1 4666 114 NEW INSIGHTS AND OPTIONS INTO THE MECHANISMS AND EFFECTS OF COMBINED TARGETED THERAPY AND IMMUNOTHERAPY IN PROSTATE CANCER. CHRONIC INFLAMMATION IS BELIEVED TO DRIVE PROSTATE CARCINOGENESIS BY PRODUCING REACTIVE OXYGEN SPECIES OR REACTIVE NITROGEN SPECIES TO INDUCE DNA DAMAGE. THIS EFFECT MIGHT SUBSEQUENTLY CAUSE EPIGENETIC AND GENOMIC ALTERATIONS, LEADING TO MALIGNANT TRANSFORMATION. ALTHOUGH ESTABLISHED THERAPEUTIC ADVANCES HAVE EXTENDED OVERALL SURVIVAL, TUMORS IN PATIENTS WITH ADVANCED PROSTATE CANCER ARE PRONE TO METASTASIS, TRANSFORMATION INTO METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, AND THERAPEUTIC RESISTANCE. THE TUMOR MICROENVIRONMENT (TME) OF PROSTATE CANCER IS INVOLVED IN CARCINOGENESIS, INVASION AND DRUG RESISTANCE. A PLETHORA OF PRECLINICAL STUDIES HAVE FOCUSED ON IMMUNE-BASED THERAPIES. UNDERSTANDING THE INTRICATE TME SYSTEM IN PROSTATE CANCER MAY HOLD MUCH PROMISE FOR DEVELOPING NOVEL THERAPIES, DESIGNING COMBINATIONAL THERAPEUTIC STRATEGIES, AND FURTHER OVERCOMING RESISTANCE TO ESTABLISHED TREATMENTS TO IMPROVE THE LIVES OF PROSTATE CANCER PATIENTS. IN THIS REVIEW, WE DISCUSS NONIMMUNE COMPONENTS AND VARIOUS IMMUNE CELLS WITHIN THE TME AND THEIR PUTATIVE ROLES DURING PROSTATE CANCER INITIATION, PROGRESSION, AND METASTASIS. WE ALSO OUTLINE THE UPDATED FUNDAMENTAL RESEARCH FOCUSING ON THERAPEUTIC ADVANCES OF TARGETED THERAPY AS WELL AS COMBINATIONAL OPTIONS FOR PROSTATE CANCER. 2023 2 2897 26 GASTRIC TUMOR MICROENVIRONMENT. A COMPELLING BODY OF EVIDENCE HAS DEMONSTRATED THAT GASTRIC CANCER HAS A VERY PARTICULAR TUMOR MICROENVIRONMENT, A SIGNATURE VERY SUITABLE TO PROMOTE TUMOR PROGRESSION AND METASTASIS. RECENT INVESTIGATIONS HAVE PROVIDED NEW INSIGHTS INTO THE MULTIPLE MOLECULAR MECHANISMS, DEFINED BY GENETIC AND EPIGENETIC MECHANISMS, SUPPORTING A VERY ACTIVE CROSS TALK BETWEEN THE COMPONENTS OF THE TUMOR MICROENVIRONMENT AND THUS DEFINING THE FATE OF TUMOR PROGRESSION. IN THIS REVIEW, WE INTEND TO HIGHLIGHT THE ROLE OF VERY ACTIVE CONTRIBUTORS AT GASTRIC CANCER TME, PARTICULARLY CANCER-ASSOCIATED FIBROBLASTS, BONE MARROW-DERIVED CELLS, TUMOR-ASSOCIATED MACROPHAGES, AND TUMOR-INFILTRATING NEUTROPHILS, ALL OF THEM SURROUNDED BY AN OVERTIME CHANGING EXTRACELLULAR MATRIX. IN ADDITION, THE VERY ACTIVE CROSS TALK BETWEEN THE COMPONENTS OF THE TUMOR MICROENVIRONMENT, DEFINED BY GENETIC AND EPIGENETIC MECHANISMS, THUS DEFINING THE FATE OF TUMOR PROGRESSION, IS ALSO REVIEWED. 