1 3614 121 IN VITRO CELL TRANSFORMATION ASSAYS: A VALUABLE APPROACH FOR CARCINOGENIC POTENTIALITY ASSESSMENT OF NANOMATERIALS. THIS REVIEW EXPLORES THE APPLICATION OF IN VITRO CELL TRANSFORMATION ASSAYS (CTAS) AS A SCREENING PLATFORM TO ASSESS THE CARCINOGENIC POTENTIAL OF NANOMATERIALS (NMS) RESULTING FROM CONTINUOUSLY GROWING INDUSTRIAL PRODUCTION AND USE. THE WIDESPREAD APPLICATION OF NMS IN VARIOUS FIELDS HAS RAISED CONCERNS ABOUT THEIR POTENTIAL ADVERSE EFFECTS, NECESSITATING SAFETY EVALUATIONS, PARTICULARLY IN LONG-TERM CONTINUOUS EXPOSURE SCENARIOS. CTAS PRESENT A REALISTIC SCREENING PLATFORM FOR KNOWN AND EMERGING NMS BY EXAMINING THEIR RESEMBLANCE TO THE HALLMARK OF MALIGNANCY, INCLUDING HIGH PROLIFERATION RATES, LOSS OF CONTACT INHIBITION, THE GAIN OF ANCHORAGE-INDEPENDENT GROWTH, CELLULAR INVASION, DYSREGULATION OF THE CELL CYCLE, APOPTOSIS RESISTANCE, AND ABILITY TO FORM TUMORS IN EXPERIMENTAL ANIMALS. THROUGH THE DELIBERATE TRANSFORMATION OF CELLS VIA CHRONIC NM EXPOSURE, RESEARCHERS CAN INVESTIGATE THE TUMORIGENIC PROPERTIES OF NMS AND THE UNDERLYING MECHANISMS OF CANCER DEVELOPMENT. THIS ARTICLE EXAMINES NM-INDUCED CELL TRANSFORMATION STUDIES, FOCUSING ON IDENTIFYING EXISTING KNOWLEDGE GAPS. SPECIFICALLY, IT EXPLORES THE PHYSICOCHEMICAL PROPERTIES OF NMS, EXPERIMENTAL MODELS, ASSAYS, DOSE AND TIME REQUIREMENTS FOR CELL TRANSFORMATION, AND THE UNDERLYING MECHANISMS OF MALIGNANCY. OUR REVIEW AIMS TO ADVANCE UNDERSTANDING IN THIS FIELD AND IDENTIFY AREAS FOR FURTHER INVESTIGATION. 2023 2 2790 40 FACTORS TO CONSIDER IN THE USE OF STEM CELLS FOR PHARMACEUTIC DRUG DEVELOPMENT AND FOR CHEMICAL SAFETY ASSESSMENT. GIVEN THE REALITY OF THE INADEQUACIES OF CURRENT CONCEPTS OF THE MECHANISMS OF CHEMICAL TOXICITIES, OF THE VARIOUS ASSAYS TO PREDICT TOXICITIES FROM CURRENT MOLECULAR, BIOCHEMICAL, IN VITRO AND ANIMAL BIOASSAYS, AND OF THE FAILURE TO GENERATE EFFICACIOUS AND SAFE CHEMICALS FOR MEDICINES, FOOD SUPPLEMENTS, INDUSTRIAL, CONSUMER AND AGRICULTURAL CHEMICALS, THE RECENT NAS REPORT, "TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY", HAS DRAWN ATTENTION TO A RENEWED EXAMINATION OF WHAT NEEDS TO BE DONE TO IMPROVE OUR CURRENT APPROACH FOR BETTER ASSESSMENT OF POTENTIAL RISK TO HUMAN HEALTH. THIS "COMMENTARY" PROVIDES A MAJOR PARADIGM CHALLENGE TO THE CURRENT CONCEPTS OF HOW CHEMICALS INDUCE TOXICITIES AND HOW THESE VARIOUS MECHANISMS OF TOXICITIES CAN CONTRIBUTE TO THE PATHOGENESIS OF SOME HUMAN DISEASES, SUCH AS BIRTH DEFECTS AND CANCER. IN CONCORDANCE WITH THE NAS REPORT TO TAKE "... ADVANTAGE OF THE ON-GOING REVOLUTION IN BIOLOGY AND BIOTECHNOLOGY", THIS "COMMENTARY" SUPPORTS THE USE OF HUMAN EMBRYONIC AND ADULT STEM CELLS, GROWN IN VITRO UNDER SIMULATED "IN VIVO NICHE CONDITIONS". THE HUMAN BEING SHOULD BE VIEWED "AS GREATER THAN THE SUM OF ITS PARTS". HOMEOSTATIC CONTROL OF THE "EMERGENT PROPERTIES" OF THE HUMAN HIERARCHY, NEEDED TO MAINTAIN HUMAN HEALTH, REQUIRES COMPLEX INTEGRATION OF ENDOGENOUS AND EXOGENOUS SIGNALING MOLECULES THAT CONTROL CELL PROLIFERATION, DIFFERENTIATION, APOPTOSIS AND SENESCENCE OF STEM, PROGENITOR AND DIFFERENTIATED CELLS. CURRENTLY, IN VITRO TOXICITY ASSAYS (MUTAGENESIS, CYTOTOXICITY, EPIGENETIC MODULATION), DONE ON 2-DIMENSIONAL PRIMARY RODENT OR HUMAN CELLS (WHICH ARE ALWAYS MIXTURES OF CELLS), ON IMMORTALIZED OR TUMORIGENIC RODENT OR HUMAN CELL LINES DO NOT REPRESENT NORMAL HUMAN CELLS IN VIVO [WHICH DO NOT GROW ON PLASTIC AND WHICH ARE IN MICRO-ENVIRONMENTS REPRESENTING 3 DIMENSIONS AND CONSTANTLY INTERACTING FACTORS]. IN ADDITION, WITH THE KNOWN