1 4430 211 MOLECULAR BIOLOGY OF ONCOGENIC INFLAMMATORY PROCESSES. I. NON-ONCOGENIC AND ONCOGENIC PATHOGENS, INTRINSIC INFLAMMATORY REACTIONS WITHOUT PATHOGENS, AND MICRORNA/DNA INTERACTIONS (REVIEW). IN SOME INFLAMMASOMES TUMOR CELLS ARE GENERATED. THE INTERNAL ENVIRONMENT OF THE INFLAMMASOME IS CONDUCIVE TO THE INDUCTION OF MALIGNANT TRANSFORMATION. EPIGENETIC CHANGES INITIATE THIS PROCESS. THE SUBVERTED STROMAL CONNECTIVE TISSUE CELLS ACT TO PROMOTE AND SUSTAIN THE PROCESS OF MALIGNANT TRANS-FORMATION. IN ITS EARLY STAGES, THE PREMALIGNANT CELLS DEPEND ON PARACRINE CIRCUITRIES FOR THE RECEPTION OF GROWTH FACTORS. THE LIGANDS ARE DERIVED FROM THE CONNECTIVE TISSUE, AND THE RECEPTORS ARE EXPRESSED ON THE RECIPIENT PREMALIGNANT CELLS. THE INITIAL EVENTS ARE NOT A DIRECT ATTACK ON THE PROTO-ONCOGENES, AND THUS IT MAY BE ENTIRELY REVERSIBLE. EPIGENETIC PROCESSES OF HYPERMETHYLATION OF THE GENES AT THE PROMOTERS OF TUMOR SUPPRESSOR GENES (TO SILENCE THEM), AND DEACETYLATION OF THE HISTONES AIMED AT THE PROMOTERS OF PROTO-ONCOGENES (TO ACTIVATE THEM) ARE ON-GOING. A LARGE NUMBER OF SHORT RNA SEQUENCES (INTERFERING, MICRO-, SHORT HAIRPIN, NON-CODING RNAS) SILENCE TUMOR SUPPRESSOR GENES, BY NEUTRALIZING THEIR MRNAS. IN A SERIAL SEQUENCE ONCOGENES UNDERGO AMPLIFICATIONS, POINT-MUTATIONS, TRANSLOCATIONS AND FUSIONS. IN ITS EARLIEST STAGE, THE PROCESS IS REVERSIBLE BY DEMETHYLATION OF THE SILENCED SUPPRESSOR GENE PROMOTERS (TO REACTIVATE THEM), OR RE-ACETYLATION OF THE HISTONES OF THE ONCOGENE PROMOTERS, THUS DE-ACTIVATING THEM. THE EXTERNAL ADMINISTRATION OF HISTONE DEACETYLASE INHIBITORS USUALLY LEADS TO THE RESTORATION OF HISTONE ACETYLATION. IN TIME, THE UNCORRECTED PROCESSES SOLIDIFY INTO CONSTITUTIVE AND IRREVERSIBLE GENE MUTATIONS. SOME OF THE PATHOGENS INDUCING INFLAMMATIONS WITH CONSQUENTIAL MALIGNANT TRANSFORMATION CONTAIN ONCOGENIC GENE SEQUENCES (PAPILLOMA VIRUSES, EPSTEIN-BARR VIRUS, KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS, HEPATITIS B AND C VIRUSES, MERKEL CELL POLYOMA VIRUS, HELICOBACTER PYLORI, ENTEROTOXIGENIC BACTEROIDES FRAGILIS). THESE INDUCED MALIGNANCIES MAY BE MULTIFOCAL. OTHER PATHOGENS ARE DEVOID OF ANY KNOWN ONCOGENIC GENOMIC SEQUENCES (MYCOPLASMA VAV-CARCINOGENESIS, CHLAMYDIA MALT-LYMPHOMA GENESIS). IN THESE CASES THE HOST'S INFLAMMATORY REACTIONS INDUCE THE MALIGNANT TRANSFORMATION IN SERIAL SEQUENCES OF GENE ALTERATIONS INITIATED BY HYPOXIA AND REACTIVE OXYGEN AND NITROGEN SPECIES GENERATION. CARCINOGENIC INTRINSIC INFLAMMATORY PROCESSES ENDOGENOUSLY INITIATED WITHOUT A PATHOGEN ARE RECOGNIZED. CHRONIC INFLAMMATORY PROCESSES SIGNAL THE RNA/DNA COMPLEX. IN RESPONSE, THE DNA MAY REVERT INTO ITS ANCIENT PRIMORDIAL 'IMMORTAL' FORMAT, WHICH THE CLINICS RECOGNIZE AS 'ONCOGENESIS'. THE DNA REMAINS THE ULTIMATE MASTER OF BIOENGINEERING IN ORDER TO SUSTAIN LIFE. A DISCUSSION ON THE MOST VERSATILE AND RESISTANT PRIMORDIAL RNA/DNA COMPLEX AND THE PRE-, PROTO-, AND UNICELLULAR WORLD IN WHICH THEY CO-EXISTED IS INCLUDED. 