2020 3 3688 46 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 4 2813 38 FIBROBLAST REPROGRAMMING IN GASTROINTESTINAL CANCER. GASTROINTESTINAL CANCERS ARE A SIGNIFICANT CAUSE OF CANCER MORTALITY WORLDWIDE AND HAVE BEEN STRONGLY LINKED WITH CHRONIC INFLAMMATION. CURRENT THERAPIES FOCUS ON EPITHELIAL/CANCER CELLS; HOWEVER, THE IMPORTANCE OF THE TUMOR MICROENVIRONMENT IN THE DEVELOPMENT AND TREATMENT OF THE DISEASE IS ALSO NOW WELL ESTABLISHED. CANCER-ASSOCIATED FIBROBLASTS (CAFS) ARE A MAJOR COMPONENT OF THE TUMOR MICROENVIRONMENT, AND ARE ACTIVELY PARTICIPATING IN TUMOR INITIATION, PROMOTION AND METASTASIS. THEY STRUCTURALLY AND FUNCTIONALLY AFFECT CANCER CELL PROLIFERATION, TUMOR IMMUNITY, ANGIOGENESIS, EXTRACELLULAR MATRIX REMODELING AND METASTASIS THROUGH A VARIETY OF SIGNALING PATHWAYS. CAFS ORIGINATE PREDOMINANTLY FROM RESIDENT MESENCHYMAL CELLS, WHICH ARE ACTIVATED AND REPROGRAMMED IN RESPONSE TO CUES FROM CANCER CELLS. IN RECENT YEARS, CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT HAS ALSO PROVEN AN IMPORTANT DRIVER OF MESENCHYMAL CELL ACTIVATION AND SUBSEQUENT CAF DEVELOPMENT, WHICH IN TURN ARE CAPABLE OF REGULATING THE TRANSITION FROM ACUTE TO CHRONIC INFLAMMATION AND CANCER. IN THIS REVIEW, WE WILL PROVIDE A CONCISE OVERVIEW OF THE MECHANISMS THAT DRIVE FIBROBLAST REPROGRAMMING IN CANCER AND THE RECENT ADVANCES ON THE DOWNSTREAM SIGNALING PATHWAYS THAT REGULATE THE FUNCTIONAL PROPERTIES OF THE ACTIVATED MESENCHYME. THIS NEW MECHANISTIC INSIGHT COULD PAVE THE WAY FOR NEW THERAPEUTIC STRATEGIES AND BETTER PROGNOSIS FOR CANCER PATIENTS. 2020 5 6591 29 TUMOR-ASSOCIATED MACROPHAGES AS A PARADIGM OF MACROPHAGE PLASTICITY, DIVERSITY, AND POLARIZATION: LESSONS AND OPEN QUESTIONS. MACROPHAGES ARE PRESENT IN ALL BODY COMPARTMENTS, INCLUDING CANCEROUS TISSUES, AND THEIR FUNCTIONS ARE PROFOUNDLY AFFECTED BY SIGNALS FROM THE MICROENVIRONMENT UNDER HOMEOSTATIC AND PATHOLOGICAL CONDITIONS. TUMOR-ASSOCIATED MACROPHAGES ARE A MAJOR CELLULAR COMPONENT OF CANCER-RELATED INFLAMMATION AND HAVE SERVED AS A PARADIGM FOR THE PLASTICITY AND FUNCTIONAL POLARIZATION OF MONONUCLEAR PHAGOCYTES. TUMOR-ASSOCIATED MACROPHAGES CAN EXERT DUAL INFLUENCE OF CANCER DEPENDING ON THE ACTIVATION STATE, WITH CLASSICALLY ACTIVATED (M1) AND ALTERNATIVELY ACTIVATED (M2) CELLS GENERALLY EXERTING ANTITUMORAL AND PROTUMORAL FUNCTIONS, RESPECTIVELY. THESE ARE EXTREMES IN A CONTINUUM OF POLARIZATION STATES IN A UNIVERSE OF DIVERSITY. TUMOR-ASSOCIATED MACROPHAGES AFFECT VIRTUALLY ALL ASPECTS OF TUMOR TISSUES, INCLUDING STEM CELLS, METABOLISM, ANGIOGENESIS, INVASION, AND METASTASIS. PROGRESS HAS BEEN MADE IN DEFINING SIGNALING MOLECULES, TRANSCRIPTION FACTORS, EPIGENETIC CHANGES, AND REPERTOIRE OF MICRORNAS UNDERLYING MACROPHAGE POLARIZATION. PRECLINICAL AND EARLY CLINICAL DATA SUGGEST THAT MACROPHAGES MAY SERVE AS TOOLS FOR THE DEVELOPMENT OF INNOVATIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES IN CANCER AND CHRONIC NONRESOLVING INFLAMMATORY DISEASES. 