GENETIC, GENDER, AND DEVELOPMENTAL STATE OF CELLS IN VIVO, ANY IN VITRO TOXICITY ASSAY WILL NEED TO MIMIC THESE CONDITIONS IN VITRO. MORE SPECIFICALLY, WHILE TISSUES CONTAIN A FEW STEM CELLS, MANY PROGENITOR/TRANSIT CELLS AND TERMINALLY DIFFERENTIATED CELLS, IT SHOULD BE OBVIOUS THAT BOTH EMBRYONIC AND ADULT STEM CELLS WOULD BE CRITICAL "TARGET" CELLS FOR TOXICITY TESTING. THE ULTIMATE POTENTIAL FOR IN VITRO TESTING OF HUMAN STEM CELLS WILL TO TRY TO MIMIC A 3-D IN VITRO MICRO-ENVIRONMENT ON MULTIPLE "ORGAN-SPECIFIC AND MULTIPLE GENOTYPIC/GENDER "ADULT STEM CELLS. THE ROLE OF STEM CELLS IN MANY CHRONIC DISEASES, SUCH AS CANCER, BIRTH DEFECTS, AND POSSIBLY ADULT DISEASES AFTER PRE-NATAL AND EARLY POST-NATAL EXPOSURES (BARKER HYPOTHESIS), DEMANDS TOXICITY STUDIES OF STEM CELLS. WHILE ALTERATION OF GENE EXPRESSION ("TOXICO-EPIGENOMICS") IS A LEGITIMATE ENDPOINT OF THESE TOXICITY STUDIES, ALTERATION OF THE QUANTITY OF STEM CELLS DURING DEVELOPMENT MUST BE SERIOUS CONSIDERED. IF THE FUTURE UTILITY OF HUMAN STEM CELLS PROVES TO BE VALID, THE ELIMINATION OF LESS RELEVANT, EXPENSIVE AND TIME-CONSUMING RODENT AND 2-D HUMAN IN VITRO ASSAYS WILL BE ELIMINATED. 2010 3 3697 26 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 4 5493 21 REVIEW OF IN VITRO TEST SYSTEMS USING DNA DAMAGE AND REPAIR FOR SCREENING OF CHEMICAL CARCINOGENS. CHEMICAL CARCINOGENS ARE MECHANISTICALLY CLASSIFIED AS GENOTOXIC WHICH INTERACT DIRECTLY WITH DNA, AND EPIGENETIC WHICH CAUSE CHRONIC TISSUE INJURY, HORMONAL IMBALANCE, AND PROMOTIONAL EFFECTS. THIS REVIEW EVALUATES IN VITRO TESTS FOR THEIR CONTRIBUTION TO A BATTERY FOR IDENTIFYING GENOTOXIC CHEMICAL CARCINOGENS. IN ADDITION TO BACTERIAL MUTAGENIC ASSAYS, NONSPECIFIC DNA DAMAGE/REPAIR TESTS ARE RECOMMENDED FOR SCREENING CHEMICALS, IN PARTICULAR THE HEPATOCYTE PRIMARY CULTURE/DNA REPAIR TEST. 1979 5 731 31 CANCER CHEMOPREVENTION: CLASSIC AND EPIGENETIC MECHANISMS INHIBITING TUMORIGENESIS. WHAT HAVE WE LEARNED SO FAR? CANCERS DERIVE FROM STEP BY STEP PROCESSES WHICH ARE DIFFERENTIATED BY THE PROGRESSIVELY ACCUMULATED MUTATIONS. FOR SOME TUMORS THERE IS A CLEAR PROGRESSIVE ADVANCEMENT FROM BENIGN LESIONS TO MALIGNANCY AND FOR THESE, PREVENTIVE SCREENING PROGRAMS EXIST. IN SUCH CASES HAVING THOSE BENIGN LESIONS ARE A CLEAR INDICATOR OF PREDISPOSITION WHILE FOR SOME OTHER CASES, FAMILIAL PATTERNS OF CANCER INCIDENCE AND THE IDENTIFICATION OF MUTATIONS ARE THE MAIN INDICATORS OF HIGHER RISK FOR HAVING THE DISEASE. FOR PATIENTS IDENTIFIED AS HAVING PREDISPOSITION, CHEMOPREVENTION IS A GOAL AND IN SOME CASES A POSSIBILITY. CHEMOPREVENTION IS THE USE OF ANY COMPOUND, EITHER NATURAL OR SYNTHETIC THAT ABROGATES CARCINOGENESIS OR TUMOR PROGRESSION, THROUGH DIFFERENT MECHANISMS, SOME OF WHICH HAVE ALREADY BEEN DESCRIBED. FOR EXAMPLE, THE CLASSIC MECHANISMS MAY INVOLVE ACTIVATION OF FREE RADICAL SCAVENGING ENZYMES, CONTROL OF CHRONIC INFLAMMATION, AND DOWNREGULATION OF SPECIFIC SIGNALING PATHWAYS. MORE RECENTLY, EPIGENETICS ALLOWED FURTHER UNDERSTANDING OF THE CHEMOPREVENTIVE POTENTIAL OF SEVERAL AGENTS, SUCH AS SULFORAPHANE, GREEN TEA DERIVED COMPOUNDS, RESVERATROL, ISOFLAVONES, AND OTHERS WHICH WE EXPLOIT IN THIS REVIEW ARTICLE. THROUGHOUT THE TEXT WE DISCUSS THE PROPERTIES COMPOUNDS SHOULD HAVE IN ORDER TO BE CLASSIFIED AS CHEMOPREVENTIVE ONES AND THE CHALLENGES IN TRANSLATIONAL RESEARCH IN THIS AREA, AS LOTS OF THE SUCCESS ACHIEVED IN VITRO CANNOT BE TRANSLATED INTO THE CLINICAL SETTINGS, DUE TO SEVERAL DIFFERENT DRAWBACKS, WHICH INCLUDE TOXICITY, COST, DOSE DEFINITION, PATIENT ADHERENCE, AND