONG-TERM COMPLICATION. IL-17A AND THE TRANSCRIPTION FACTOR RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) PLAY FUNDAMENTAL ROLES IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES; IN HUMAN STUDIES, WE DETECTED A DENSE INFILTRATION OF RORGAMMAT-DEPENDENT CD4(+) IL17A(+) T HELPER (TH)17 CELLS IN SPECIMENS OF CRC, ULCERATIVE COLITIS, AND ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER. HOWEVER, THE MECHANISTIC ROLE OF RORGAMMAT(+) HEMATOPOIETIC CELLS IN COLITIS-ASSOCIATED TUMORIGENESIS REMAINS UNCLEAR. TO INVESTIGATE COLITIS-ASSOCIATED COLON TUMORIGENESIS, WE CONDUCTED STUDIES IN THE AOM+DSS MOUSE MODEL THAT REVEALED THE IMPORTANCE OF RORGAMMAT FOR COLON TUMOR PROGRESSION. IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES, MICE SHOWED SIGNS OF INTENSE CHRONIC COLITIS, BUT DEVELOPED SIGNIFICANTLY FEWER MACROSCOPIC TUMOR NODULES. THE REDUCTION OF TUMOR DEVELOPMENT IN RORGAMMAT(-/-) MICE WAS NOT DUE TO REDUCED COLON TUMOR INITIATION. HOWEVER, THE PROLIFERATION RATE OF TUMOR CELLS WAS REDUCED IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 CELLS AND TUMOR CELLS SHOWED PRONOUNCED SIGNS OF SENESCENCE-ASSOCIATED EPIGENETIC AND LYSOSOMAL CHANGES. THESE RESULTS INDICATE AN IMPORTANT ROLE FOR THE IMMUNOLOGICAL MILIEU IN COLITIS-ASSOCIATED CANCER, WHICH IS SHAPED IN-PART BY RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES THAT SUPPORT CRC GROWTH. 2015 2 3218 43 HELICOBACTER INFECTION IS REQUIRED FOR INFLAMMATION AND COLON CANCER IN SMAD3-DEFICIENT MICE. ACCUMULATING EVIDENCE SUGGESTS THAT INTESTINAL MICROBIAL ORGANISMS MAY PLAY AN IMPORTANT ROLE IN TRIGGERING AND SUSTAINING INFLAMMATION IN INDIVIDUALS AFFLICTED WITH INFLAMMATORY BOWEL DISEASE (IBD). MOREOVER, INDIVIDUALS WITH IBD ARE AT INCREASED RISK FOR DEVELOPING COLORECTAL CANCER, SUGGESTING THAT CHRONIC INFLAMMATION MAY INITIATE GENETIC OR EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. WE TESTED THE HYPOTHESIS THAT BACTERIA MAY CONTRIBUTE TO THE DEVELOPMENT OF COLON CANCER BY SYNERGIZING WITH DEFECTIVE TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, A PATHWAY COMMONLY MUTATED IN HUMAN COLON CANCER. ALTHOUGH OTHERS HAVE REPORTED THAT MICE DEFICIENT IN THE TGF-BETA SIGNALING MOLECULE SMAD3 DEVELOP COLON CANCER, WE FOUND THAT SMAD3-DEFICIENT MICE MAINTAINED FREE OF THE GRAM-NEGATIVE ENTEROHEPATIC BACTERIA HELICOBACTER SPP. FOR UP TO 9 MONTHS DO NOT DEVELOP COLON CANCER. FURTHERMORE, INFECTION OF SMAD3(-/-) MICE WITH HELICOBACTER TRIGGERS COLON CANCER IN 50% TO 66% OF THE ANIMALS. USING REAL-TIME PCR, WE FOUND THAT HELICOBACTER ORGANISMS CONCENTRATE IN THE CECUM, THE