2013 6 2225 39 EPIGENETIC MODIFICATIONS IN TUMOR-ASSOCIATED MACROPHAGES: A NEW PERSPECTIVE FOR AN OLD FOE. TUMORIGENESIS IS FREQUENTLY ACCOMPANIED BY CHRONIC INFLAMMATION, AND THE TUMOR MICROENVIRONMENT (TME) CAN BE CONSIDERED AN ECOSYSTEM THAT CONSISTS OF TUMOR CELLS, ENDOTHELIOCYTES, FIBROBLASTS, IMMUNE CELLS AND ACELLULAR COMPONENTS SUCH AS EXTRACELLULAR MATRIX. FOR TUMOR CELLS, THEIR SURVIVAL ADVANTAGES ARE DEPENDENT ON BOTH GENETIC AND EPIGENETIC ALTERATIONS, WHILE OTHER CELLS MAINLY PRESENT EPIGENETIC MODIFICATIONS. MACROPHAGES ARE THE MOST PLASTIC TYPE OF IMMUNE CELLS AND UNDERGO DIVERSE EPIGENETIC ALTERATIONS IN THE TME. SOME OF THESE EPIGENETIC MODIFICATIONS MITIGATE AGAINST CANCER PROGRESSION, AND OTHERS ACCELERATE THIS PROCESS. DUE TO THE COMPLEX ROLES OF MACROPHAGES IN THE TME, IT IS URGENT TO UNDERSTAND THEIR EPIGENETIC MODIFICATIONS ASSOCIATED WITH THE TME. HERE, WE MAINLY SUMMARIZE RECENT FINDINGS ON TME-ASSOCIATED EPIGENETIC ALTERATIONS OF TUMOR-ASSOCIATED MACROPHAGES (TAMS), INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS OF HISTONE PROTEINS, CHROMATIN REMODELING, AND NONCODING RNA-MEDIATED EPIGENETIC REGULATION. AT THE END OF THIS REVIEW, WE ALSO DISCUSS THE TRANSLATIONAL POTENTIAL OF THESE EPIGENETIC MODIFICATIONS FOR DEVELOPING NOVEL CANCER THERAPIES TARGETING TAMS. 2022 7 6592 37 TUMOR-ASSOCIATED MACROPHAGES IN HEPATOCELLULAR CARCINOMA PATHOGENESIS, PROGNOSIS AND THERAPY. HEPATOCELLULAR CARCINOMA (HCC) CONSTITUTES A MAJOR HEALTH BURDEN GLOBALLY, AND IT IS CAUSED BY INTRINSIC GENETIC MUTATIONS ACTING IN CONCERT WITH A MULTITUDE OF EPIGENETIC AND EXTRINSIC RISK FACTORS. CANCER INDUCES MYELOPOIESIS IN THE BONE MARROW, AS WELL AS THE MOBILIZATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH RESIDE IN THE SPLEEN. MONOCYTES PRODUCED IN THE BONE MARROW AND THE SPLEEN FURTHER INFILTRATE TUMORS, WHERE THEY DIFFERENTIATE INTO TUMOR-ASSOCIATED MACROPHAGES (TAMS). THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION AND HEPATOCARCINOGENESIS HAS BEEN THOROUGHLY INVESTIGATED OVER THE PAST DECADE; HOWEVER, SEVERAL ASPECTS OF THE ROLE OF TAMS IN HCC DEVELOPMENT ARE YET TO BE DETERMINED. IN RESPONSE TO CERTAIN STIMULI AND SIGNALING, MONOCYTES DIFFERENTIATE INTO MACROPHAGES WITH ANTITUMOR PROPERTIES, WHICH ARE CLASSIFIED AS M1-LIKE. ON THE OTHER HAND, UNDER DIFFERENT STIMULI AND SIGNALING, THE POLARIZATION OF MACROPHAGES SHIFTS TOWARDS AN M2-LIKE PHENOTYPE WITH A TUMOR PROMOTING CAPACITY. M2-LIKE MACROPHAGES DRIVE TUMOR GROWTH BOTH DIRECTLY AND INDIRECTLY, VIA THE SUPPRESSION OF CYTOTOXIC CELL POPULATIONS, INCLUDING CD8+ T CELLS AND NK CELLS. THE TUMOR MICROENVIRONMENT AFFECTS THE RESPONSE TO IMMUNOTHERAPIES. THEREFORE, AN ENHANCED UNDERSTANDING OF ITS IMMUNOBIOLOGY IS ESSENTIAL FOR THE DEVELOPMENT OF NEXT-GENERATION IMMUNOTHERAPIES. THE UTILIZATION OF VARIOUS MONOCYTE-CENTERED ANTICANCER TREATMENT MODALITIES HAS BEEN UNDER CLINICAL INVESTIGATION, SELECTIVELY TARGETING AND MODULATING THE PROCESSES OF MONOCYTE RECRUITMENT, ACTIVATION AND MIGRATION. THIS REVIEW SUMMARIZES THE CURRENT EVIDENCE ON THE ROLE OF TAMS IN HCC PATHOGENESIS AND PROGRESSION, AS WELL AS IN THEIR POTENTIAL INVOLVEMENT IN TUMOR THERAPY, SHEDDING LIGHT ON EMERGING ANTICANCER TREATMENT METHODS TARGETING MONOCYTES. 