REGIMEN OF USE. 2018 6 5282 23 PROMOTION OF HEPATOCARCINOGENESIS IN HUMANS AND ANIMAL MODELS. RISK ASSESSMENT BASED ON RODENT CARCINOGENICITY DATA DEPENDS ON THE ASSUMPTION OF SIMILARITY BETWEEN RODENTS AND HUMANS. WHILE THIS ASSUMPTION IS CONCEIVABLE IN THE CASE OF GENOTOXIC INITIATING CARCINOGENS, CONSIDERABLE SPECIES DIFFERENCES HAVE BEEN OBSERVED WITH NONGENOTOXIC TUMOR PROMOTERS. THIS HETEROGENEOUS GROUP OF AGENTS INCREASES THE PROBABILITY OF CANCER BY STIMULATING SELECTION AND CLONAL EXPANSION OF CELLS TRANSFORMED DURING TUMOR INITIATION. SINCE TUMOR PROMOTERS DIFFERENTIALLY AFFECT NORMAL TISSUE AND PRENEOPLASTIC CELL CLONES, THEIR ACTION CANNOT BE DISCUSSED WITHOUT KNOWLEDGE OF PERSISTENT GENOMIC AND EPIGENETIC ALTERATIONS OCCURRING DURING INITIATION AND FORMATION OF PRENEOPLASTIC CELLS. CHEMICAL CARCINOGENESIS, AND IN PARTICULAR, TUMOR PROMOTION, IS KNOWN TO BE TISSUE SPECIFIC. WE FOCUS ON HEPATOCARCINOGENESIS IN HUMANS AND IN ANIMAL MODELS AND EMPHASIZE TWO DIFFERENT MODES OF ACTION: (1) CHRONIC CYTOTOXICITY LEADING TO PROMOTION OF LIVER CARCINOGENESIS IN BOTH HUMANS AND ANIMAL MODELS; (2) SUSTAINED ACTIVATION OF ORPHAN RECEPTORS SUCH AS CAR, PPARALPHA AND AH RECEPTOR LEADING TO PROMOTION OF RODENT BUT PROBABLY NOT HUMAN HEPATOCARCINOGENESIS. FURTHER STUDIES ON THE DIFFERENT MODES OF ACTION MAY HELP TO AVOID OVERESTIMATION OF THE RISK OF LIVER TUMOR PROMOTION. 2008 7 6675 24 USING EPIGENETIC THERAPY TO OVERCOME CHEMOTHERAPY RESISTANCE. IT HAS BEEN KNOWN FOR DECADES THAT AS CANCER PROGRESSES, TUMORS DEVELOP GENETIC ALTERATIONS, MAKING THEM HIGHLY PRONE TO DEVELOPING RESISTANCE TO THERAPIES. CLASSICALLY, IT HAS BEEN THOUGHT THAT THESE ACQUIRED GENETIC CHANGES ARE FIXED. THIS HAS LED TO THE PARADIGM OF MOVING FROM ONE CANCER THERAPY TO THE NEXT WHILE AVOIDING PAST THERAPIES. HOWEVER, EMERGING DATA ON EPIGENETIC CHANGES DURING TUMOR PROGRESSION AND USE OF EPIGENETIC THERAPIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS LEADING TO CHEMOTHERAPY RESISTANCE HAVE THE POTENTIAL TO BE REVERSIBLE WITH EPIGENETIC THERAPY. IN FACT, PROMISING CLINICAL DATA EXIST THAT TREATMENT WITH EPIGENETIC AGENTS CAN DIMINISH CHEMOTHERAPY RESISTANCE IN A NUMBER OF TUMOR TYPES INCLUDING CHRONIC MYELOGENOUS LEUKEMIA, COLORECTAL, OVARIAN, LUNG AND BREAST CANCER. THE POTENTIAL FOR EPIGENETIC-MODIFYING DRUGS TO ALLOW FOR TREATMENT OF RESISTANT DISEASE IS EXCITING AND CLINICAL TRIALS HAVE JUST BEGUN TO EVALUATE THIS AREA. 2016 8 4429 28 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 9 5290 18 PROSTATE CANCER PREVENTION: AGENT DEVELOPMENT STRATEGIES. DESPITE ADVANCES IN SURGERY, RADIATION, AND MEDICAL THERAPY OVER THE PAST DECADE AND THE WIDESPREAD ADOPTION OF PSA SCREENING, PROSTATE CANCER CONTINUES TO BE THE SECOND LEADING CAUSE OF CANCER DEATH IN MEN IN THE UNITED STATES. INVASIVE CANCER IS THE END RESULT OF CARCINOGENESIS, A CHRONIC PROCESS OCCURRING OVER MANY YEARS DRIVEN BY GENETIC AND EPIGENETIC ALTERATIONS. THE PROTRACTED NATURE OF THIS TRANSFORMATION TO THE MALIGNANT PHENOTYPE PROVIDES AN OPPORTUNITY TO INTERVENE PHARMACOLOGICALLY TO PREVENT, REVERSE, OR DELAY CARCINOGENESIS, I.E. CHEMOPREVENTION. HEREIN, WE DESCRIBE THE UNIQUE FEATURES OF CANCER PREVENTION, AS OPPOSED TO CANCER TREATMENT, AGENT DEVELOPMENT CLINICAL TRIALS, AND PROVIDE A SUMMARY OF THE ONGOING RESEARCH IN THIS FIELD BEING SUPPORTED BY THE NATIONAL CANCER INSTITUTE. 