1 6359 121 THE ROLE OF INFLAMMATION IN THE PATHOGENESIS OF LUNG CANCER. INTRODUCTION: IT IS REPORTED THAT CANCER MAY ARISE IN CHRONICALLY INFLAMED TISSUE. THERE IS MOUNTING EVIDENCE SUGGESTING THAT THE CONNECTION BETWEEN INFLAMMATION AND LUNG CANCER IS NOT COINCIDENTAL BUT MAY INDEED BE CAUSAL. THE INFLAMMATORY MOLECULES MAY BE RESPONSIBLE FOR AUGMENTED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE AND AN INCREASE IN REACTIVE OXYGEN SPECIES. THE CYTOKINES AND GROWTH FACTORS UNUSUALLY PRODUCED IN CHRONIC PULMONARY DISORDERS HAVE BEEN FOUND TO HAVE HARMFUL PROPERTIES THAT PAVE THE WAY FOR EPITHELIAL-TO-MESENCHYMAL TRANSITION AND TUMOR MICROENVIRONMENT. HOWEVER, THE ROLE OF INFLAMMATION IN LUNG CANCER IS NOT YET FULLY UNDERSTOOD. AREAS COVERED: THE ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF LUNG CANCER AND SOME OF THE POSSIBLE MECHANISMS INVOLVED, WITH PARTICULAR FOCUS ON INFLAMMATORY MEDIATORS, GENETIC AND EPIGENETIC ALTERATIONS, INFLAMMATORY MARKERS, TUMOR MICROENVIRONMENT AND ANTI-INFLAMMATORY DRUGS ARE DISCUSSED. A FRAMEWORK FOR UNDERSTANDING THE CONNECTION BETWEEN INFLAMMATION AND LUNG CANCER IS PROVIDED, WHICH MAY AFFORD THE OPPORTUNITY TO INTERCEDE IN SPECIFIC INFLAMMATORY DAMAGE MEDIATING LUNG CARCINOGENESIS AND THERAPEUTIC RESISTANCE. EXPERT OPINION: ADVANCES IN TUMOR IMMUNOLOGY SUPPORT THE CLINICAL IMPLEMENTATION OF IMMUNOTHERAPIES FOR LUNG CANCER. ALONG WITH THERAPEUTIC BENEFITS, IMMUNOTHERAPY PRESENTS THE CHALLENGES OF DRUG-RELATED TOXICITIES. GENE MODIFICATION OF IMMUNOCYTOKINE MAY LOWER THE ASSOCIATED TOXIC EFFECTS. 2011 2 5738 58 SMOKING AND LUNG CANCER: THE ROLE OF INFLAMMATION. WORLDWIDE OVER 1 MILLION PEOPLE DIE DUE TO LUNG CANCER EACH YEAR. IT IS ESTIMATED THAT CIGARETTE SMOKING EXPLAINS ALMOST 90% OF LUNG CANCER RISK IN MEN AND 70 TO 80% IN WOMEN. CLINICALLY EVIDENT LUNG CANCERS HAVE MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. THESE ABNORMALITIES MAY RESULT IN ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR-SUPPRESSOR GENES. CHRONIC INFLAMMATION, WHICH IS KNOWN TO PROMOTE CANCER, MAY RESULT BOTH FROM SMOKING AND FROM GENETIC ABNORMALITIES. THESE MEDIATORS IN TURN MAY BE RESPONSIBLE FOR INCREASED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE, AND INCREASE IN REACTIVE OXYGEN SPECIES (ROS). THUS, THE PULMONARY ENVIRONMENT PRESENTS A UNIQUE MILIEU IN WHICH LUNG CARCINOGENESIS PROCEEDS IN COMPLICITY WITH THE HOST CELLULAR NETWORK. THE PULMONARY DISEASES THAT ARE ASSOCIATED WITH THE GREATEST RISK FOR LUNG CANCER ARE CHARACTERIZED BY ABUNDANT AND DEREGULATED INFLAMMATION. PULMONARY DISORDERS SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA ARE CHARACTERIZED BY PROFOUND ABNORMALITIES IN INFLAMMATORY AND FIBROTIC PATHWAYS. THE CYTOKINES AND GROWTH FACTORS ABERRANTLY PRODUCED IN COPD AND THE DEVELOPING TUMOR MICROENVIRONMENT HAVE BEEN FOUND TO HAVE DELETERIOUS PROPERTIES THAT SIMULTANEOUSLY PAVE THE WAY FOR BOTH EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND DESTRUCTION OF SPECIFIC HOST CELL-MEDIATED IMMUNE RESPONSES. FULL DEFINITION OF THESE PATHWAYS WILL AFFORD THE OPPORTUNITY TO INTERVENE IN SPECIFIC INFLAMMATORY EVENTS MEDIATING LUNG TUMORIGENESIS AND RESISTANCE TO THERAPY. 