2022 8 6201 38 THE INFLAMMATORY MICROENVIRONMENT AND MICROBIOME IN PROSTATE CANCER DEVELOPMENT. CHRONIC INFLAMMATION PROMOTES THE DEVELOPMENT OF SEVERAL TYPES OF SOLID CANCERS AND MIGHT CONTRIBUTE TO PROSTATE CARCINOGENESIS. THIS HYPOTHESIS PARTLY ORIGINATES IN THE FREQUENT OBSERVATION OF INFLAMMATORY CELLS IN THE PROSTATE MICROENVIRONMENT OF ADULT MEN. INFLAMMATION IS ASSOCIATED WITH PUTATIVE PROSTATE CANCER PRECURSOR LESIONS, TERMED PROLIFERATIVE INFLAMMATORY ATROPHY. INFLAMMATION MIGHT DRIVE PROSTATE CARCINOGENESIS VIA OXIDATIVE STRESS AND GENERATION OF REACTIVE OXYGEN SPECIES THAT INDUCE MUTAGENESIS. ADDITIONALLY, INFLAMMATORY STRESS MIGHT CAUSE EPIGENETIC ALTERATIONS THAT PROMOTE NEOPLASTIC TRANSFORMATION. PROLIFERATIVE INFLAMMATORY ATROPHY IS ENRICHED FOR PROLIFERATIVE LUMINAL EPITHELIAL CELLS OF INTERMEDIATE PHENOTYPE THAT MIGHT BE PRONE TO GENOMIC ALTERATIONS LEADING TO PROSTATIC INTRAEPITHELIAL NEOPLASIA AND PROSTATE CANCER. STUDIES IN ANIMALS SUGGEST THAT INFLAMMATORY CHANGES IN THE PROSTATE MICROENVIRONMENT CONTRIBUTE TO REPROGRAMMING OF PROSTATE EPITHELIAL CELLS, A POSSIBLE STEP IN TUMOUR INITIATION. PROSTATIC INFECTION, CONCURRENT WITH EPITHELIAL BARRIER DISRUPTION, MIGHT BE A KEY DRIVER OF AN INFLAMMATORY MICROENVIRONMENT; THE DISCOVERY OF A URINARY MICROBIOME INDICATES A POTENTIAL SOURCE OF FREQUENT EXPOSURE OF THE PROSTATE TO A DIVERSE NUMBER OF MICROORGANISMS. HENCE, CURRENT EVIDENCE SUGGESTS THAT INFLAMMATION AND ATROPHY ARE INVOLVED IN PROSTATE CARCINOGENESIS AND SUGGESTS A ROLE FOR THE MICROBIOME IN ESTABLISHING AN INFLAMMATORY PROSTATE MICROENVIRONMENT THAT MIGHT PROMOTE PROSTATE CANCER DEVELOPMENT AND PROGRESSION. 2018 9 3694 44 INFLAMMATORY COMPONENTS OF THE THYROID CANCER MICROENVIRONMENT: AN AVENUE FOR IDENTIFICATION OF NOVEL BIOMARKERS. THE INCIDENCE OF THYROID CANCER IN THE UNITED STATES IS ON THE RISE WITH AN APPRECIABLY HIGH DISEASE RECURRENCE RATE OF 20-30%. ANAPLASTIC THYROID CANCER (ATC), ALTHOUGH RARE IN OCCURRENCE, IS AN AGGRESSIVE FORM OF CANCER WITH LIMITED TREATMENT OPTIONS AND BLEAK CURE RATES. THIS CHAPTER USES DISCUSSIONS OF IN VITRO MODELS THAT ARE REPRESENTATIVE OF PAPILLARY, ANAPLASTIC, AND FOLLICULAR THYROID CANCER TO EVALUATE THE CROSSTALK BETWEEN SPECIFIC CELLS OF THE TUMOR MICROENVIRONMENT (TME), WHICH SERVES AS A HIGHLY HETEROGENEOUS REALM OF SIGNALING CASCADES AND METABOLISM THAT ARE ASSOCIATED WITH TUMORIGENESIS. THE CELLULAR CONSTITUENTS OF THE TME CARRY OUT VARYING CHARACTERISTIC IMMUNOMODULATORY FUNCTIONS THAT ARE DISCUSSED THROUGHOUT THIS CHAPTER. THE AFOREMENTIONED CELL TYPES INCLUDE CANCER-ASSOCIATED FIBROBLASTS (CAFS), ENDOTHELIAL CELLS (ECS), AND CANCER STEM CELLS (CSCS), AS WELL AS SPECIFIC IMMUNE CELLS, INCLUDING NATURAL KILLER (NK) CELLS, DENDRITIC CELLS (DCS), MAST CELLS, T REGULATORY (TREG) CELLS, CD8+ T CELLS, AND TUMOR-ASSOCIATED