2014 10 3110 31 GENOTYPE- OR PHENOTYPE-TARGETING ANTICANCER THERAPIES? LESSONS FROM TUMOR EVOLUTIONARY BIOLOGY. DESPITE THE EFFICACY OF MOST CANCER THERAPIES, DRUG RESISTANCE REMAINS A MAJOR PROBLEM IN THE CLINIC. THE ERADICATION OF THE ENTIRE TUMOR AND THE CURE OF THE PATIENT BY CHEMOTHERAPY ALONE ARE RARE, IN PARTICULAR FOR ADVANCED DISEASE. FROM AN EVOLUTIONARY PERSPECTIVE, THE SELECTIVE PRESSURE EXERTED BY CHEMOTHERAPY LEADS TO THE EMERGENCE OF RESISTANT CLONES WHERE RESISTANCE CAN BE ASSOCIATED WITH MANY DIFFERENT FUNCTIONAL MECHANISMS AT THE SINGLE CELL LEVEL OR CAN INVOLVE CHANGES IN THE TUMOR MICRO-ENVIRONMENT. IN THE LAST DECADE, TUMOR GENOMICS HAS CONTRIBUTED TO THE IMPROVEMENT OF OUR UNDERSTANDING OF TUMORIGENESIS AND HAS LED TO THE IDENTIFICATION OF NUMEROUS CELLULAR TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPIES. HOWEVER, SINCE TUMORS ARE BY NATURE EXTREMELY HETEROGENEOUS, THE DRUG EFFICACY AND ECONOMICAL SUSTAINABILITY OF THIS APPROACH IS NOW DEBATABLE. IMPORTANTLY, TUMOR CELL HETEROGENEITY DEPENDS NOT ONLY ON GENETIC MODIFICATIONS BUT ALSO ON NON-GENETIC PROCESSES INVOLVING EITHER STOCHASTIC EVENTS OR EPIGENETIC MODIFICATIONS MAKING GENETIC BIOMARKERS OF UNCERTAIN UTILITY. IN THIS REVIEW, WE WISH TO HIGHLIGHT HOW EVOLUTIONARY BIOLOGY CAN IMPACT OUR UNDERSTANDING OF CARCINOGENESIS AND RESISTANCE TO THERAPIES. WE WILL DISCUSS NEW APPROACHES BASED ON APPLIED ECOLOGY AND EVOLUTION DYNAMICS THAT CAN BE USED TO CONVERT THE CANCER INTO A CHRONIC DISEASE WHERE THE DRUGS WOULD CONTROL TUMOR GROWTH. FINALLY, WE WILL DISCUSS THE WAY METABOLIC DYSFUNCTION OR PHENOTYPIC CHANGES CAN HELP DEVELOPING NEW DELIVERY SYSTEMS OR PHENOTYPETARGETED DRUGS AND HOW EXPLORING NEW SOURCES OF ACTIVE COMPOUNDS CAN CONDUCT TO THE DEVELOPMENT OF DRUGS WITH ORIGINAL MECHANISMS OF ACTION. 2016 11 2416 26 EPIGENETIC SIGNALING OF CANCER STEM CELLS DURING INFLAMMATION. MALIGNANT TUMORS POSE A GREAT CHALLENGE TO HUMAN HEALTH, WHICH HAS LED TO MANY STUDIES INCREASINGLY ELUCIDATING THE TUMORIGENIC PROCESS. CANCER STEM CELLS (CSCS) HAVE PROFOUND IMPACTS ON TUMORIGENESIS AND DEVELOPMENT OF DRUG RESISTANCE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN THE RELATIONSHIP BETWEEN INFLAMMATION AND CSCS BUT THE MECHANISM UNDERLYING THIS RELATIONSHIP HAS NOT BEEN FULLY ELUCIDATED. INFLAMMATORY CYTOKINES PRODUCED DURING CHRONIC INFLAMMATION ACTIVATE SIGNALING PATHWAYS THAT REGULATE THE GENERATION OF CSCS THROUGH EPIGENETIC MECHANISMS. IN THIS REVIEW, WE FOCUS ON THE EFFECTS OF INFLAMMATION ON CANCER STEM CELLS, PARTICULARLY THE ROLE OF SIGNALING PATHWAYS SUCH AS NF-KAPPAB PATHWAY, STAT3 PATHWAY AND SMAD PATHWAY INVOLVED IN REGULATING EPIGENETIC CHANGES. WE HOPE TO PROVIDE A NOVEL PERSPECTIVE FOR IMPROVING STRATEGIES FOR TUMOR TREATMENT. 2021 12 733 27 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 13 737 32 CANCER STEM CELLS. THERE IS AN INCREASING EVIDENCE SUPPORTING THE CANCER STEM CELL HYPOTHESIS. NORMAL STEM CELLS IN THE ADULT ORGANISM ARE RESPONSIBLE FOR TISSUE RENEWAL AND REPAIR OF AGED OR DAMAGED TISSUE. A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS IS THEIR ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. THE STEM CELLS ARE IMMORTAL, AND RATHER RESISTANT TO ACTION OF DRUGS. THEY ARE ABLE TO DIFFERENTIATE AND FORM SPECIFIC TYPES OF TISSUE DUE TO THE INFLUENCE OF MICROENVIRONMENTAL AND SOME OTHER FACTORS. STEM CELLS DIVIDE ASYMMETRICALLY PRODUCING TWO DAUGHTER CELLS -- ONE IS A NEW STEM CELL AND THE SECOND IS PROGENITOR CELL, WHICH HAS THE ABILITY FOR DIFFERENTIATION AND PROLIFERATION, BUT NOT THE CAPABILITY FOR SELF-RENEWAL. CANCER STEM CELLS ARE IN MANY ASPECTS SIMILAR TO THE STEM CELLS. IT HAS BEEN PROVEN THAT TUMOR CELLS ARE HETEROGENEOUS