2008 3 928 34 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. 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. 2009 4 2335 36 EPIGENETIC REGULATION OF INFLAMMATORY CYTOKINES AND ASSOCIATED GENES IN HUMAN MALIGNANCIES. INFLAMMATION IS A MULTIFACETED DEFENSE RESPONSE OF IMMUNE SYSTEM AGAINST INFECTION. CHRONIC INFLAMMATION HAS BEEN IMPLICATED AS AN IMMINENT THREAT FOR MAJOR HUMAN MALIGNANCIES AND IS DIRECTLY LINKED TO VARIOUS STEPS INVOLVED IN TUMORIGENESIS. INFLAMMATORY CYTOKINES, INTERLEUKINS, INTERFERONS, TRANSFORMING GROWTH FACTORS, CHEMOKINES, AND ADHESION MOLECULES HAVE BEEN ASSOCIATED WITH CHRONIC INFLAMMATION. NUMEROUS CYTOKINES ARE REPORTED TO BE ABERRANTLY REGULATED BY DIFFERENT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS IN TUMOR TISSUES, CONTRIBUTING TO PATHOGENESIS OF TUMOR IN MULTIPLE WAYS. SOME OF THESE CYTOKINES ALSO WORK AS EPIGENETIC REGULATORS OF OTHER CRUCIAL GENES IN TUMOR BIOLOGY, EITHER DIRECTLY OR INDIRECTLY. SUCH REGULATIONS ARE REPORTED IN LUNG, BREAST, CERVICAL, GASTRIC, COLORECTAL, PANCREATIC, PROSTATE, AND HEAD AND NECK CANCERS. EPIGENETICS OF INFLAMMATORY MEDIATORS IN CANCER IS CURRENTLY SUBJECT OF EXTENSIVE RESEARCH. THESE INVESTIGATIONS MAY HELP IN UNDERSTANDING CANCER BIOLOGY AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES. THE PURPOSE OF THIS PAPER IS TO HAVE A BRIEF VIEW OF THE ABERRANT REGULATION OF INFLAMMATORY CYTOKINES IN HUMAN MALIGNANCIES. 2015 5 6475 38 TOBACCO, INFLAMMATION, AND RESPIRATORY TRACT CANCER. CIGARETTE SMOKING IS THE MOST RECOGNIZED RISK FACTOR FOR MANY INFLAMMATORY DISEASES SUCH AS CARDIOVASCULAR DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND FOR A NUMBER OF MALIGNANCES SUCH AS LUNG CANCER. LUNG CANCER IS CURRENTLY CONSIDERED THE LEADING CAUSE OF CANCER-RELATED DEATHS BECAUSE ITS AGGRESSIVE NATURE AND THE LACK OF EFFECTIVE THERAPEUTIC OPTIONS. RECENT ADVANCES IN MOLECULAR BIOLOGY AND IMMUNOLOGY HAVE IMPROVED THE KNOWLEDGE ON DIFFERENT MECHANISMS IMPLICATED IN LUNG CELL MALIGNANT TRANSFORMATION, PROGRESSION AND METASTASIS, THUS PRESENTING AN EXCITING NEW ERA FOR LUNG ANTICANCER THERAPIES. THE WAY BY WHICH CIGARETTE SMOKE MAY INDUCE LUNG MALIGNANCY INCLUDES A LARGE NUMBER OF DIFFERENT MECHANISMS AND SUBSTANCES, MOST OF THEM CURRENTLY UNKNOWN. THUS, IDENTIFIED CARCINOGENIC COMPOUNDS OF CIGARETTE SMOKE MAY INDUCE THEMSELVES A DIRECT CYTOTOXICITY AND MUTAGENIC ACTION ON LUNG EPITHELIAL CELLS BY MEANS OF GENERATION