PREFERRED SITE OF TUMOR DEVELOPMENT. MUCINOUS ADENOCARCINOMAS DEVELOP 5 TO 30 WEEKS AFTER INFECTION AND ARE PRECEDED BY AN EARLY INFLAMMATORY PHASE, CONSISTING OF INCREASED PROLIFERATION OF EPITHELIAL CELLS; INCREASED NUMBERS OF CYCLOOXYGENASE-2-POSITIVE CELLS, CD4(+) T CELLS, MACROPHAGES; AND INCREASED MHC CLASS II EXPRESSION. COLONIC TISSUE REVEALED INCREASED TRANSCRIPTS FOR THE ONCOGENE C-MYC AND THE PROINFLAMMATORY CYTOKINES INTERLEUKIN-1ALPHA (IL-1ALPHA), IL-1BETA, IL-6, IFN-GAMMA, AND TUMOR NECROSIS FACTOR-ALPHA, SOME OF WHICH HAVE BEEN IMPLICATED IN COLON CANCER. THESE RESULTS SUGGEST THAT BACTERIA MAY BE IMPORTANT IN TRIGGERING COLORECTAL CANCER, NOTABLY IN THE CONTEXT OF GENE MUTATIONS IN THE TGF-BETA SIGNALING PATHWAY, ONE OF THE MOST COMMONLY AFFECTED CELLULAR PATHWAYS IN COLORECTAL CANCER IN HUMANS. 2006 3 1479 31 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 4 5566 36 ROLE OF INFLAMMATION IN THE DEVELOPMENT OF COLORECTAL CANCER. CHRONIC INFLAMMATION CAN LEAD TO THE DEVELOPMENT OF MANY DISEASES, INCLUDING CANCER. INFLAMMATORY BOWEL DISEASE (IBD) THAT INCLUDES BOTH ULCERATIVE COLITIS (UC) AND CROHNMP'S DISEASE (CD) ARE RISK FACTORS FOR THE DEVELOPMENT OF COLORECTAL CANCER (CRC). MANY CYTOKINES PRODUCED PRIMARILY BY THE GUT IMMUNE CELLS EITHER DURING OR IN RESPONSE TO LOCALIZED INFLAMMATION IN THE COLON AND RECTUM ARE KNOWN TO STIMULATE THE COMPLEX INTERACTIONS BETWEEN THE DIFFERENT CELL TYPES IN THE GUT ENVIRONMENT RESULTING IN ACUTE INFLAMMATION. SUBSEQUENTLY, CHRONIC INFLAMMATION, TOGETHER WITH GENETIC AND EPIGENETIC CHANGES, HAVE BEEN SHOWN TO LEAD TO THE DEVELOPMENT AND PROGRESSION OF CRC. VARIOUS CELL TYPES PRESENT IN THE COLON, SUCH AS ENTEROCYTES, PANETH CELLS, GOBLET CELLS, AND MACROPHAGES, EXPRESS RECEPTORS FOR INFLAMMATORY CYTOKINES AND RESPOND TO TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-1 BETA (IL-1BETA), IL-6, AND OTHER CYTOKINES. AMONG THE SEVERAL CYTOKINES PRODUCED, TNF-ALPHA AND IL-1BETA ARE THE KEY PRO-INFLAMMATORY MOLECULES THAT PLAY CRITICAL ROLES IN THE DEVELOPMENT OF CRC. THE CURRENT REVIEW IS INTENDED TO CONSOLIDATE THE PUBLISHED FINDINGS TO FOCUS ON THE ROLE OF PRO-INFLAMMATORY CYTOKINES, NAMELY TNF-ALPHA AND IL-1BETA, ON INFLAMMATION (AND THE ALTERED IMMUNE RESPONSE) IN THE GUT, TO BETTER UNDERSTAND THE DEVELOPMENT OF CRC IN IBD, USING VARIOUS EXPERIMENTAL MODEL SYSTEMS, PRECLINICAL AND CLINICAL STUDIES. MOREOVER, THIS REVIEW ALSO HIGHLIGHTS THE CURRENT THERAPEUTIC STRATEGIES AVAILABLE (MONOTHERAPY AND COMBINATION THERAPY) TO ALLEVIATE THE SYMPTOMS OR TREAT INFLAMMATION-ASSOCIATED CRC BY USING MONOCLONAL ANTIBODIES OR APTAMERS TO BLOCK PRO-INFLAMMATORY MOLECULES, INHIBITORS OF TYROSINE KINASES IN THE INFLAMMATORY SIGNALING CASCADE, COMPETITIVE INHIBITORS OF PRO-INFLAMMATORY MOLECULES, AND THE NUCLEIC ACID DRUGS LIKE SMALL ACTIVATING RNAS (SARNAS) OR MICRORNA (MIRNA) MIMICS TO ACTIVATE TUMOR SUPPRESSOR OR REPRESS ONCOGENE/PRO-INFLAMMATORY CYTOKINE GENE EXPRESSION. 