2012 2 4539 44 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 3 5491 42 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 4 6710 37 VIRAL-INDUCED HUMAN CARCINOGENESIS: AN OXIDATIVE STRESS PERSPECTIVE. ONCOGENIC TRANSFORMATION OCCURS VIA MANY DIFFERENT MECHANISMS. ALTERATIONS IN THE EXPRESSION OF CERTAIN KEY GENES (ONCOGENES AND/OR TUMOR SUPPRESSOR GENES) CONTRIBUTE TO THE DEVELOPMENT OF THE TUMORIGENIC STATE OF UNCONTROLLED CELL PROLIFERATION. TUMOR VIRUSES' STUDIES HAVE CONTRIBUTED OVER THE LAST 2 DECADES SIGNIFICANTLY IN CANCER ETIOLOGY, FIRST BY PROVIDING VALUABLE INFORMATION ON THE MECHANISMS AND DISSECTION OF CELL SIGNALING AND GROWTH CONTROL PATHWAYS AND SECOND BY BEING CAUSATIVE AGENTS OF HUMAN NEOPLASIA. VIRUSES CONTRIBUTE TO THE DEVELOPMENT OF THE NEOPLASTIC STATE THROUGH MANY MECHANISMS: INACTIVATION OF TUMOR SUPPRESSOR GENES, HYPERSTIMULATION OF CELLULAR PROTO-ONCOGENE TRANSCRIPTION, OR BY VIRAL PROTEIN INTERFERENCE WITH THE CELLULAR TRANSCRIPTION, SIGNAL TRANSDUCTION, DNA REPAIR AND APOPTOSIS PATHWAYS AND INDUCTION OF CHRONIC OXIDATIVE STRESS. ON THE OTHER HAND, ONLY RECENTLY RESEARCH HAS PROVIDED EVIDENCE OF THE EPIGENETIC PATHWAY INVOLVEMENT AND ESPECIALLY THE DNA METHYLATION MACHINERY. TO THIS END, BOTH HYPOMETHYLATION-INDUCED ONCOGENIC ACTIVATION AND/OR HYPERMETHYLATION-INDUCED TUMOR SUPPRESSOR GENE SILENCING ARE LINKED WITH VIRAL-INDUCED CARCINOGENESIS. IN THIS REVIEW, WE DISCUSS THE CURRENT STATUS OF KNOWLEDGE ON VIRAL-ASSOCIATED CARCINOGENESIS WITH EMPHASIS ON THE MECHANISMS OF OXIDATIVE STRESS AND DNA DAMAGE INDUCTION IN HUMANS BY VIRUSES AS WELL AS IMPLICATIONS IN CANCER TREATMENT. 2010 5 3950 34 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 6 45 39 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 7 6906 36 [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 8 376 28 AN EPI(C)GENETIC WAR: PATHOGENS, CANCER AND HUMAN GENOME. CANCER IS CHARACTERIZED BY INTER- AND INTRA-TUMOR HETEROGENEITY AND THIS IS ALSO OBSERVED IN THE CONTEXT OF CANCERS CAUSED BY PATHOGENS. NEARLY 20% OF ALL CANCERS ARE ATTRIBUTABLE TO PATHOGENIC ORGANISMS. PATHOGENIC INFECTIONS RESULT IN DEREGULATION OF GENE EXPRESSION BOTH BY GENETIC AND EPIGENETIC MECHANISMS, THEREBY CAUSING MALIGNANT TRANSFORMATION. ANOTHER CHARACTERISTIC OF PATHOGEN-INDUCED CANCERS IS THE OCCURRENCE OF CHRONIC INFLAMMATION DUE TO ACTIVATION OF THE INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM. THIS