OF SOMATIC MUTATIONS, EPIGENETIC EVENTS, EPITHELIAL CELL TO MESENCHYMAL CELL TRANSFORMATIONS, AS WELL AS BY CHRONIC CELL DAMAGE. HOWEVER, THE FACT THAT THERE IS A RELATIVE HIGH PREVALENCE OF EX-SMOKER WHO MAY DEVELOP LUNG CANCER AFTER YEARS OF SMOKING CESSATION SUGGEST THAT OTHER CAUSES ARE ALSO IMPLICATED. THUS CIGARETTE SMOKE-INDUCED CHRONIC LUNG INFLAMMATORY MICROENVIRONMENT, OXIDATIVE STRESS AND CELL STRUCTURAL ALTERATIONS SUCH AS THE INCREASE OF CELL PROLIFERATION, ANGIOGENESIS AND APOPTOSIS ARREST ARE IRREVERSIBLE PROCESSES THAT HAVE A HIGH INFLUENCE IN LUNG TUMOR GROWTH. IN THIS REVIEW WE FOCUSED IN CURRENT KNOWLEDGE ON THE MECHANISMS IMPLICATED IN CIGARETTE SMOKE-INDUCED LUNG CHRONIC INFLAMMATORY PROCESSES LEADING TO LUNG CARCINOGENESIS, AS WELL AS IN CURRENT THERAPIES BASED ON NOVEL MOLECULAR ADVANCES. 2012 6 3697 31 INFLAMMATORY MARKERS IN CANCER: POTENTIAL RESOURCES. CANCER IS A LEADING CAUSE OF DEATH WORLDWIDE AND A MAJOR BURDEN ON DEVELOPING AND LESS DEVELOPED COUNTRIES OF THE WORLD WITH LIMITED RESOURCES FOR PREVENTION AND EFFECTIVE TREATMENT OF CANCER. ALTHOUGH CANCER IS MULTIFACTORIAL IN ORIGIN, VARIOUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST THAT CHRONIC INFLAMMATION HAS AN IMPORTANT ROLE IN ALL STAGES OF CANCER, FROM INITIATION TO PROGRESSION AND EVEN SURVIVAL OF THE PATIENT. INFLAMMATORY PRODUCTS LIKE CYTOKINES, CHEMOKINES, LEUCOCYTES, PROSTAGLANDINS, CYCLOOXYGENASE, REACTIVE OXYGEN AND NITROGEN SPECIES, METALLOPROTEINASE INDUCE GENETIC AND EPIGENETIC CHANGES IN NORMAL CELLS DAMAGING ITS DNA, INHIBITING ITS REPAIR, ALTERING TRANSCRIPTION FACTORS, PREVENTING APOPTOSIS, AND STIMULATING ANGIOGENESIS, AND THUS RESULTING IN CARCINOGENESIS. THUS, THESE INFLAMMATORY MEDIATORS HAVE A POTENTIAL ROLE TO BECOME CANCER BIOMARKERS FOR ALL STAGES OF CANCER AS MANY OF THEM CAN BE MEASURED IN A COST-EFFECTIVE MANNER. HOWEVER, LARGE SCALE PROSPECTIVE TRIALS ARE REQUIRED TO VALIDATE THESE POTENTIAL CANCER BIOMARKERS. NONETHELESS, A TRANSITION FROM POTENTIAL TO PRACTICAL UTILIZATION OF THESE MARKERS WILL BE AN EFFECTIVE TOOL FOR THE AMELIORATION OF CANCER BURDEN AND MORTALITY IN A RESOURCE LIMITED SETTING. 2020 7 5412 33 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 8 6395 37 THE ROLE OF THE MEDIATORS OF INFLAMMATION IN CANCER DEVELOPMENT. EPIGENETIC DISORDERS SUCH AS POINT MUTATIONS IN CELLULAR TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS ARE NEEDED TO TRANSFORMATION OF NORMAL CELLS INTO CANCER CELLS. THESE EVENTS RESULT IN ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS, TRIGGERING TO AN INFLAMMATORY RESPONSE WHICH CAN LEAD THE DEVELOPMENT OF CANCER. THE INFLAMMATORY RESPONSE IS A UNIVERSAL DEFENSE MECHANISM ACTIVATED IN RESPONSE TO AN INJURY TISSUE, OF ANY NATURE, THAT INVOLVES BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, THROUGH