MACROPHAGES (TAMS). TAM-MEDIATED INFLAMMATION IS ASSOCIATED WITH A POOR PROGNOSIS OF THYROID CANCER, AND THE MOLECULAR BASIS OF THE CELLULAR CROSSTALK BETWEEN MACROPHAGES AND THYROID CANCER CELLS WITH RESPECT TO INDUCING A METASTATIC PHENOTYPE IS NOT YET KNOWN. THE DYNAMIC NATURE OF THE PHYSIOLOGICAL TRANSITION TO PATHOLOGICAL METASTATIC PHENOTYPES WHEN ESTABLISHING THE TME ENCOMPASSES A WIDE RANGE OF CHARACTERISTICS THAT ARE FURTHER EXPLORED WITHIN THIS CHAPTER, INCLUDING THE ROLES OF SOMATIC MUTATIONS AND EPIGENETIC ALTERATIONS THAT DRIVE THE GENETIC HETEROGENEITY OF CANCER CELLS, ALLOWING FOR SELECTIVE ADVANTAGES THAT AID IN THEIR PROLIFERATION. INDUCTION OF THESE PROLIFERATING CELLS IS TYPICALLY ACCOMPLISHED THROUGH INFLAMMATORY INDUCTION, WHEREBY CHRONIC INFLAMMATION SETS UP A CONSTANT PHYSIOLOGICAL STATE OF INFLAMMATORY CELL RECRUITMENT. THE SECRETIONS OF THESE INFLAMMATORY CELLS CAN ALTER THE GENETIC MAKEUP OF PROLIFERATING CELLS, WHICH CAN IN TURN, PROMOTE TUMOR GROWTH.THIS CHAPTER ALSO PRESENTS AN IN-DEPTH ANALYSIS OF MOLECULAR INTERACTIONS WITHIN THE TME, INCLUDING SECRETORY CYTOKINES AND EXOSOMES. SINCE THE EXOSOMAL CARGO OF A CELL IS A REFLECTION AND FINGERPRINT OF THE ORIGINATING PARENTAL CELLS, THE PROFILING OF EXOSOMAL MIRNA DERIVED FROM THYROID CANCER CELLS AND MACROPHAGES IN THE TME MAY SERVE AS AN IMPORTANT STEP IN BIOMARKER DISCOVERY. IDENTIFICATION OF A DISTINCT SET OF TUMOR SUPPRESSIVE MIRNAS DOWNREGULATED IN ATC-SECRETED EXOSOMES INDICATES THEIR ROLE IN THE REGULATION OF TUMOR SUPPRESSIVE GENES THAT MAY INCREASE THE METASTATIC PROPENSITY OF ATC. ADDITIONALLY, THE HIGH EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN STUDIES LOOKING AT THYROID CANCER AND ACTIVATED MACROPHAGE CONDITIONED MEDIA SUGGESTS THE EXISTENCE OF AN INFLAMMATORY TME IN THYROID CANCER. NEW FINDINGS ARE SUGGESTIVE OF THE PRESENCE OF A METASTATIC NICHE IN ATC TISSUES THAT IS INFLUENCED BY THYROID TUMOR MICROENVIRONMENT SECRETOME-INDUCED EPITHELIAL TO MESENCHYMAL TRANSITION (EMT), MEDIATED BY A RECIPROCAL INTERACTION BETWEEN THE PRO-INFLAMMATORY M1 MACROPHAGES AND THE THYROID CANCER CELLS. THUS, TARGETING THE METASTATIC THYROID CARCINOMA MICROENVIRONMENT COULD OFFER POTENTIAL THERAPEUTIC BENEFITS AND SHOULD BE EXPLORED FURTHER IN PRECLINICAL AND TRANSLATIONAL MODELS OF HUMAN METASTATIC THYROID CANCER. 2021 10 770 24 CD8(+) T CELL DYSFUNCTION BY TOX INTOXICATION: A PROTUMORIGENIC EVENT IN THE TUMOR MICROENVIRONMENT. ACCUMULATING EVIDENCE SUGGESTS THE ROLE OF CELLULAR COMPONENTS IN ACHIEVING ANTITUMOR TO PROTUMOR MICROENVIRONMENTS. AMONG THE VARIOUS TYPES OF CELLS WITHIN THE TUMOR NICHE, THE STATE OF CD8(+) T CELLS APPARENTLY CHANGES FROM CYTOTOXIC T EFFECTOR CELLS AND MEMORY T CELLS TO EXHAUSTED CD8(+) T CELLS. THESE CHANGES IN THE PHENOTYPE OF CD8(+) T CELLS PROMOTE THE PROTUMOR MICROENVIRONMENT. RECENTLY, COMPREHENSIVE EXPERIMENTAL