REVIEW FOCUSES ON THE EPIGENETIC CHANGES INDUCED BY ONCOVIRUSES, PARASITES, CANCER-CAUSING BACTERIA AND 'ENDOGENOUS PATHOGENS' TO TRIGGER HOST CELL PROLIFERATION INDEFINITELY AS WELL AS THE INFLAMMATION ASSOCIATED WITH PATHOGEN-INDUCED CANCERS. THE OPPORTUNITY OF TARGETING COMPONENTS OF BOTH PATHOGEN AND HOST EPIGENETIC MACHINERY TO LIMIT TUMOR PROGRESSION IS ALSO DISCUSSED. 2018 9 3917 46 LINK BETWEEN CHRONIC INFLAMMATION AND HUMAN PAPILLOMAVIRUS-INDUCED CARCINOGENESIS (REVIEW). INFLAMMATION IS A DEFENSE STRATEGY AGAINST INVADING AGENTS AND HARMFUL MOLECULES THAT IS ACTIVATED IMMEDIATELY FOLLOWING A STIMULUS, AND INVOLVES THE RELEASE OF CYTOKINES AND CHEMOKINES, WHICH ACTIVATE THE INNATE IMMUNE RESPONSE. THESE MEDIATORS ACT TOGETHER TO INCREASE BLOOD FLOW AND VASCULAR PERMEABILITY, FACILITATING RECRUITMENT OF EFFECTOR CELLS TO THE SITE OF INJURY. FOLLOWING RESOLUTION OF THE INJURY AND REMOVAL OF THE STIMULUS, INFLAMMATION IS DISABLED, BUT IF THE STIMULUS PERSISTS, INFLAMMATION BECOMES CHRONIC AND IS STRONGLY ASSOCIATED WITH CANCER. THIS IS LIKELY TO BE DUE TO THE FACT THAT THE INFLAMMATION LEADS TO A WOUND THAT DOES NOT HEAL, REQUIRING A CONSTANT RENEWAL OF CELLS, WHICH INCREASES THE RISK OF NEOPLASTIC TRANSFORMATION. DEBRIS FROM PHAGOCYTOSIS, INCLUDING THE REACTIVE SPECIES OF OXYGEN AND NITROGEN THAT CAUSE DAMAGE TO DNA ALREADY DAMAGED BY THE LEUKOTRIENES AND PROSTAGLANDINS, HAS AN IMPACT ON INFLAMMATION AND VARIOUS CARCINOGENIC ROUTES. THERE IS AN ASSOCIATION BETWEEN CHRONIC INFLAMMATION, PERSISTENT INFECTION AND CANCER, WHERE ONCOGENIC ACTION IS MEDIATED BY AUTOCRINE AND PARACRINE SIGNALS, CAUSING CHANGES IN SOMATIC CELLS UNDER THE INFLUENCE OF THE MICROBIAL GENOME OR OF EPIGENETIC FACTORS. AMONG THE INFECTIOUS AGENTS ASSOCIATED WITH CANCER, CERTAIN GENOTYPES OF HUMAN PAPILLOMAVIRUS (HPV) STAND OUT. HPV IS RESPONSIBLE FOR VIRTUALLY ALL CASES OF CERVICAL CANCER AND A LOWER PROPORTION OF CANCERS OF THE VAGINA, VULVA, ANUS, PENIS AND A NUMBER OF EXTRAGENITAL CANCERS. IN THE PRESENT REVIEW, RECENT ADVANCES IN THE MECHANISMS INVOLVED IN THE INFLAMMATORY RESPONSE ARE PRESENTED WITH THEIR PARTICIPATION IN THE PROCESS OF CARCINOGENESIS, EMPHASIZING THE ROLE OF CHRONIC INFLAMMATION IN THE DEVELOPMENT OF HPV-INDUCED CERVICAL CANCER. 