COMPRISING RARE TUMOR INITIATING CELLS AND ABUNDANT NON-TUMOR INITIATING CELLS. TUMOR INITIATING CELLS -- CANCER STEM CELLS HAVE THE ABILITY OF SELF-RENEWAL AND PROLIFERATION, ARE RESISTANT TO DRUGS, AND EXPRESS TYPICAL MARKERS OF STEM CELLS. IT IS NOT CLEAR WHETHER CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR BY REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS. PROBABLY BOTH MECHANISMS ARE INVOLVED IN THE ORIGIN OF CANCER STEM CELLS. DYSREGULATION OF STEM CELL SELF-RENEWAL IS A LIKELY REQUIREMENT FOR THE DEVELOPMENT OF CANCER. ISOLATION AND IDENTIFICATION OF CANCER STEM CELLS IN HUMAN TUMORS AND IN TUMOR CELL LINES HAS BEEN SUCCESSFUL. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. CANCER STEM CELL MODEL IS ALSO CONSISTENT WITH SOME CLINICAL OBSERVATIONS. ALTHOUGH STANDARD CHEMOTHERAPY KILLS MOST CELLS IN A TUMOR, CANCER STEM CELLS REMAIN VIABLE. DESPITE THE SMALL NUMBER OF SUCH CELLS, THEY MIGHT BE THE CAUSE OF TUMOR RECURRENCE, SOMETIMES MANY YEARS AFTER THE "SUCCESSFUL" TREATMENT OF PRIMARY TUMOR. GROWTH OF METASTASES IN DISTINCT AREAS OF BODY AND THEIR CELLULAR HETEROGENEITY MIGHT BE CONSEQUENCE OF CANCER STEM CELL DIFFERENTIATION AND/OR DEDIFFERENTIATION AND ASYMMETRIC DIVISION OF CANCER STEM CELLS. FURTHER CHARACTERIZATION OF CANCER STEM CELLS IS NEEDED IN ORDER TO FIND WAYS TO DESTROY THEM, WHICH MIGHT CONTRIBUTE SIGNIFICANTLY TO THE THERAPEUTIC MANAGEMENT OF MALIGNANT TUMORS. 2005 14 6449 37 THERAPEUTIC TARGETING OF TELOMERASE. TELOMERE LENGTH AND CELL FUNCTION CAN BE PRESERVED BY THE HUMAN REVERSE TRANSCRIPTASE TELOMERASE (HTERT), WHICH SYNTHESIZES THE NEW TELOMERIC DNA FROM A RNA TEMPLATE, BUT IS NORMALLY RESTRICTED TO CELLS NEEDING A HIGH PROLIFERATIVE CAPACITY, SUCH AS STEM CELLS. CONSEQUENTLY, TELOMERASE-BASED THERAPIES TO ELONGATE SHORT TELOMERES ARE DEVELOPED, SOME OF WHICH HAVE SUCCESSFULLY REACHED THE STAGE I IN CLINICAL TRIALS. TELOMERASE IS ALSO PERMISSIVE FOR TUMORIGENESIS AND 90% OF ALL MALIGNANT TUMORS USE TELOMERASE TO OBTAIN IMMORTALITY. THUS, REVERSAL OF TELOMERASE UPREGULATION IN TUMOR CELLS IS A POTENTIAL STRATEGY TO TREAT CANCER. NATURAL AND SMALL-MOLECULE TELOMERASE INHIBITORS, IMMUNOTHERAPEUTIC APPROACHES, OLIGONUCLEOTIDE INHIBITORS, AND TELOMERASE-DIRECTED GENE THERAPY ARE USEFUL TREATMENT STRATEGIES. TELOMERASE IS MORE WIDELY EXPRESSED THAN ANY OTHER TUMOR MARKER. THE LOW EXPRESSION IN NORMAL TISSUES, TOGETHER WITH THE LONGER TELOMERES IN NORMAL STEM CELLS VERSUS CANCER CELLS, PROVIDES SOME DEGREE OF SPECIFICITY WITH LOW RISK OF TOXICITY. HOWEVER, LONG TERM TELOMERASE INHIBITION MAY ELICIT NEGATIVE EFFECTS IN HIGHLY-PROLIFERATIVE CELLS WHICH NEED TELOMERASE FOR SURVIVAL, AND IT MAY INTERFERE WITH TELOMERE-INDEPENDENT PHYSIOLOGICAL FUNCTIONS. MOREOVER, ONLY A FEW HTERT MOLECULES ARE REQUIRED TO OVERCOME SENESCENCE IN CANCER CELLS, AND TELOMERASE INHIBITION REQUIRES PROLIFERATING CELLS OVER A SUFFICIENT NUMBER OF POPULATION DOUBLINGS TO INDUCE TUMOR SUPPRESSIVE SENESCENCE. THESE LIMITATIONS MAY EXPLAIN THE MODERATE SUCCESS RATES IN MANY CLINICAL STUDIES. DESPITE EXTENSIVE STUDIES, ONLY ONE VACCINE AND ONE TELOMERASE ANTAGONIST ARE ROUTINELY USED IN CLINICAL WORK. FOR COMPLETE ERADICATION OF ALL SUBPOPULATIONS OF CANCER CELLS A SIMULTANEOUS TARGETING OF SEVERAL MECHANISMS WILL LIKELY BE NEEDED. POSSIBLE TECHNICAL IMPROVEMENTS HAVE BEEN PROPOSED INCLUDING THE DEVELOPMENT OF MORE SPECIFIC INHIBITORS, METHODS TO INCREASE THE EFFICACY OF VACCINATION METHODS, AND PERSONALIZED APPROACHES. TELOMERASE ACTIVATION AND CELL REJUVENATION IS SUCCESSFULLY USED