2021 5 4154 38 MECHANISTIC ROLES OF EPITHELIAL AND IMMUNE CELL SIGNALING DURING THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER. TO DATE, SUBSTANTIAL EVIDENCE HAS SHOWN A SIGNIFICANT ASSOCIATION BETWEEN INFLAMMATORY BOWEL DISEASES (IBD) AND DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC). THE INCIDENCE/PREVALENCE OF IBD IS HIGHER IN WESTERN COUNTRIES INCLUDING THE US, AUSTRALIA, AND THE UK. ALTHOUGH CAC DEVELOPMENT IS GENERALLY CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AS WELL AS EPIGENETIC CHANGES, PRECISE MECHANISMS OF HOW CHRONIC INFLAMMATION LEADS TO THE DEVELOPMENT OF CAC ARE LARGELY UNKNOWN. PRECEDING INTESTINAL INFLAMMATION IS ONE OF THE MAJOR INFLUENTIAL FACTORS FOR CAC TUMORIGENESIS. MUCOSAL IMMUNE RESPONSES INCLUDING ACTIVATION OF ABERRANT SIGNALING PATHWAYS BOTH IN INNATE AND ADAPTIVE IMMUNE CELLS PLAY A PIVOTAL ROLE IN CAC. TUMOR PROGRESSION AND METASTASIS ARE SHAPED BY A TIGHTLY CONTROLLED TUMOR MICROENVIRONMENT WHICH IS ORCHESTRATED BY SEVERAL IMMUNE CELLS AND STROMAL CELLS INCLUDING MACROPHAGES, NEUTROPHILS, DENDRITIC CELLS, MYELOID DERIVED SUPPRESSOR CELLS, T CELLS, AND MYOFIBROBLASTS. IN THIS ARTICLE, WE WILL DISCUSS THE CONTRIBUTING FACTORS OF EPITHELIAL AS WELL AS IMMUNE CELL SIGNALING IN INITIATION OF CAC TUMORIGENESIS AND MUCOSAL IMMUNE REGULATORY FACTORS IN THE COLONIC TUMOR MICROENVIRONMENT. IN DEPTH UNDERSTANDING OF THESE FACTORS IS NECESSARY TO DEVELOP NOVEL ANTI-INFLAMMATORY AND ANTI-CANCER THERAPIES FOR CAC IN THE NEAR FUTURE. 2016 6 6444 36 THERAPEUTIC ASPECTS OF C-MYC SIGNALING IN INFLAMMATORY AND CANCEROUS COLONIC DISEASES. COLONIC INFLAMMATION IS REQUIRED TO HEAL INFECTIONS, WOUNDS, AND MAINTAIN TISSUE HOMEOSTASIS. AS THE SEVENTH HALLMARK OF CANCER, HOWEVER, IT MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, INCLUDING TUMOR INITIATION, PROMOTION, INVASION AND METASTATIC DISSEMINATION, AND ALSO EVASION IMMUNE SURVEILLANCE. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY, AND, FURTHER, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. BOTH SPORADICAL AND COLITIS-ASSOCIATED COLORECTAL CARCINOGENESIS ARE MULTI-STEP, COMPLEX PROCESSES ARISING FROM THE UNCONTROLLED PROLIFERATION AND SPREADING OF MALIGNANTLY TRANSFORMED CELL CLONES WITH THE OBVIOUS ABILITY TO EVADE THE HOST'S PROTECTIVE IMMUNITY. IN CELLS UPON DNA DAMAGE SEVERAL PROTO-ONCOGENES, INCLUDING C-MYC ARE ACTIVATED IN PARELELL WITH THE INACTIVATION OF TUMOR SUPPRESSOR GENES. THE TARGET GENES OF THE C-MYC PROTEIN PARTICIPATE IN DIFFERENT CELLULAR FUNCTIONS, INCLUDING CELL CYCLE, SURVIVAL, PROTEIN SYNTHESIS, CELL ADHESION, AND MICRO-RNA EXPRESSION. THE TRANSCRIPTIONAL PROGRAM REGULATED BY C-MYC IS CONTEXT DEPENDENT, THEREFORE THE FINAL CELLULAR RESPONSE TO ELEVATED C-MYC LEVELS MAY RANGE FROM INCREASED PROLIFERATION TO AUGMENTED APOPTOSIS. CONSIDERING PHYSIOLOGICAL INTESTINAL HOMEOSTASIS, C-MYC DISPLAYS A FUNDAMENTAL ROLE IN THE REGULATION OF CELL PROLIFERATION AND CRYPT CELL NUMBER. HOWEVER, C-MYC GENE IS FREQUENTLY DEREGULATED IN INFLAMMATION, AND OVEREXPRESSED IN BOTH SPORADIC AND COLITIS-ASSOCIATED COLON ADENOCARCINOMAS. RECENT RESULTS DEMONSTRATED THAT ENDOGENOUS C-MYC IS ESSENTIAL FOR EFFICIENT INDUCTION OF P53-DEPENDENT APOPTOSIS FOLLOWING DNA DAMAGE, BUT C-MYC FUNCTION IS ALSO INVOLVED IN AND REGULATED BY AUTOPHAGY-RELATED MECHANISMS, WHILE ITS EXPRESSION IS AFFECTED BY DNA-METHYLATION, OR HISTONE ACETYLATION. MOLECULES DIRECTLY TARGETING C-MYC, OR AGENTS ACTING ON OTHER GENES INVOLVED IN THE C-MYC PATHWAY COULD BE SELECTED FOR COMBINED REGIMENTS. HOWEVER, DUE TO ITS CONTEXT-DEPENDENT CELLULAR FUNCTION, IT IS CLINICALLY ESSENTIAL TO CONSIDER WHICH CYTOTOXIC DRUGS ARE USED IN COMBINATION WITH C-MYC TARGETED AGENTS IN VARIOUS TISSUES. INCREASING OUR KNOWLEDGE ABOUT MYC-DEPENDENT PATHWAYS MIGHT PROVIDE DIRECTION TO NOVEL ANTI-INFLAMMATORY AND COLORECTAL CANCER THERAPIES. 2016 7 925 34 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 8 4732 37 NOVEL BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER: AN INTERPLAY BETWEEN METABOLIC DYSREGULATION AND EXCESSIVE INFLAMMATION. PERSISTENT INFLAMMATION CAN TRIGGER ALTERED EPIGENETIC, INFLAMMATORY, AND BIOENERGETIC STATES. INFLAMMATORY BOWEL DISEASE (IBD) IS AN IDIOPATHIC DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT, WITH EVIDENCE OF SUBSEQUENT METABOLIC SYNDROME DISORDER. STUDIES HAVE DEMONSTRATED THAT AS MANY AS 42% OF PATIENTS WITH ULCERATIVE COLITIS (UC) WHO ARE FOUND TO HAVE HIGH-GRADE DYSPLASIA, EITHER ALREADY HAD COLORECTAL CANCER (CRC) OR DEVELOP IT WITHIN A SHORT TIME. THE PRESENCE OF LOW-GRADE DYSPLASIA IS ALSO PREDICTIVE OF CRC. MANY SIGNALING PATHWAYS ARE SHARED AMONG IBD AND CRC, INCLUDING CELL SURVIVAL, CELL PROLIFERATION, ANGIOGENESIS, AND INFLAMMATORY SIGNALING PATHWAYS. CURRENT IBD THERAPEUTICS TARGET A SMALL SUBSET OF MOLECULAR DRIVERS OF IBD, WITH MANY FOCUSED