DATA DELINEATED THE ROLE OF THYMOCYTE SELECTION-ASSOCIATED HIGH-MOBILITY GROUP-BOX PROTEIN (TOX), WHICH REGULATES THE TRANSCRIPTIONAL PROCESS AND EPIGENETIC REMODELING, WITH IMPLICATIONS IN TUMOR AND CHRONIC VIRAL INFECTIONS. THIS PERSPECTIVE SUMMARIZES THE MOLECULAR MECHANISMS THAT LINK CD8(+) T CELLS, TOX, AND TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING AS WELL AS FUTURE DIRECTIONS FOR DETERMINING NEW AVENUES OF CANCER THERAPEUTICS. 2021 11 4154 34 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 12 2334 30 EPIGENETIC REGULATION OF INFLAMMATORY CYTOKINE-INDUCED EPITHELIAL-TO-MESENCHYMAL CELL TRANSITION AND CANCER STEM CELL GENERATION. THE NEOPLASTIC TRANSFORMATION OF NORMAL TO METASTATIC CANCER CELLS IS A COMPLEX MULTISTEP PROCESS INVOLVING THE PROGRESSIVE ACCUMULATION OF INTERACTING GENETIC AND EPIGENETIC CHANGES THAT ALTER GENE FUNCTION AND AFFECT CELL PHYSIOLOGY AND HOMEOSTASIS. EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND CHANGES IN NONCODING RNA EXPRESSION, AND DEREGULATION OF EPIGENETIC PROCESSES CAN ALTER GENE EXPRESSION DURING THE MULTISTEP PROCESS OF CARCINOGENESIS. CANCER PROGRESSION AND METASTASIS THROUGH AN 'INVASION-METASTASIS CASCADE' INVOLVING AN EPITHELIAL-TO-MESENCHYMAL CELL TRANSITION (EMT), THE GENERATION OF CANCER STEM CELLS (CSCS), INVASION OF ADJACENT TISSUES, AND DISSEMINATION ARE FUELED BY INFLAMMATION, WHICH IS CONSIDERED A HALLMARK OF CANCER. CHRONIC INFLAMMATION IS GENERATED BY INFLAMMATORY CYTOKINES SECRETED BY THE TUMOR AND THE TUMOR-ASSOCIATED CELLS WITHIN THE TUMOR MICROENVIRONMENT. INFLAMMATORY CYTOKINE SIGNALING INITIATES SIGNALING PATHWAYS LEADING TO THE ACTIVATION OF MASTER TRANSCRIPTION FACTORS (TFS) SUCH AS SMADS, STAT3, AND NF-KAPPAB. MOREOVER, THE SAME INFLAMMATORY RESPONSES ALSO ACTIVATE EMT-INDUCING TF (EMT-TF) FAMILIES SUCH AS SNAIL, TWIST, AND ZEB, AND EPIGENETIC REGULATORS INCLUDING DNA AND HISTONE MODIFYING ENZYMES AND MICORNAS, THROUGH COMPLEX INTERCONNECTED POSITIVE AND NEGATIVE FEEDBACK LOOPS TO REGULATE EMT AND CSC GENERATION. HERE, WE REVIEW THE MOLECULAR REGULATORY FEEDBACK LOOPS AND NETWORKS INVOLVED IN INFLAMMATORY CYTOKINE-INDUCED EMT AND CSC GENERATION. 2019 13 3170 24 GUT INFLAMMATION AND TUMORIGENESIS: EVERY SITE HAS A DIFFERENT TALE TO TELL. GUT INFLAMMATION HAS BEEN CORRELATED WITH CANCEROGENESIS BY DISRUPTING GASTROINTESTINAL HOMEOSTASIS. NUMEROUS CHRONIC INFLAMMATORY DISORDERS OF THE TUBULAR GASTROINTESTINAL TRACT (E.G., GASTROESOPHAGEAL REFLUX DISEASE, HELICOBACTER PYLORI-INDUCED AND AUTOIMMUNE CHRONIC GASTRITIS, CELIAC DISEASE, AND INFLAMMATORY BOWEL DISEASES) HAVE BEEN VARIABLY ASSOCIATED WITH AN INCREASED NEOPLASTIC RISK. GASTROINTESTINAL INFLAMMATION-INDUCED NEOPLASMS INCLUDE EPITHELIAL TUMORS (ESOPHAGEAL SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA, GASTRIC ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, SMALL BOWEL ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, AND COLORECTAL CANCER) AND LYMPHOMAS (SUCH AS GASTRIC MARGINAL ZONE LYMPHOMAS AND ENTEROPATHY-ASSOCIATED T CELL LYMPHOMA). IN THE LAST DECADES, NUMEROUS STUDIES HAVE INVESTIGATED THE PATHOGENETIC MECHANISMS AND THE MICROENVIRONMENTAL/MICROBIOME CHANGES THAT TRIGGER GENETIC AND/OR EPIGENETIC ALTERATIONS EVENTUALLY LEADING TO TUMORIGENESIS, OFTEN THROUGH A HISTOLOGICALLY RECOGNIZABLE INFLAMMATION-DYSPLASIA-CARCINOMA CANCEROGENIC SEQUENCE. IN THE PRESENT REVIEW, AN OVERVIEW OF THE CURRENT KNOWLEDGE ON THE LINKS BETWEEN INFLAMMATORY DISEASES AND NEOPLASMS OF THE TUBULAR GI TRACT, APPLYING A SITE-BY-SITE APPROACH, IS PROVIDED. 2023 14 5412 40 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 2853 23 FROM HELICOBACTER PYLORI INFECTION TO GASTRIC CANCER: CURRENT EVIDENCE ON THE IMMUNE RESPONSE. GASTRIC CANCER (GC) IS THE RESULT OF A MULTIFACTORIAL PROCESS WHOSE MAIN COMPONENTS ARE INFECTION BY HELICOBACTER PYLORI (H. PYLORI), BACTERIAL VIRULENCE FACTORS, HOST IMMUNE RESPONSE AND ENVIRONMENTAL FACTORS. THE DEVELOPMENT OF THE NEOPLASTIC MICROENVIRONMENT ALSO DEPENDS ON GENETIC AND EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH RESULTS IN DEREGULATION OF CELL SIGNALING PATHWAYS AND APOPTOSIS PROCESS. THIS REVIEW SUMMARIZES THE MAIN ASPECTS OF THE PATHOGENESIS OF GC AND THE IMMUNE RESPONSE INVOLVED IN CHRONIC INFLAMMATION GENERATED BY H. PYLORI. 2022 16 3244 33 HEPATIC STELLATE CELLS AND EXTRACELLULAR MATRIX IN HEPATOCELLULAR CARCINOMA: MORE COMPLICATED THAN EVER. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER DEATH. RECENT EPIDEMIOLOGICAL DATA INDICATE THAT THE MORTALITY RATE OF HCC WILL DOUBLE OVER THE NEXT DECADES IN THE USA AND EUROPE. LIVER CANCER PROGRESSES IN A LARGE PERCENTAGE OF CASES DURING THE CLINICAL COURSE OF CHRONIC FIBRO-INFLAMMATORY LIVER DISEASES LEADING TO CIRRHOSIS. THEREFORE, HCC DEVELOPMENT IS REGARDED AS THE RESULT OF DIFFERENT ENVIRONMENTAL RISK FACTORS EACH INVOLVING DIFFERENT GENETIC, EPIGENETIC- AND CHROMOSOMAL ALTERATIONS AND GENE MUTATIONS. DURING TUMOUR PROGRESSION, THE MALIGNANT HEPATOCYTES AND THE ACTIVATED HEPATIC STELLATE CELLS ARE ACCOMPANIED BY CANCER-ASSOCIATED FIBROBLASTS, MYOFIBROBLASTS AND IMMUNE CELLS GENERALLY CALLED TUMOUR STROMAL CELLS. THIS NEW AND DYNAMIC MILIEU FURTHER ENHANCES THE RESPONSIVENESS OF TUMOUR CELLS TOWARDS SOLUBLE MEDIATORS SECRETED BY TUMOUR STROMAL CELLS, THUS DIRECTLY AFFECTING THE MALIGNANT HEPATOCYTES. THIS RESULTS IN ALTERED MOLECULAR PATHWAYS WITH CELL PROLIFERATION AS THE MOST IMPORTANT MECHANISM OF LIVER CANCER PROGRESSION. GIVEN THIS CONTEXTUAL COMPLEXITY, IT IS OF UTMOST IMPORTANCE TO CHARACTERIZE THE MOLECULAR PATHOGENESIS OF HCC, AND TO IDENTIFY THE DOMINANT PATHWAYS/DRIVERS AND ABERRANT SIGNALLING PATHWAYS. THIS WILL ALLOW AN EFFECTIVE THERAPY FOR HCC THAT SHOULD COMBINE STRATEGIES AFFECTING BOTH CANCER