2015 10 3799 37 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 2338 43 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 12 6444 52 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 13 3666 43 INFECTION, STEM CELLS AND CANCER SIGNALS. THE ASSOCIATION OF CANCER WITH PRECEDING PARASITIC INFECTIONS HAS BEEN OBSERVED FOR OVER 200 YEARS. SOME SUCH CANCERS ARISE FROM INFECTION OF TISSUE STEM CELLS BY VIRUSES WITH INSERTION OF VIRAL ONCOGENES INTO THE HOST DNA (MOUSE POLYOMA VIRUS, MOUSE MAMMARY TUMOR VIRUS). IN OTHER CASES THE VIRUS DOES NOT INSERT ITS DNA INTO THE HOST CELLS, BUT RATHER COMMANDEERS THE METABOLISM OF THE INFECTED CELLS, SO THAT THE CELLS CONTINUE TO PROLIFERATE AND DO NOT DIFFERENTIATE (HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER). CYTOPLASMIC EPSTEIN BARR VIRUS INFECTION IS ASSOCIATED WITH A SPECIFIC GENE TRANSLOCATION (IG/C-MYC) THAT ACTIVATES PROLIFERATION OF AFFECTED CELLS (BURKITT LYMPHOMA). IN CHRONIC OSTEOMYELITIS AN INFLAMMATORY REACTION TO THE INFECTION APPEARS TO ACT THROUGH PRODUCTION OF INFLAMMATORY CYTOKINES AND OXYGEN RADICAL FORMATION TO INDUCE EPITHELIAL CANCERS. INFECTION WITH HELICOBACTER PYLORI LEADS TO EPIGENETIC CHANGES IN METHYLATION AND INFECTION BY A PARASITE. CLONORCHIS SINENSIS ALSO ACTS AS A PROMOTER OF CANCER OF THE BILE DUCTS OF THE LIVER (CHOLANIOCARCINOMA). THE COMMON THREAD AMONG THESE DIVERSE PATHWAYS IS THAT THE INFECTIONS ACT TO ALTER TISSUE STEM CELL SIGNALING WITH CONTINUED PROLIFERATION OF TUMOR TRANSIT AMPLIFYING CELLS. 2011 14 2033 41 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 15 208 36 ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) LINKING IMMUNITY, CHRONIC INFLAMMATION, AND CANCER. ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) IS CRITICALLY INVOLVED IN CLASS SWITCH RECOMBINATION AND SOMATIC HYPERMUTATION OF IG LOCI RESULTING IN DIVERSIFICATION OF ANTIBODIES REPERTOIRE AND PRODUCTION OF HIGH-AFFINITY ANTIBODIES AND AS SUCH REPRESENTS A PHYSIOLOGICAL TOOL TO INTRODUCE DNA ALTERATIONS. THESE PROCESSES TAKE PLACE WITHIN GERMINAL CENTERS OF SECONDARY LYMPHOID ORGANS. UNDER PHYSIOLOGICAL CONDITIONS, AID IS EXPRESSED PREDOMINANTLY IN ACTIVATED B LYMPHOCYTES. BECAUSE OF THE MUTAGENIC AND RECOMBINOGENIC POTENTIAL OF AID, ITS EXPRESSION AND ACTIVITY IS TIGHTLY REGULATED ON DIFFERENT LEVELS TO MINIMIZE THE RISK OF UNWANTED DNA DAMAGE. HOWEVER, CHRONIC INFLAMMATION AND, PROBABLY, COMBINATION OF OTHER NOT-YET-IDENTIFIED FACTORS ARE ABLE TO CREATE A MICROENVIRONMENT SUFFICIENT FOR TRIGGERING AN ABERRANT AID EXPRESSION IN B CELLS AND, IMPORTANTLY, IN NON-B-CELL BACKGROUND. UNDER THESE CIRCUMSTANCES, AID MAY TARGET ALSO NON-IG GENES, INCLUDING CANCER-RELATED GENES AS ONCOGENES, TUMOR SUPPRESSOR GENES, AND GENOMIC STABILITY GENES, AND MODULATE BOTH GENETIC AND EPIGENETIC INFORMATION. DESPITE ONGOING PROGRESS, THE COMPLETE UNDERSTANDING OF FUNDAMENTAL ASPECTS IS STILL LACKING AS (1) WHAT ARE THE CRUCIAL FACTORS TRIGGERING AN ABERRANT AID EXPRESSION/ACTIVITY INCLUDING THE IMPACT OF TH2-DRIVEN INFLAMMATION AND (2) TO WHAT EXTENT MAY ABERRANT AID IN HUMAN NON-B CELLS LEAD TO ABNORMAL CELL STATE ASSOCIATED WITH AN INCREASED RATE OF GENOMIC ALTERATIONS AS POINT MUTATIONS, SMALL INSERTIONS OR DELETIONS, AND/OR RECURRENT CHROMOSOMAL TRANSLOCATIONS DURING SOLID TUMOR DEVELOPMENT AND PROGRESSION. 