ON THE INFLAMMATORY ASPECT OF THE PATHWAYS. THUS, THERE IS A GREAT NEED TO IDENTIFY BIOMARKERS OF BOTH IBD AND CRC, THAT CAN BE PREDICTIVE OF THERAPEUTIC EFFICACY, DISEASE SEVERITY, AND PREDISPOSITION TO CRC. IN THIS STUDY, WE EXPLORED THE CHANGES IN BIOMARKERS SPECIFIC FOR INFLAMMATORY, METABOLIC, AND PROLIFERATIVE PATHWAYS, TO HELP DETERMINE THE RELEVANCE TO BOTH IBD AND CRC. OUR ANALYSIS DEMONSTRATED, FOR THE FIRST TIME IN IBD, THE LOSS OF THE TUMOR SUPPRESSOR PROTEIN RAS ASSOCIATED FAMILY PROTEIN 1A (RASSF1A), VIA EPIGENETIC CHANGES, THE HYPERACTIVATION OF THE OBLIGATE KINASE OF THE NOD2 PATHOGEN RECOGNITION RECEPTOR (RECEPTOR INTERACTING PROTEIN KINASE 2 [RIPK2]), THE LOSS OF ACTIVATION OF THE METABOLIC KINASE, AMP ACTIVATED PROTEIN KINASE (AMPKALPHA1), AND, LASTLY, THE ACTIVATION OF THE TRANSCRIPTION FACTOR AND KINASE YES ASSOCIATED PROTEIN (YAP) KINASE, THAT IS INVOLVED IN PROLIFERATION OF CELLS. THE EXPRESSION AND ACTIVATION STATUS OF THESE FOUR ELEMENTS ARE MIRRORED IN IBD, CRC, AND IBD-CRC PATIENTS AND, IMPORTANTLY, IN MATCHED BLOOD AND BIOPSY SAMPLES. THE LATTER WOULD SUGGEST THAT BIOMARKER ANALYSIS CAN BE PERFORMED NON-INVASIVELY, TO UNDERSTAND IBD AND CRC, WITHOUT THE NEED FOR INVASIVE AND COSTLY ENDOSCOPIC ANALYSIS. THIS STUDY, FOR THE FIRST TIME, ILLUSTRATES THE NEED TO UNDERSTAND IBD OR CRC BEYOND AN INFLAMMATORY PERSPECTIVE AND THE VALUE OF THERAPEUTICS DIRECTED TO RESET ALTERED PROLIFERATIVE AND METABOLIC STATES WITHIN THE COLON. THE USE OF SUCH THERAPEUTICS MAY TRULY DRIVE PATIENTS INTO REMISSION. 2023 9 5554 34 ROLE OF EPIGENETICS IN TRANSFORMATION OF INFLAMMATION INTO COLORECTAL CANCER. MOLECULAR MECHANISMS ASSOCIATED WITH INFLAMMATION-PROMOTED TUMORIGENESIS HAVE BECOME AN IMPORTANT TOPIC IN CANCER RESEARCH. VARIOUS ABNORMAL EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, CHROMATIN REMODELING, AND NONCODING RNA REGULATION, OCCUR DURING THE TRANSFORMATION OF CHRONIC INFLAMMATION INTO COLORECTAL CANCER (CRC). THESE CHANGES NOT ONLY ACCELERATE TRANSFORMATION BUT ALSO LEAD TO CANCER PROGRESSION AND METASTASIS BY ACTIVATING CARCINOGENIC SIGNALING PATHWAYS. THE NF-KAPPAB AND STAT3 SIGNALING PATHWAYS PLAY A PARTICULARLY IMPORTANT ROLE IN THE TRANSFORMATION OF INFLAMMATION INTO CRC, AND BOTH ARE CRITICAL TO CELLULAR SIGNAL TRANSDUCTION AND CONSTANTLY ACTIVATED IN CANCER BY VARIOUS ABNORMAL CHANGES INCLUDING EPIGENETICS. THE NF-KAPPAB AND STAT3 SIGNALS CONTRIBUTE TO THE MICROENVIRONMENT FOR TUMORIGENESIS THROUGH SECRETION OF A LARGE NUMBER OF PRO-INFLAMMATORY CYTOKINES AND THEIR CROSSTALK IN THE NUCLEUS MAKES IT EVEN MORE DIFFICULT TO TREAT CRC. COMPARED