THE COLLECTIVE ACTION OF A VARIETY OF SOLUBLE MEDIATORS. MANY INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN SEVERAL TYPES OF CANCER, LINKING CHRONIC INFLAMMATION TO TUMORIGENESIS PROCESS. THUS, INFLAMMATORY RESPONSES PLAY DECISIVE ROLES AT DIFFERENT STAGES OF TUMOR DEVELOPMENT, INCLUDING INITIATION, PROMOTION, GROWTH, INVASION, AND METASTASIS, AFFECTING ALSO THE IMMUNE SURVEILLANCE. IMMUNE CELLS THAT INFILTRATE TUMORS ENGAGE IN AN EXTENSIVE AND DYNAMIC CROSSTALK WITH CANCER CELLS, AND SOME OF THE MOLECULAR EVENTS THAT MEDIATE THIS DIALOG HAVE BEEN REVEALED. A RANGE OF INFLAMMATION MEDIATORS, INCLUDING CYTOKINES, CHEMOKINES, FREE RADICALS, PROSTAGLANDINS, GROWTH AND TRANSCRIPTION FACTORS, MICRORNAS, AND ENZYMES AS, CYCLOOXYGENASE AND MATRIX METALLOPROTEINASE, COLLECTIVELY ACTS TO CREATE A FAVORABLE MICROENVIRONMENT FOR THE DEVELOPMENT OF TUMORS. IN THIS REVIEW ARE PRESENTED THE MAIN MEDIATORS OF THE INFLAMMATORY RESPONSE AND DISCUSSED THE LIKELY MECHANISMS THROUGH WHICH, THEY INTERACT WITH EACH OTHER TO CREATE A CONDITION FAVORABLE TO DEVELOPMENT OF CANCER. 2015 9 3672 23 INFLAMMATION AND CANCER: AN ANCIENT LINK WITH NOVEL POTENTIALS. INFECTION AND CHRONIC INFLAMMATION CONTRIBUTE TO ABOUT 1 IN 4 OF ALL CANCER CASES. MEDIATORS OF THE INFLAMMATORY RESPONSE, E.G., CYTOKINES, FREE RADICALS, PROSTAGLANDINS AND GROWTH FACTORS, CAN INDUCE GENETIC AND EPIGENETIC CHANGES INCLUDING POINT MUTATIONS IN TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS, CAUSING ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS AND LEADING TO THE DEVELOPMENT AND PROGRESSION OF CANCER. RECENT DISCOVERY OF AN INTERACTION BETWEEN MICRORNAS AND INNATE IMMUNITY DURING INFLAMMATION HAS FURTHER STRENGTHENED THE ASSOCIATION BETWEEN INFLAMMATION AND CANCER. 2007 10 1606 30 DNA METHYLATION, BACTERIA AND AIRWAY INFLAMMATION: LATEST INSIGHTS. PURPOSE OF REVIEW: DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT HAS BEEN IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BY REGULATING DIFFERENTIATION, PROLIFERATION, APOPTOSIS, AND ACTIVATION OF IMMUNE CELLS. CHANGES IN THE METHYLATION STATUS OF RELEVANT GENES HAVE BEEN LINKED TO THE ORIGIN, PERPETUATION, AND SEVERITY OF AIRWAY DISEASES. THE DNA METHYLATION PROFILE CAN BE ALSO MODIFIED BY THE ACTION OF VIRAL AND BACTERIAL COLONIZATION. BACTERIA AND SPECIALLY STAPHYLOCOCCUS AUREUS TOXINS ARE RECOGNIZED INFLAMMATORY AMPLIFYING FACTORS IN BOTH LOWER AND UPPER AIRWAY CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE EXISTENT KNOWLEDGE ABOUT THE ROLE OF DNA METHYLATION CHANGES IN CHRONIC AIRWAY DISEASES AND THE CONTRIBUTION OF BACTERIAL INFECTION ON THIS EVENT. RECENT FINDINGS: IT HAS BEEN DEMONSTRATED THAT CHANGES IN DNA METHYLATION, EITHER INTRINSIC OR INDUCED BY ALLERGEN OR INFECTION, MAY BE LINKED TO THE PATHOGENESIS OF