IN REGENERATIVE MEDICINE FOR TISSUE ENGINEERING AND RECONSTRUCTIVE SURGERY. HOWEVER, THERE ARE ALSO A NUMBER OF PITFALLS IN THE TREATMENT WITH TELOMERASE ACTIVATING PROCEDURES FOR THE WHOLE ORGANISM AND FOR LONGER PERIODS OF TIME. EXTENDED CELL LIFESPAN MAY ACCUMULATE RARE GENETIC AND EPIGENETIC ABERRATIONS THAT CAN CONTRIBUTE TO MALIGNANT TRANSFORMATION. THEREFORE, NOVEL VECTOR SYSTEMS HAVE BEEN DEVELOPED FOR A 'MILD' INTEGRATION OF TELOMERASE INTO THE HOST GENOME AND LOSS OF THE VECTOR IN RAPIDLY-PROLIFERATING CELLS. IT IS CURRENTLY UNCLEAR IF THIS TECHNIQUE CAN ALSO BE USED IN HUMAN BEINGS TO TREAT CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS. 2016 15 736 31 CANCER STEM CELLS--NEW APPROACH TO CANCEROGENENSIS AND TREATMENT. RECENTLY, THERE IS AN INCREASING EVIDENCE SUPPORTING THE THEORY OF CANCER STEM CELLS NOT ONLY IN LEUKEMIA BUT ALSO IN SOLID CANCER. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. THIS REVIEW IS FOCUSING ON THE RECENT DISCOVERY OF STEM CELLS IN LEUKEMIA, HUMAN BRAIN TUMORS AND BREAST CANCER. A SMALL POPULATION OF CELLS IN THE TUMOR (LESS THAN 1%) SHOWS THE POTENTIAL TO GIVE RISE TO THE TUMOR AND ITS GROWTH. THESE CELLS HAVE A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS--ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. FURTHERMORE THEY ARE IMMORTAL, RATHER RESISTANT TO TREATMENT AND EXPRESS TYPICAL MARKERS OF STEM CELLS. THE ORIGIN OF THESE RESIDENT CANCER STEM CELLS IS NOT CLEAR. WHETHER THE CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS REMAINS TO BE INVESTIGATED. WE PROPOSE THE IDEA OF THE RELATION BETWEEN NORMAL TISSUE STEM CELLS AND CANCER STEM CELLS AND THEIR POPULATIONS--PROGENITOR CELLS. BASED ON THIS WE HIGHLIGHT ONE OF THE MAJOR CHARACTERISTIC OF STEM CELL--PLASTICITY, WHICH IS EQUALLY IMPORTANT IN THE PHYSIOLOGICAL REGENERATION PROCESS AS WELL AS CARCINOGENESIS. FURTHERMORE, WE CONSIDER THE MICROENVIRONMENT AS A LIMITING FACTOR FOR TUMOR GENESIS IN AML, BREAST CANCER AND BRAIN TUMORS. THUS THE BIOLOGICAL PROPERTIES OF CANCER STEM CELLS ARE JUST BEGINNING TO BE REVEALED, THE CONTINUATION OF THESE STUDIES SHOULD LEAD TO THE DEVELOPMENT OF CANCER STEM CELLS TARGET THERAPIES FOR CANCER TREATMENT. 2008 16 6715 28 VITAMIN A AND THE EPIGENOME. THE EPIGENETIC PHENOMENA REFER TO HERITABLE CHANGES IN GENE EXPRESSION OTHER THAN THOSE IN THE DNA SEQUENCE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS. MAJOR RESEARCH PROGRESS IN THE LAST FEW YEARS HAS PROVIDED FURTHER PROOF THAT ENVIRONMENTAL FACTORS, INCLUDING DIET AND NUTRITION, CAN INFLUENCE PHYSIOLOGIC AND PATHOLOGIC PROCESSES THROUGH EPIGENETIC ALTERATIONS, WHICH IN TURN INFLUENCE GENE EXPRESSION. THIS INFLUENCE IS TERMED NUTRITIONAL EPIGENETICS, AND ONE PROMINENT EXAMPLE IS THE REGULATION OF GENE TRANSCRIPTION BY VITAMIN A THROUGH INTERACTION TO ITS NUCLEAR RECEPTOR. VITAMIN A IS CRITICAL THROUGHOUT LIFE. TOGETHER WITH ITS DERIVATIVES, IT REGULATES DIVERSE PROCESSES INCLUDING REPRODUCTION, EMBRYOGENESIS, VISION, GROWTH, CELLULAR DIFFERENTIATION AND PROLIFERATION, MAINTENANCE OF EPITHELIAL CELLULAR INTEGRITY AND IMMUNE FUNCTION. HERE WE REVIEW THE EPIGENETIC ROLE OF VITAMIN A IN CANCER, STEM CELLS DIFFERENTIATION, PROLIFERATION, AND IMMUNITY. THE DATA PRESENTED HERE SHOW THAT RETINOIC ACID IS A POTENT AGENT CAPABLE OF INDUCING ALTERATIONS IN EPIGENETIC MODIFICATIONS THAT PRODUCE VARIOUS EFFECTS ON THE PHENOTYPE. MEDICAL BENEFITS OF VITAMIN A AS AN EPIGENETIC MODULATOR, ESPECIALLY WITH RESPECT TO ITS CHRONIC USE AS NUTRITIONAL SUPPLEMENT, SHOULD RELY ON OUR FURTHER UNDERSTANDING OF ITS EPIGENETIC EFFECTS DURING HEALTH AND DISEASE, AS WELL AS THROUGH DIFFERENT GENERATIONS. 