WITH GENE MUTATION THAT IS IRREVERSIBLE, EPIGENETIC INHERITANCE IS REVERSIBLE OR CAN BE ALTERED BY THE INTERVENTION. THEREFORE, UNDERSTANDING THE ROLE OF EPIGENETIC INHERITANCE IN THE INFLAMMATION-CANCER TRANSFORMATION MAY ELUCIDATE THE PATHOGENESIS OF CRC AND PROMOTE THE DEVELOPMENT OF INNOVATIVE DRUGS TARGETING TRANSFORMATION TO PREVENT AND TREAT THIS MALIGNANCY. THIS REVIEW SUMMARIZES THE LITERATURE ON THE ROLES OF EPIGENETIC MECHANISMS IN THE OCCURRENCE AND DEVELOPMENT OF INFLAMMATION-INDUCED CRC. EXPLORING THE ROLE OF EPIGENETICS IN THE TRANSFORMATION OF INFLAMMATION INTO CRC MAY HELP STIMULATE FUTURES STUDIES ON THE ROLE OF MOLECULAR THERAPY IN CRC. 2019 10 3799 25 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 11 4004 34 LOSS OF THE POLYCOMB MARK FROM BIVALENT PROMOTERS LEADS TO ACTIVATION OF CANCER-PROMOTING GENES IN COLORECTAL TUMORS. IN COLON TUMORS, THE TRANSCRIPTION OF MANY GENES BECOMES DEREGULATED BY POORLY DEFINED EPIGENETIC MECHANISMS THAT HAVE BEEN STUDIED MAINLY IN ESTABLISHED CELL LINES. IN THIS STUDY, WE USED FROZEN HUMAN COLON TISSUES TO ANALYZE PATTERNS OF HISTONE MODIFICATION AND DNA CYTOSINE METHYLATION IN CANCER AND MATCHED NORMAL MUCOSA SPECIMENS. DNA METHYLATION IS STRONGLY TARGETED TO BIVALENT H3K4ME3- AND H3K27ME3-ASSOCIATED PROMOTERS, WHICH LOSE BOTH HISTONE MARKS AND ACQUIRE DNA METHYLATION. HOWEVER, WE FOUND THAT LOSS OF THE POLYCOMB MARK H3K27ME3 FROM BIVALENT PROMOTERS WAS ACCOMPANIED OFTEN BY ACTIVATION OF GENES ASSOCIATED WITH CANCER PROGRESSION, INCLUDING NUMEROUS STEM CELL REGULATORS, ONCOGENES, AND PROLIFERATION-ASSOCIATED GENES. INDEED, WE FOUND MANY OF THESE SAME GENES WERE ALSO ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS WHERE CHRONIC INFLAMMATION PREDISPOSES THEM TO COLON CANCER. BASED ON OUR FINDINGS, WE PROPOSE THAT A LOSS OF POLYCOMB REPRESSION AT BIVALENT GENES COMBINED WITH AN ENSUING SELECTION FOR TUMOR-DRIVING EVENTS PLAYS A MAJOR ROLE IN CANCER PROGRESSION. 2014 12 4535 28 MULTIPLE ROLES OF TOLL-LIKE RECEPTOR 4 IN COLORECTAL CANCER. TOLL-LIKE RECEPTOR (TLR) SIGNALING HAS BEEN IMPLICATED IN THE INFLAMMATORY RESPONSES IN INTESTINAL EPITHELIAL CELLS (IECS). SUCH INFLAMMATORY SIGNALS MEDIATE COMPLEX INTERACTIONS BETWEEN COMMENSAL BACTERIA AND TLRS AND ARE REQUIRED FOR IEC PROLIFERATION, IMMUNE RESPONSE, REPAIR, AND HOMEOSTASIS. THE UPREGULATION OF CERTAIN TLRS IN COLORECTAL CANCER (CRC) TISSUES SUGGESTS THAT TLRS MAY PLAY AN ESSENTIAL ROLE IN THE PROGNOSIS OF CHRONIC AND INFLAMMATORY DISEASES THAT ULTIMATELY CULMINATE IN CRC. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE LITERATURE ON THE INVOLVEMENT OF THE TLR PATHWAY IN THE INITIATION, PROGRESSION, AND METASTASIS OF CRC, AS WELL AS INHERITED GENETIC VARIATION AND EPIGENETIC REGULATION. THE DIFFERENTIAL EXPRESSION OF TLRS IN EPITHELIAL CELLS HAS ALSO BEEN DISCUSSED. IN PARTICULAR, WE EMPHASIZE THE PHYSIOLOGICAL ROLE OF TLR4 IN CRC DEVELOPMENT AND PATHOGENESIS, AND PROPOSE NOVEL AND PROMISING APPROACHES FOR CRC THERAPEUTICS WITH THE AID OF TLR LIGANDS. 2014 13 2036 24 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 14 5412 29 REGULATION OF ANTITUMOR IMMUNITY BY INFLAMMATION-INDUCED EPIGENETIC ALTERATIONS. CHRONIC INFLAMMATION PROMOTES TUMOR DEVELOPMENT, PROGRESSION, AND METASTATIC DISSEMINATION AND CAUSES TREATMENT RESISTANCE. THE ACCUMULATION OF GENETIC ALTERATIONS AND LOSS OF NORMAL CELLULAR REGULATORY PROCESSES ARE NOT ONLY ASSOCIATED WITH CANCER GROWTH AND PROGRESSION BUT ALSO RESULT IN THE EXPRESSION OF TUMOR-SPECIFIC AND TUMOR-ASSOCIATED ANTIGENS THAT MAY ACTIVATE ANTITUMOR IMMUNITY. THIS ANTAGONISM BETWEEN INFLAMMATION AND IMMUNITY AND THE ABILITY OF CANCER CELLS TO AVOID IMMUNE DETECTION AFFECT THE COURSE OF CANCER DEVELOPMENT AND TREATMENT OUTCOMES. WHILE INFLAMMATION, PARTICULARLY ACUTE INFLAMMATION, SUPPORTS T-CELL PRIMING, ACTIVATION, AND INFILTRATION INTO INFECTED TISSUES, CHRONIC INFLAMMATION IS MOSTLY IMMUNOSUPPRESSIVE. HOWEVER, THE MAIN MECHANISMS THAT DICTATE THE OUTCOME OF THE INFLAMMATION-IMMUNITY INTERPLAY ARE NOT WELL UNDERSTOOD. RECENT DATA SUGGEST THAT INFLAMMATION TRIGGERS EPIGENETIC ALTERATIONS IN CANCER CELLS AND COMPONENTS OF THE TUMOR MICROENVIRONMENT. THESE ALTERATIONS CAN AFFECT AND MODULATE NUMEROUS ASPECTS OF CANCER DEVELOPMENT, INCLUDING TUMOR GROWTH, THE METABOLIC STATE, METASTATIC SPREAD, IMMUNE ESCAPE, AND IMMUNOSUPPRESSIVE OR IMMUNOSUPPORTIVE LEUKOCYTE GENERATION. IN THIS REVIEW, WE DISCUSS THE ROLE OF INFLAMMATION IN INITIATING EPIGENETIC ALTERATIONS IN IMMUNE CELLS, CANCER-ASSOCIATED FIBROBLASTS, AND CANCER CELLS AND SUGGEST HOW AND WHEN EPIGENETIC INTERVENTIONS CAN BE COMBINED WITH IMMUNOTHERAPIES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 15 3659 28 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 16 1173 31 CONTRIBUTION OF TLR SIGNALING TO THE PATHOGENESIS OF COLITIS-ASSOCIATED CANCER IN INFLAMMATORY BOWEL DISEASE. IN THE INTESTINE A BALANCE BETWEEN PROINFLAMMATORY AND REPAIR SIGNALS OF THE IMMUNE SYSTEM IS ESSENTIAL FOR THE MAINTENANCE OF INTESTINAL HOMEOSTASIS. THE INNATE IMMUNITY ENSURES A PRIMARY HOST RESPONSE TO MICROBIAL INVASION, WHICH INDUCES AN INFLAMMATORY PROCESS TO LOCALIZE THE INFECTION AND PREVENT SYSTEMIC DISSEMINATION OF