ASTHMA AND ALLERGY. THESE CHANGES IN METHYLATION MAY SUPPRESS THE PRODUCTION OF ANTI-INFLAMMATORY MEDIATORS AND INCREASE THE SURVIVAL AND ACTIVATION OF PRO-INFLAMMATORY CELLS, AS WELL AS MODIFY THE IMMUNE RESPONSE IN RESPONSE TO BACTERIAL INFECTION, INCREASING THEIR SURVIVAL AND PATHOGENICITY WITHIN THE INFECTED ORGANISM. SUMMARY: UNDERSTANDING THE INTRINSIC EPIGENETIC MECHANISMS, AS WELL AS THE EFFECT OF ENVIRONMENT -FOR EXAMPLE, BACTERIAL INFECTION IN THE PATHOGENESIS OF AIRWAYS DISEASES - WILL GREATLY IMPROVE THE MANAGEMENT AND THE DIAGNOSIS OF THESE DISEASES. 2015 11 2676 33 ETIOPATHOGENESIS OF OVARIAN CANCER. AN INFLAMM-AGING ENTITY? OVARIAN CANCER IS ONE OF THE MOST COMMON GYNECOLOGIC CANCERS AND HAS THE HIGHEST MORTALITY RATE. THE RISK/PROTECTIVE FACTORS OF OVARIAN CANCER SUGGEST THAT ITS ETIOLOGY IS MULTIFACTORIAL. SEVERAL FACTORS ARE INVOLVED IN AGE-RELATED INCREASES IN CARCINOGENESIS, INCLUDING THE ACCUMULATION OF SENESCENT CELLS, INFLAMMAGING (A CHRONIC INFLAMMATORY STATE THAT PERSISTS IN THE ELDERLY), AND IMMUNOSENESCENCE (AGING OF THE IMMUNE SYSTEM) CHANGES ASSOCIATED WITH POOR IMMUNE SURVEILLANCE. AT SITES OF INFLAMMATION, EXPOSURE TO HIGH LEVELS OF INFLAMMATORY MEDIATORS, SUCH AS REACTIVE OXYGEN SPECIES, CYTOKINES, PROSTAGLANDINS, AND GROWTH FACTORS, CONTRIBUTES TO INCREASED CELL DIVISION AND GENETIC AND EPIGENETIC CHANGES. THESE EXPOSURE-INDUCED CHANGES PROMOTE EXCESSIVE CELL PROLIFERATION, INCREASED SURVIVAL, MALIGNANT TRANSFORMATION, AND CANCER DEVELOPMENT. FURTHERMORE, THE PROINFLAMMATORY TUMOR MICROENVIRONMENT CONTRIBUTES TO OVARIAN CANCER METASTASIS AND CHEMORESISTANCE. THIS NARRATIVE REVIEW OF THE LITERATURE WAS CARRIED OUT TO DELINEATE THE POSSIBLE ROLE OF INFLAMMAGING IN THE ETIOPATHOGENESIS OF OVARIAN CANCER DEVELOPMENT. WE DISCUSS THE CURRENT CARCINOGENIC HYPOTHESES, SITES OF ORIGIN, AND ETIOLOGICAL FACTORS OF OVARIAN CANCER. TREATMENT OF INFLAMMATION MAY REPRESENT AN ATTRACTIVE STRATEGY FOR BOTH THE PREVENTION AND THERAPY OF OVARIAN CANCER. 2022 12 4043 22 MACROPHAGES IN CHRONIC LIVER FAILURE: DIVERSITY, PLASTICITY AND THERAPEUTIC TARGETING. CHRONIC LIVER INJURY RESULTS IN IMMUNE-DRIVEN PROGRESSIVE FIBROSIS, WITH RISK OF CIRRHOSIS DEVELOPMENT AND IMPACT ON MORBIDITY AND MORTALITY. PERSISTENT LIVER CELL DAMAGE AND DEATH CAUSES IMMUNE CELL ACTIVATION AND INFLAMMATION. PATIENTS WITH ADVANCED CIRRHOSIS ADDITIONALLY EXPERIENCE PATHOLOGICAL BACTERIAL TRANSLOCATION, EXPOSURE TO MICROBIAL PRODUCTS AND CHRONIC ENGAGEMENT OF THE IMMUNE SYSTEM. BACTERIAL INFECTIONS HAVE A HIGH INCIDENCE IN CIRRHOSIS, WITH SPONTANEOUS BACTERIAL PERITONITIS BEING THE MOST COMMON, WHILE THE SUBSEQUENT SYSTEMIC INFLAMMATION, ORGAN FAILURE AND IMMUNE DYSREGULATION INCREASE THE MORTALITY RISK. TISSUE-RESIDENT AND RECRUITED MACROPHAGES PLAY A CENTRAL PART IN THE DEVELOPMENT OF