2017 17 6031 17 THE CANCER EPIGENOME: ITS ORIGINS, CONTRIBUTIONS TO TUMORIGENESIS, AND TRANSLATIONAL IMPLICATIONS. EPIGENETIC ABNORMALITIES IN LUNG AND OTHER CANCERS CONTINUE TO BE DEFINED AT A RAPID PACE. WE ARE COMING TO APPRECIATE THAT CANCERS HAVE AN "EPIGENETIC LANDSCAPE" WHEREIN GENES VULNERABLE TO ABNORMALITIES, SUCH AS PROMOTER DNA HYPERMETHYLATION AND ASSOCIATED GENE SILENCING, TEND TO RESIDE IN DEFINED NUCLEAR POSITIONS AND CHROMOSOME DOMAINS AND RELATIONSHIPS TO CHROMATIN REGULATION, WHICH FACILITATES STATES OF STEM CELL RENEWAL. THESE SAME GENES AND DOMAINS ARE ALSO VULNERABLE TO EPIGENETIC ABNORMALITIES INDUCED BY FACTORS TO WHICH CELLS ARE EXPOSED DURING CANCER RISK STATES, SUCH AS CHRONIC INFLAMMATION. WE CAN USE ALL OF THIS BASIC INFORMATION FOR TRANSLATIONAL PURPOSES IN TERMS OF DERIVING BIOMARKERS FOR CANCER RISK STATES AND DETECTION AND THERAPEUTIC STRATEGIES. 2012 18 2832 36 FOCUSING THE SPOTLIGHT ON THE ZEBRAFISH INTESTINE TO ILLUMINATE MECHANISMS OF COLORECTAL CANCER. COLORECTAL CANCER, ENCOMPASSING COLON AND RECTAL CANCER, ARISES FROM THE EPITHELIAL LINING OF THE LARGE BOWEL. IT IS MOST PREVALENT IN WESTERNISED SOCIETIES AND IS INCREASING IN FREQUENCY AS THE WORLD BECOMES MORE INDUSTRIALISED. UNFORTUNATELY, METASTATIC COLORECTAL CANCER IS NOT CURED BY CHEMOTHERAPY AND THE ANNUAL NUMBER OF DEATHS CAUSED BY COLORECTAL CANCER, CURRENTLY 700,000, IS EXPECTED TO RISE. OUR UNDERSTANDING OF THE CONTRIBUTION THAT GENETIC MUTATIONS MAKE TO COLORECTAL CANCER, ALTHOUGH INCOMPLETE, IS REASONABLY WELL ADVANCED. HOWEVER, IT HAS ONLY RECENTLY BECOME WIDELY APPRECIATED THAT IN ADDITION TO THE ONGOING ACCUMULATION OF GENETIC MUTATIONS, CHRONIC INFLAMMATION ALSO PLAYS A CRITICAL ROLE IN THE INITIATION AND PROGRESSION OF THIS DISEASE. WHILE A ROBUST AND TRACTABLE GENETIC MODEL OF COLORECTAL CANCER IN ZEBRAFISH, SUITABLE FOR PRE-CLINICAL STUDIES, IS NOT YET AVAILABLE, THE IDENTIFICATION OF GENES REQUIRED FOR THE RAPID PROLIFERATION OF ZEBRAFISH INTESTINAL EPITHELIAL CELLS DURING DEVELOPMENT HAS HIGHLIGHTED A NUMBER OF ESSENTIAL GENES THAT COULD BE TARGETED TO DISABLE COLORECTAL CANCER CELLS. MOREOVER, APPRECIATION OF THE UTILITY OF ZEBRAFISH TO STUDY INTESTINAL INFLAMMATION IS ON THE RISE. IN PARTICULAR, ZEBRAFISH PROVIDE UNIQUE OPPORTUNITIES TO INVESTIGATE THE IMPACT OF GENETIC AND ENVIRONMENTAL FACTORS ON THE INTEGRITY OF INTESTINAL EPITHELIAL BARRIER FUNCTION. WITH CURRENTLY AVAILABLE TOOLS, THE INTERPLAY BETWEEN EPIGENETIC REGULATORS, INTESTINAL INJURY, MICROBIOTA COMPOSITION AND INNATE IMMUNE CELL MOBILISATION CAN BE ANALYSED IN EXQUISITE DETAIL. THIS PROVIDES EXCELLENT OPPORTUNITIES TO DEFINE CRITICAL EVENTS THAT COULD POTENTIALLY BE TARGETED THERAPEUTICALLY. FURTHER INTO THE FUTURE, THE USE OF ZEBRAFISH LARVAE AS HOSTS FOR XENOGRAFTS OF HUMAN COLORECTAL CANCER TISSUE, WHILE STILL IN ITS INFANCY, HOLDS GREAT PROMISE THAT ZEBRAFISH COULD ONE DAY PROVIDE A PRACTICAL, PRECLINICAL PERSONALIZED MEDICINE PLATFORM FOR THE RAPID ASSESSMENT OF THE METASTATIC POTENTIAL AND DRUG-SENSITIVITY OF PATIENT-DERIVED CANCERS. 