2012 16 1232 37 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 17 4479 40 MOLECULAR PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR THERAPY. THE DEVELOPMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC) IS A MULTISTEP PROCESS REQUIRING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS, INFLUENCED BY A PATIENT'S GENETIC PREDISPOSITION AS WELL AS BY ENVIRONMENTAL INFLUENCES, INCLUDING TOBACCO, ALCOHOL, CHRONIC INFLAMMATION, AND VIRAL INFECTION. TUMORIGENIC GENETIC ALTERATIONS CONSIST OF TWO MAJOR TYPES: TUMOR SUPPRESSOR GENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN INACTIVATED; AND ONCOGENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN ACTIVATED. TUMOR SUPPRESSOR GENES CAN BE INACTIVATED THROUGH GENETIC EVENTS SUCH AS MUTATION, LOSS OF HETEROZYGOSITY, OR DELETION, OR BY EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION OR CHROMATIN REMODELING. ONCOGENES CAN BE ACTIVATED THROUGH OVEREXPRESSION DUE TO GENE AMPLIFICATION, INCREASED TRANSCRIPTION, OR CHANGES IN STRUCTURE DUE TO MUTATIONS THAT LEAD TO INCREASED TRANSFORMING ACTIVITY. THIS REVIEW FOCUSES ON THE MOLECULAR MECHANISMS OF ORAL CARCINOGENESIS AND THE USE OF BIOLOGIC THERAPY TO SPECIFICALLY TARGET MOLECULES ALTERED IN OSCC. THE RAPID PROGRESS THAT HAS BEEN MADE IN OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS CONTRIBUTING TO THE DEVELOPMENT OF OSCC IS LEADING TO IMPROVEMENTS IN THE EARLY DIAGNOSIS OF TUMORS AND THE REFINEMENT OF BIOLOGIC TREATMENTS INDIVIDUALIZED TO THE SPECIFIC CHARACTERISTICS OF A PATIENT'S TUMOR. 2008 18 3599 39 IMPORTANCE OF EPIGENETIC CHANGES IN CANCER ETIOLOGY, PATHOGENESIS, CLINICAL PROFILING, AND TREATMENT: WHAT CAN BE LEARNED FROM HEMATOLOGIC MALIGNANCIES? EPIGENETIC ALTERATIONS REPRESENT A KEY CANCER HALLMARK, EVEN IN HEMATOLOGIC MALIGNANCIES (HMS) OR BLOOD CANCERS, WHOSE CLINICAL FEATURES DISPLAY A HIGH INTER-INDIVIDUAL VARIABILITY. EVIDENCE ACCUMULATED IN RECENT YEARS INDICATES THAT INACTIVATING DNA HYPERMETHYLATION PREFERENTIALLY TARGETS THE SUBSET OF POLYCOMB GROUP (PCG) GENES THAT ARE REGULATORS OF DEVELOPMENTAL PROCESSES. CONVERSELY, ACTIVATING DNA HYPOMETHYLATION TARGETS ONCOGENIC SIGNALING PATHWAY GENES, BUT OUTCOMES OF BOTH EVENTS LEAD IN THE OVEREXPRESSION OF ONCOGENIC SIGNALING PATHWAYS THAT CONTRIBUTE TO THE STEM-LIKE STATE OF CANCER CELLS. ON THE BASIS OF RECENT EVIDENCE FROM POPULATION-BASED, CLINICAL AND EXPERIMENTAL STUDIES, WE HYPOTHESIZE THAT FACTORS ASSOCIATED WITH RISK