INFLAMMATION AND FIBROSIS PROGRESSION. IN THE LIVER, ADIPOSE TISSUE, PERITONEUM AND INTESTINES, DIVERSE MACROPHAGE POPULATIONS EXHIBIT GREAT PHENOTYPIC AND FUNCTIONAL PLASTICITY DETERMINED BY THEIR ONTOGENY, EPIGENETIC PROGRAMMING AND LOCAL MICROENVIRONMENT. THESE CHANGES CAN, AT DIFFERENT TIMES, PROMOTE OR AMELIORATE DISEASE STATES AND THEREFORE REPRESENT POTENTIAL TARGETS FOR MACROPHAGE-DIRECTED THERAPIES. IN THIS REVIEW, WE DISCUSS THE EVIDENCE FOR MACROPHAGE PHENOTYPIC AND FUNCTIONAL ALTERATIONS IN TISSUE COMPARTMENTS DURING THE DEVELOPMENT AND PROGRESSION OF CHRONIC LIVER FAILURE IN DIFFERENT AETIOLOGIES AND HIGHLIGHT THE POTENTIAL OF MACROPHAGE MODULATION AS A THERAPEUTIC STRATEGY FOR LIVER DISEASE. 2021 13 4445 37 MOLECULAR LINKS BETWEEN COPD AND LUNG CANCER: NEW TARGETS FOR DRUG DISCOVERY? COPD AND LUNG CANCER ARE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE, AND THEY SHARE A COMMON ENVIRONMENTAL RISK FACTOR IN CIGARETTE SMOKE EXPOSURE AND A GENETIC PREDISPOSITION REPRESENTED BY THEIR INCIDENCE IN ONLY A FRACTION OF SMOKERS. THIS REFLECTS THE ABILITY OF CIGARETTE SMOKE TO INDUCE AN INFLAMMATORY RESPONSE IN THE AIRWAYS OF SUSCEPTIBLE SMOKERS. MOREOVER, COPD COULD BE A DRIVING FACTOR IN LUNG CANCER, BY INCREASING OXIDATIVE STRESS AND THE RESULTING DNA DAMAGE AND REPRESSION OF THE DNA REPAIR MECHANISMS, CHRONIC EXPOSURE TO PRO-INFLAMMATORY CYTOKINES, REPRESSION OF INNATE IMMUNITY AND INCREASED CELLULAR PROLIFERATION. AREAS COVERED: WE HAVE FOCUSED OUR REVIEW ON THE POTENTIAL PATHOGENIC MOLECULAR LINKS BETWEEN TOBACCO SMOKING-RELATED COPD AND LUNG CANCER AND THE POTENTIAL MOLECULAR TARGETS FOR NEW DRUG DEVELOPMENT BY UNDERSTANDING THE COMMON SIGNALING PATHWAYS INVOLVED IN COPD AND LUNG CANCER. EXPERT COMMENTARY: RESEARCH IN THIS FIELD IS MOSTLY LIMITED TO ANIMAL MODELS OR SMALL CLINICAL TRIALS. LARGE CLINICAL TRIALS ARE NEEDED BUT MOSTLY COMBINED MODELS OF COPD AND LUNG CANCER ARE NECESSARY TO INVESTIGATE THE PROCESSES CAUSED BY CHRONIC INFLAMMATION, INCLUDING GENETIC AND EPIGENETIC ALTERATION, AND THE EXPRESSION OF INFLAMMATORY MEDIATORS THAT LINK COPD AND LUNG CANCER, TO IDENTIFY NEW MOLECULAR THERAPEUTIC TARGETS. 2019 14 551 37 AUTOIMMUNITY AS AN ETIOLOGICAL FACTOR OF CANCER: THE TRANSFORMATIVE POTENTIAL OF CHRONIC TYPE 2 INFLAMMATION. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND AN ALARMING TREND OF INCREASED CANCER INCIDENCE IN ADULTS YOUNGER THAN 50 YEARS OF AGE AND PROJECTED A SUBSTANTIAL RISE IN CANCER INCIDENCE OVER THE NEXT 10 YEARS IN THIS AGE GROUP. THIS TREND WAS EXEMPLIFIED IN THE INCIDENCE OF NON-CARDIA GASTRIC CANCER AND ITS DISPROPORTIONATE IMPACT ON NON-HISPANIC WHITE FEMALES UNDER THE AGE OF 50. THE TREND IS CONCURRENT WITH THE INCREASING INCIDENCE OF AUTOIMMUNE DISEASES IN INDUSTRIALIZED COUNTRIES, SUGGESTING A CAUSAL LINK BETWEEN THE