2016 19 2704 21 EXERCISE AND COLORECTAL CANCER: PREVENTION AND MOLECULAR MECHANISMS. EXERCISE AND PHYSICAL ACTIVITY HAVE BEEN SHOWN TO BE STRONGLY ASSOCIATED WITH A DECREASED INCIDENCE RATE OF VARIOUS CHRONIC DISEASES ESPECIALLY NUMEROUS HUMAN MALIGNANCIES. A HUGE NUMBER OF CLINICAL TRIALS AND META-ANALYSIS HAVE DEMONSTRATED THAT EXERCISE IS SIGNIFICANTLY EFFECTIVE IN LOWERING THE RISK OF COLORECTAL CANCER. IN ADDITION, IT IS SUGGESTED AS AN EFFECTIVE THERAPEUTIC MODALITY AGAINST THIS CANCER TYPE. THEREFORE, IN THIS REVIEW, WE WILL REVIEW COMPREHENSIBLY THE EFFECTS OF EXERCISE IN PREVENTING, TREATING, AND ALLEVIATING THE ADVERSE EFFECTS OF CONVENTIONAL THERAPEUTIC OPTIONS IN COLORECTAL CANCER. MOREOVER, THE POSSIBLE MECHANISMS UNDERLYING THE POSITIVE EFFECTS OF EXERCISE AND PHYSICAL ACTIVITY IN COLORECTAL CANCER, INCLUDING REGULATION OF INFLAMMATION, APOPTOSIS, GROWTH FACTOR AXIS, IMMUNITY, EPIGENETIC, ETC. WILL BE ALSO DISCUSSED. 2022 20 1918 31 ENVIRONMENTAL CARCINOGENESIS AND TRANSGENERATIONAL TRANSMISSION OF CARCINOGENIC RISK: FROM GENETICS TO EPIGENETICS. THE DOMINANT PATHOGENIC MODEL, SOMATIC MUTATION THEORY (SMT), CONSIDERS CARCINOGENESIS AS A 'GENETIC ACCIDENT' DUE TO THE ACCUMULATION OF 'STOCHASTIC' DNA MUTATIONS. THIS MODEL WAS PROPOSED AND ACCEPTED BY THE SCIENTIFIC COMMUNITY WHEN CANCER MAINLY AFFECTED THE ELDERLY, BUT IT DOES NOT EXPLAIN THE EPIDEMIOLOGICAL OBSERVATION OF THE CONTINUOUS INCREASE IN CANCER INCIDENCE AMONG CHILDREN AND YOUNG ADULTS. SOMATIC MUTATION THEORY HAS BEEN PROPOSED FOR A REVISION BASED ON THE EMERGING EXPERIMENTAL EVIDENCE, AS IT DOES NOT FULLY ADDRESS SOME ISSUES THAT HAVE PROVEN TO BE CRUCIAL FOR CARCINOGENESIS, NAMELY: THE INFLAMMATORY CONTEXT OF CANCER; THE KEY ROLE PLAYED BY THE STROMA, MICROENVIRONMENT, ENDOTHELIAL CELLS, ACTIVATED MACROPHAGES, AND SURROUNDING TISSUES; AND THE DISTORTED DEVELOPMENTAL COURSE FOLLOWED BY THE NEOPLASTIC TISSUE. FURTHERMORE, SMT IS OFTEN NOT ABLE TO CONSIDER EITHER THE EXISTENCE OF SPECIFIC MUTATIONS RESULTING IN A WELL-DEFINED CANCER TYPE, OR A CLEAR RELATIONSHIP BETWEEN MUTATIONS AND TUMOR PROGRESSION. MOREOVER, IT DOES NOT EXPLAIN THE MECHANISM OF ACTION OF THE NON-MUTAGENIC AND ENVIRONMENTAL CARCINOGENS. IN THE LAST DECADE, CANCER RESEARCH HAS HIGHLIGHTED THE PROMINENT ROLE OF AN ALTERED REGULATION OF GENE EXPRESSION, SUGGESTING THAT CANCER SHOULD BE CONSIDERED AS A RESULT OF A POLYCLONAL EPIGENETIC DISRUPTION OF STEM/PROGENITOR CELLS, MEDIATED BY TUMOUR-INDUCING GENES. THE MATERNAL AND FETAL EXPOSURE TO A WIDE RANGE OF CHEMICALS AND ENVIRONMENTAL CONTAMINANTS IS RAISING THE ATTENTION OF THE SCIENTIFIC COMMUNITY. INDEED, THE MOST POWERFUL PROCARCINOGENIC MECHANISMS OF ENDOCRINE DISRUPTORS AND OTHER POLLUTANTS IS LINKED TO THEIR POTENTIAL TO INTERFERE EPIGENETICALLY WITH THE EMBRYO-FETAL PROGRAMMING OF TISSUES AND ORGANS, ALTERING THE REGULATION OF THE GENES INVOLVED IN THE CELL CYCLE, CELL PROLIFERATION, APOPTOSIS, AND OTHER KEY SIGNALING PATHWAYS. THE EMBRYO-FETAL EXPOSURE TO ENVIRONMENTAL, STRESSFUL, AND PROINFLAMMATORY TRIGGERS (FIRST HIT), SEEMS TO ACT AS A 'DISEASE PRIMER', MAKING FETAL CELLS AND TISSUES MORE SUSCEPTIBLE TO THE SUBSEQUENT ENVIRONMENTAL EXPOSURES (SECOND HIT), TRIGGERING THE CARCINOGENIC PATHWAYS. FURTHERMORE, EVEN AT THE MOLECULAR LEVEL, IN CARCINOGENESIS, 'EPIGENETICS PRECEDES GENETICS' AS GLOBAL DNA HYPOMETHYLATION, AND THE HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES ARE COMMON BOTH IN CANCEROUS AND IN PRECANCEROUS CELLS, AND GENERALLY PRECEDE MUTATIONS. THESE EPIGENETIC MODELS MAY BETTER EXPLAIN THE INCREASE OF CANCER AND CHRONIC/DEGENERATIVE DISEASES IN THE LAST DECADES AND COULD BE USEFUL TO ADOPT APPROPRIATE PRIMARY PREVENTION MEASURES, ESSENTIALLY BASED ON THE REDUCTION OF MATERNAL-FETAL AND CHILD EXPOSURE TO SEVERAL PROCARCINOGENIC AGENTS AND FACTORS DISPERSED IN THE ENVIRONMENT AND IN THE FOOD-CHAINS, AS RECENTLY SUGGESTED BY THE WORLD HEALTH ORGANIZATION. 2018