AND THE TUMOUR STROMAL CELLS. THIS REVIEW PROVIDES AN OVERVIEW OF THE RECENT CHALLENGES AND ISSUES REGARDING HEPATIC STELLATE CELLS, EXTRACELLULAR MATRIX DYNAMICS, LIVER FIBROSIS/CIRRHOSIS AND THERAPY, TUMOUR MICROENVIRONMENT AND HCC. 2014 17 4060 36 MAST CELLS, ANGIOGENESIS AND LYMPHANGIOGENESIS IN HUMAN GASTRIC CANCER. GASTRIC CANCER IS DIAGNOSED IN NEARLY ONE MILLION NEW PATIENTS EACH YEAR AND IT REMAINS THE SECOND LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ALTHOUGH GASTRIC CANCER REPRESENTS A HETEROGENEOUS GROUP OF DISEASES, CHRONIC INFLAMMATION HAS BEEN SHOWN TO PLAY A ROLE IN TUMORIGENESIS. CANCER DEVELOPMENT IS A MULTISTEP PROCESS CHARACTERIZED BY GENETIC AND EPIGENETIC ALTERATIONS DURING TUMOUR INITIATION AND PROGRESSION. THE STROMAL MICROENVIRONMENT IS IMPORTANT IN MAINTAINING NORMAL TISSUE HOMEOSTASIS OR PROMOTING TUMOUR DEVELOPMENT. A PLETHORA OF IMMUNE CELLS (I.E., LYMPHOCYTES, MACROPHAGES, MAST CELLS, MONOCYTES, MYELOID-DERIVED SUPPRESSOR CELLS, TREG CELLS, DENDRITIC CELLS, NEUTROPHILS, EOSINOPHILS, NATURAL KILLER (NK) AND NATURAL KILLER T (NKT) CELLS) ARE COMPONENTS OF GASTRIC CANCER MICROENVIRONMENT. MAST CELL DENSITY IS INCREASED IN GASTRIC CANCER AND THERE IS A CORRELATION WITH ANGIOGENESIS, THE NUMBER OF METASTATIC LYMPH NODES AND THE SURVIVAL OF THESE PATIENTS. MAST CELLS EXERT A PROTUMORIGENIC ROLE IN GASTRIC CANCER THROUGH THE RELEASE OF ANGIOGENIC (VEGF-A, CXCL8, MMP-9) AND LYMPHANGIOGENIC FACTORS (VEGF-C AND VEGF-F). GASTRIC MAST CELLS EXPRESS THE PROGRAMMED DEATH LIGANDS (PD-L1 AND PD-L2) WHICH ARE RELEVANT AS IMMUNE CHECKPOINTS IN CANCER. SEVERAL CLINICAL UNDERGOING TRIALS TARGETING IMMUNE CHECKPOINTS COULD BE AN INNOVATIVE THERAPEUTIC STRATEGY IN GASTRIC CANCER. ELUCIDATION OF THE ROLE OF SUBSETS OF MAST CELLS IN DIFFERENT HUMAN GASTRIC CANCERS WILL DEMAND STUDIES OF INCREASING COMPLEXITY BEYOND THOSE ASSESSING MERELY MAST CELL DENSITY AND MICROLOCALIZATION. 2019 18 6151 28 THE FIRE WITHIN: CELL-AUTONOMOUS MECHANISMS IN INFLAMMATION-DRIVEN CANCER. INFLAMMATORY CELLS ARE IMPORTANT FOR TUMOR INITIATION AND PROMOTION, PROVIDING CANCER CELLS WITH CYTOKINES THAT ENHANCE CELL PROLIFERATION AND SURVIVAL. ALTHOUGH MALIGNANT EPITHELIAL CELLS WERE TRADITIONALLY CONSIDERED TO BE ON THE RECEIVING END OF THESE MICROENVIRONMENTAL INTERACTIONS, RECENT STUDIES SHOW THAT EPITHELIAL CELLS CAN UNDERGO INFLAMMATORY REPROGRAMMING ON THEIR OWN. SUCH EPIGENETIC SWITCHES ARE OFTEN TRIGGERED BY CHRONIC TISSUE INJURY AND PLAY IMPORTANT ROLES IN TISSUE REPAIR. BY CONVERTING TERMINALLY DIFFERENTIATED CELLS THAT HARBOR EVEN A SINGLE ONCOGENIC MUTATION TO A LESS DIFFERENTIATED STATE WITH A HIGHER PROLIFERATIVE POTENTIAL, CELL-AUTONOMOUS INFLAMMATION IS AN IMPORTANT CONTRIBUTOR TO TUMOR INITIATION. 2019 19 5554 40 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 20 1232 39 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