TWO. WHILE AUTOIMMUNITY HAS BEEN SUSPECTED TO BE A RISK FACTOR FOR SOME CANCERS, THE EXACT MECHANISMS UNDERLYING THE CONNECTION BETWEEN AUTOIMMUNITY AND CANCER REMAIN UNCLEAR AND ARE OFTEN CONTROVERSIAL. THE LINK HAS BEEN ATTRIBUTED TO SEVERAL MEDIATORS SUCH AS IMMUNE SUPPRESSION, INFECTION, DIET, ENVIRONMENT, OR, PERHAPS MOST PLAUSIBLY, CHRONIC INFLAMMATION BECAUSE OF ITS WELL-RECOGNIZED ROLE IN TUMORIGENESIS. IN THAT REGARD, AUTOIMMUNE CONDITIONS ARE COMMON CAUSES OF CHRONIC INFLAMMATION AND MAY TRIGGER REPETITIVE CYCLES OF ANTIGEN-SPECIFIC CELL DAMAGE, TISSUE REGENERATION, AND WOUND HEALING. ILLUSTRATING THE CONNECTION BETWEEN AUTOIMMUNE DISEASES AND CANCER ARE PATIENTS WHO HAVE AN INCREASED RISK OF CANCER DEVELOPMENT ASSOCIATED WITH GENETICALLY PREDISPOSED INSUFFICIENCY OF CYTOTOXIC T LYMPHOCYTE-ASSOCIATED PROTEIN 4 (CTLA4), A PROTOTYPICAL IMMUNE CHECKPOINT AGAINST AUTOIMMUNITY AND ONE OF THE MAIN TARGETS OF CANCER IMMUNE THERAPY. THE TUMORIGENIC PROCESS TRIGGERED BY CTLA4 INSUFFICIENCY HAS BEEN SHOWN IN A MOUSE MODEL TO BE DEPENDENT ON THE TYPE 2 CYTOKINES INTERLEUKIN-4 (IL4) AND INTERLEUKIN-13 (IL13). IN THIS TYPE 2 INFLAMMATORY MILIEU, CROSSTALK WITH TYPE 2 IMMUNE CELLS MAY INITIATE EPIGENETIC REPROGRAMMING OF EPITHELIAL CELLS, LEADING TO A METAPLASTIC DIFFERENTIATION AND EVENTUALLY MALIGNANT TRANSFORMATION EVEN IN THE ABSENCE OF CLASSICAL ONCOGENIC MUTATIONS. THOSE FINDINGS COMPLEMENT A LARGE BODY OF EVIDENCE FOR TYPE 1, TYPE 3, OR OTHER INFLAMMATORY MEDIATORS IN INFLAMMATORY TUMORIGENESIS. THIS REVIEW ADDRESSES THE POTENTIAL OF AUTOIMMUNITY AS A CAUSAL FACTOR FOR TUMORIGENESIS, THE UNDERLYING INFLAMMATORY MECHANISMS THAT MAY VARY DEPENDING ON HOST-ENVIRONMENT VARIATIONS, AND IMPLICATIONS TO CANCER PREVENTION AND IMMUNOTHERAPY. 2021 15 3681 41 INFLAMMATION, DNA METHYLATION AND COLITIS-ASSOCIATED CANCER. INFLAMMATION CAN RESULT FROM A RANGE OF SOURCES INCLUDING MICROBIAL INFECTIONS, EXPOSURE TO ALLERGENS AND TOXIC CHEMICALS, AUTOIMMUNE DISEASE AND OBESITY. A WELL-BALANCED IMMUNE RESPONSE CAN BE ANTI-TUMORIGENIC; HOWEVER, A SUSTAINED OR CHRONIC INFLAMMATORY RESPONSE IS GENERALLY HARMFUL AS THE IMMUNE RESPONSE BECOMES DISTORTED. A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND CANCER IS NOW WELL ACCEPTED AND MANY CHRONICALLY INFLAMED ORGANS OF THE GASTROINTESTINAL TRACT SHOW THIS ASSOCIATION. FOR EXAMPLE, PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING BOTH ULCERATIVE COLITIS AND CROHN'S DISEASE, HAVE A 2- TO 3-FOLD GREATER LIFETIME RISK OF DEVELOPING COLORECTAL CANCER COMPARED WITH THE GENERAL POPULATION. THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC) IS THOUGHT TO BE MULTIFACETED AND IS PROBABLY DUE TO A COMBINATION OF GENETIC FACTORS, EPIGENETIC FACTORS AND THE DURATION, EXTENT AND SEVERITY OF DISEASE. RECENTLY, EPIGENETIC ALTERATIONS, IN