FOR DEVELOPING A HM, SUCH AS METABOLIC SYNDROME AND CHRONIC INFLAMMATION, TRIGGER EPIGENETIC MECHANISMS TO INCREASE THE TRANSCRIPTIONAL EXPRESSION OF ONCOGENES AND ACTIVATE ONCOGENIC SIGNALING PATHWAYS. AMONG OTHERS, SIGNALING PATHWAYS ASSOCIATED WITH SUCH RISK FACTORS INCLUDE PRO-INFLAMMATORY NUCLEAR FACTOR KAPPAB (NF-KAPPAB), AND MITOGENIC, GROWTH, AND SURVIVAL JANUS KINASE (JAK) INTRACELLULAR NON-RECEPTOR TYROSINE KINASE-TRIGGERED PATHWAYS, WHICH INCLUDE SIGNALING PATHWAYS SUCH AS TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT), RAS GTPASES/MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS)/EXTRACELLULAR SIGNAL-RELATED KINASES (ERKS), PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR), AND BETA-CATENIN PATHWAYS. RECENT FINDINGS ON EPIGENETIC MECHANISMS AT WORK IN HMS AND THEIR IMPORTANCE IN THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES ARE HEREIN SUMMARIZED AND DISCUSSED. FURTHERMORE, THE ROLE OF EPIGENETIC PROCESSES IN THE DETERMINATION OF BIOLOGICAL IDENTITY, THE CONSEQUENCES FOR INTERINDIVIDUAL VARIABILITY IN DISEASE CLINICAL PROFILE, AND THE POTENTIAL OF EPIGENETIC DRUGS IN HMS ARE ALSO CONSIDERED. 2013 19 4888 38 OXIDATIVE DAMAGE IN THE PROGRESSION OF CHRONIC LIVER DISEASE TO HEPATOCELLULAR CARCINOMA: AN INTRICATE PATHWAY. THE HISTO-PATHOLOGIC AND MOLECULAR MECHANISMS LEADING TO INITIATION AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STILL ILL-DEFINED; HOWEVER, THERE IS INCREASING EVIDENCE THAT THE GRADUAL ACCUMULATION OF MUTATIONS, GENETIC AND EPIGENETIC CHANGES WHICH OCCUR IN PRENEOPLASTIC HEPATOCYTES RESULTS IN THE DEVELOPMENT OF DYSPLASTIC FOCI, NODULES, AND FINALLY, OVERT HCC. AS WELL AS MANY OTHER NEOPLASIAS, LIVER CANCER IS CONSIDERED AN "INFLAMMATORY CANCER", ARISING FROM A CONTEXT OF INFLAMMATION, AND CHARACTERIZED BY INFLAMMATION-RELATED MECHANISMS THAT FAVOR TUMOR CELL SURVIVAL, PROLIFERATION, AND INVASION. MOLECULAR MECHANISMS THAT LINK INFLAMMATION AND NEOPLASIA HAVE BEEN WIDELY INVESTIGATED, AND IT HAS BEEN WELL ESTABLISHED THAT INFLAMMATORY CELLS RECRUITED AT THESE SITES WITH ONGOING INFLAMMATORY ACTIVITY RELEASE CHEMOKINES THAT ENHANCE THE PRODUCTION OF REACTIVE OXYGEN SPECIES. THE LATTER, IN TURN, PROBABLY HAVE A MAJOR PATHOGENIC ROLE IN THE CONTINUUM STARTING FROM HEPATITIS FOLLOWED BY CHRONIC INFLAMMATION, AND ULTIMATELY LEADING TO CANCER. THE RELATIONSHIP AMONGST CHRONIC LIVER INJURY, FREE RADICAL PRODUCTION, AND DEVELOPMENT OF HCC IS EXPLORED IN THE PRESENT REVIEW, PARTICULARLY IN THE LIGHT OF THE COMPLEX NETWORK THAT INVOLVES OXIDATIVE DNA DAMAGE, CYTOKINE SYNTHESIS, TELOMERE DYSFUNCTION, AND MICRORNA REGULATION. 2014 20 6395 46 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