PATHOGENS. THE KEY ELEMENTS OF THIS PROCESS ARE THE GERMLINE ENCODED PATTERN RECOGNITION RECEPTORS INCLUDING TOLL-LIKE RECEPTORS (TLRS). IF PATHOGENS CANNOT BE ELIMINATED, THEY MAY ELICIT CHRONIC INFLAMMATION, WHICH MAY BE PARTLY MEDIATED VIA TLRS. ADDITIONALLY, CHRONIC INFLAMMATION HAS LONG BEEN SUGGESTED TO TRIGGER TISSUE TUMOROUS TRANSFORMATION. INFLAMMATION, THE SEVENTH HALLMARK OF CANCER, MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, AND EVADE THE IMMUNE SYSTEM. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY. FURTHERMORE, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. COLORECTAL CANCERS IN INFLAMMATORY BOWEL DISEASE PATIENTS ARE CONSIDERED TYPICAL EXAMPLES OF INFLAMMATION-RELATED CANCERS. ALTHOUGH DATA REGARDING THE ROLE OF TLRS IN THE PATHOMECHANISM OF CANCER-ASSOCIATED COLITIS ARE RATHER CONFLICTING, FUNCTIONALLY THESE MOLECULES CAN BE CLASSIFIED AS "LARGELY ANTITUMORIGENIC" AND "LARGELY PRO-TUMORIGENIC" WITH THE CAVEAT THAT THE UNDERLYING SIGNALING PATHWAYS ARE MAINLY CONTEXT (I.E., ORGAN-, TISSUE-, CELL-) AND LIGAND-DEPENDENT. 2014 17 1150 35 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 18 6590 27 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I. 2015 19 1232 30 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 20 6331 31 THE ROLE OF COX-2 IN INTESTINAL INFLAMMATION AND COLORECTAL CANCER. COLORECTAL CANCER (CRC) IS A HETEROGENEOUS DISEASE, INCLUDING AT LEAST THREE MAJOR FORMS: HEREDITARY, SPORADIC AND COLITIS-ASSOCIATED CRC. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET AND LIFESTYLE ARE THE RISK FACTORS FOR CRC. AS ELEVATED CYCLOOXYGENASE-2 (COX-2) EXPRESSION WAS FOUND IN MOST CRC TISSUE AND IS ASSOCIATED WITH WORSE SURVIVAL AMONG CRC PATIENTS, INVESTIGATORS HAVE SOUGHT TO EVALUATE THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND SELECTIVE COX-2 INHIBITORS (COXIBS) ON CRC. THE EPIDEMIOLOGICAL STUDIES, CLINICAL TRIALS AND ANIMAL EXPERIMENTS INDICATE THAT NSAIDS ARE AMONG THE MOST PROMISING CHEMOPREVENTIVE AGENTS FOR THIS DISEASE. NSAIDS EXERT THEIR ANTI-INFLAMMATORY AND ANTITUMOR EFFECTS PRIMARILY BY REDUCING PROSTAGLANDIN PRODUCTION BY INHIBITION OF COX-2 ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT BREAKTHROUGHS IN OUR UNDERSTANDING OF THE ROLES OF COX-2 IN CRC AND INFLAMMATORY BOWEL DISEASE. THESE RECENT DATA PROVIDE A RATIONALE FOR RE-EVALUATING COX-2 AS BOTH THE PROGNOSTIC AND THE PREDICTIVE MARKER IN A WIDE VARIETY OF MALIGNANCIES AND FOR RENEWING THE INTEREST IN EVALUATING RELATIVE BENEFITS AND RISK OF COXIBS IN APPROPRIATELY SELECTED PATIENTS FOR CANCER PREVENTION AND TREATMENT. 2010