PARTICULAR ALTERATIONS IN DNA METHYLATION, HAVE BEEN OBSERVED DURING INFLAMMATION AND INFLAMMATION-ASSOCIATED CARCINOGENESIS. THE MEDIATORS OF THIS, THE SIGNIFICANCE OF THESE CHANGES IN DNA METHYLATION AND THE EFFECT THIS HAS ON GENE EXPRESSION AND THE MALIGNANT TRANSFORMATION OF THE EPITHELIAL CELLS DURING IBD AND CAC ARE DISCUSSED IN THIS REVIEW. THE RECENT ADVANCES IN TECHNOLOGIES TO STUDY GENOME-WIDE DNA METHYLATION AND THE THERAPEUTIC POTENTIAL OF UNDERSTANDING THESE MOLECULAR MECHANISMS ARE ALSO HIGHLIGHTED. 2012 16 733 35 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 17 4738 32 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 18 4112 36 MECHANISMS CONTRIBUTING TO THE COMORBIDITY OF COPD AND LUNG CANCER. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OFTEN CO-OCCUR, AND INDIVIDUALS WITH COPD ARE AT A HIGHER RISK OF DEVELOPING LUNG CANCER. WHILE THE UNDERLYING MECHANISM FOR THIS RISK IS NOT WELL UNDERSTOOD, ITS MAJOR CONTRIBUTING FACTORS HAVE BEEN PROPOSED TO INCLUDE GENOMIC, IMMUNE, AND MICROENVIRONMENT DYSREGULATION. HERE, WE REVIEW THE EVIDENCE AND SIGNIFICANT STUDIES THAT EXPLORE THE MECHANISMS UNDERLYING THE HEIGHTENED LUNG CANCER RISK IN PEOPLE WITH COPD. GENETIC AND EPIGENETIC CHANGES, AS WELL AS THE ABERRANT EXPRESSION OF NON-CODING RNAS, PREDISPOSE THE LUNG EPITHELIUM TO CARCINOGENESIS BY ALTERING THE EXPRESSION OF CANCER- AND IMMUNE-RELATED GENES. OXIDATIVE STRESS GENERATED BY TOBACCO SMOKING PLAYS A ROLE IN REDUCING GENOMIC INTEGRITY, PROMOTING EPITHELIAL-MESENCHYMAL-TRANSITION, AND GENERATING A CHRONIC INFLAMMATORY ENVIRONMENT. THIS LEADS TO ABNORMAL IMMUNE RESPONSES THAT PROMOTE CANCER DEVELOPMENT, THOUGH NOT ALL SMOKERS DEVELOP LUNG CANCER. SEX DIFFERENCES IN THE METABOLISM OF TOBACCO SMOKE PREDISPOSE FEMALES TO DEVELOPING COPD AND ACCUMULATING DAMAGE FROM OXIDATIVE STRESS THAT POSES A RISK FOR THE DEVELOPMENT OF LUNG CANCER. DYSREGULATION OF THE LUNG MICROENVIRONMENT AND MICROBIOME CONTRIBUTES TO CHRONIC INFLAMMATION, WHICH IS OBSERVED IN COPD AND KNOWN TO FACILITATE CANCER INITIATION IN VARIOUS TUMOR TYPES. FURTHER, THERE IS A NEED TO BETTER CHARACTERIZE AND IDENTIFY THE PROPORTION OF INDIVIDUALS WITH COPD WHO ARE AT A HIGH RISK FOR DEVELOPING LUNG CANCER. WE EVALUATE POSSIBLE NOVEL AND INDIVIDUALIZED SCREENING STRATEGIES, INCLUDING BIOMARKERS IDENTIFIED IN GENETIC STUDIES AND EXHALED BREATH CONDENSATE ANALYSIS. WE ALSO DISCUSS THE USE OF CORTICOSTEROIDS AND STATINS AS CHEMOPREVENTIVE AGENTS TO PREVENT LUNG CANCER. IT IS CRUCIAL THAT WE OPTIMIZE THE CURRENT METHODS FOR THE EARLY DETECTION AND MANAGEMENT OF LUNG CANCER AND COPD IN ORDER TO IMPROVE THE HEALTH OUTCOMES FOR A LARGE AFFECTED POPULATION. 2023 19 2333 28 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 20 3921 38 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004