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Transcript of NEOPLASIA Abdulmalik Alsheikh,M.D,FRCPC. CARCINOGENESIS Carcinogenesis is a multistep process at...
NEOPLASIANEOPLASIA
Abdulmalik Abdulmalik Alsheikh,M.D,FRCPCAlsheikh,M.D,FRCPC
CARCINOGENESISCARCINOGENESIS
Carcinogenesis is a multistep Carcinogenesis is a multistep process at both the phenotypic and process at both the phenotypic and the genetic levels.the genetic levels.
It starts with a genetic damage:It starts with a genetic damage: EnvironmentalEnvironmental
ChemicalChemical RadiationRadiation ViralViral
InheretedInhereted
CarcinogenesisCarcinogenesis
Genetic damage lead to “ mutation”Genetic damage lead to “ mutation” single cell which has the genetic single cell which has the genetic
damage undergoes neoplastic damage undergoes neoplastic prliferation ( clonal expansion) prliferation ( clonal expansion) forming the tumor massforming the tumor mass
CarcinogenesisCarcinogenesis
Where are the targets of the genetic Where are the targets of the genetic damage??damage??
Four regulatory genes are the main Four regulatory genes are the main targets:targets: Growth promoting protooncogenesGrowth promoting protooncogenes
Protooncogene > mutation > oncogeneProtooncogene > mutation > oncogene Growth inhibiting (supressors) genesGrowth inhibiting (supressors) genes Genes regulating apoptosisGenes regulating apoptosis DNA repair genesDNA repair genes
CarcinogenesisCarcinogenesis
Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype: Self-sufficiency in growth signalsSelf-sufficiency in growth signals Insensitivity to growth-inhibitory signalsInsensitivity to growth-inhibitory signals Evasion of apoptosisEvasion of apoptosis Limitless replicative potentialLimitless replicative potential Sustained angiogenesisSustained angiogenesis Ability to invade and metastsizeAbility to invade and metastsize
CarcinogenesisCarcinogenesis
A - Self-sufficiency in Growth signals:A - Self-sufficiency in Growth signals: Oncogene: Gene that promote Oncogene: Gene that promote
autonomous cell growth in cancer cellsautonomous cell growth in cancer cells They are derived by mutations in They are derived by mutations in
protooncogenesprotooncogenes They are characterized by the ability to They are characterized by the ability to
promote cell growth in the absence of promote cell growth in the absence of normal growth-promoting signalsnormal growth-promoting signals
Oncoproteins : are the products Oncoproteins : are the products
CarcinogenesisCarcinogenesis
Remember the cell cycle !!Remember the cell cycle !! Binding of a growth factor to its receptor Binding of a growth factor to its receptor
on the cell membraneon the cell membrane Activation of the growth factor receptor Activation of the growth factor receptor
leading to activation of signal-leading to activation of signal-transducing proteins transducing proteins
Transmission of the signal to the nucleusTransmission of the signal to the nucleus Induction of the DNA transcriptionInduction of the DNA transcription Entry in the cell cycle and cell divisionEntry in the cell cycle and cell division
CarcinogenesisCarcinogenesis
HOW CANCER CELLS ACQUIRE HOW CANCER CELLS ACQUIRE SELF-SUFFICIENCY IN GROWTH SELF-SUFFICIENCY IN GROWTH SIGNALS??SIGNALS??
CarcinogenesisCarcinogenesis
1- Growth factors:1- Growth factors: Cancer cells are capable to synthesize Cancer cells are capable to synthesize
the same growth factors to which they the same growth factors to which they are responsive are responsive
E.g. Sarcomas ---- > TGF-E.g. Sarcomas ---- > TGF- Glioblastoma-----> PDGFGlioblastoma-----> PDGF
CarcinogenesisCarcinogenesis
2-Growth factors receptors:2-Growth factors receptors: Receptors --- mutation ----continous Receptors --- mutation ----continous
signals to cells and uncontroled signals to cells and uncontroled growthgrowth
Receptors --- overexpression ---cells Receptors --- overexpression ---cells become very sensitive ----become very sensitive ----hyperresponsive to normal levels of hyperresponsive to normal levels of growth factorsgrowth factors
CarcinogenesisCarcinogenesis
Example : Example : Epidermal Growth Factor ( EGF ) Epidermal Growth Factor ( EGF )
Receptor familyReceptor family HER2 HER2
Amplified in breast cancers and other tumorsAmplified in breast cancers and other tumors High levels of HER2 in breast cancer indicate High levels of HER2 in breast cancer indicate
poor prognosispoor prognosis Anti- HER2 antibodies are used in treatmentAnti- HER2 antibodies are used in treatment
CarcinogenesisCarcinogenesis
3- Signal-transducing proteins :3- Signal-transducing proteins : They receive signals from activated They receive signals from activated
growth factors receptors and growth factors receptors and transmitte them to the nucleus. transmitte them to the nucleus. Examples :Examples : RASRAS ABLABL
CarcinogenesisCarcinogenesis
RAS :RAS : 30% of all human tumors contain 30% of all human tumors contain
mutated RAS gene . E.g : colon . mutated RAS gene . E.g : colon . Pancreas cancersPancreas cancers
Mutations of the RAS gene is the most Mutations of the RAS gene is the most common oncogene abnormality in common oncogene abnormality in human tumorshuman tumors
Mutations in RAS --- cells continue to Mutations in RAS --- cells continue to proliferateproliferate
CarcinogenesisCarcinogenesis ABL gene ABL gene
ABL protooncogene has a tyrosine kinase ABL protooncogene has a tyrosine kinase activityactivity
Its activity is controlled by negative Its activity is controlled by negative regulatory mechanismregulatory mechanism
E.g. : chronic myeloid leukemia ( CML ) :E.g. : chronic myeloid leukemia ( CML ) : t( 9,22) ---ABL gene transferred from ch. 9 to ch. 22t( 9,22) ---ABL gene transferred from ch. 9 to ch. 22 Fusion with BCR ---> BCR-ABL Fusion with BCR ---> BCR-ABL BCR-ABL has tyrosine kinase acttivity ---BCR-ABL has tyrosine kinase acttivity ---
( oncogenec)( oncogenec)
CarcinogenesisCarcinogenesis
CML patients are treated with CML patients are treated with ( Gleevec) which is inhibitor of ABL ( Gleevec) which is inhibitor of ABL kinase kinase
CarcinogenesisCarcinogenesis
4- Nuclear transcription factors :4- Nuclear transcription factors : Mutations may affect genes that Mutations may affect genes that
regulate transcription of DNA regulate transcription of DNA growth growth autonomyautonomy
E.g. MYCE.g. MYC MYC protooncogene produce MYC protein MYC protooncogene produce MYC protein
when cell receives growth signalswhen cell receives growth signals MYC protein binds to DNA leading to MYC protein binds to DNA leading to
activation of growth-related genesactivation of growth-related genes
CarcinogenesisCarcinogenesis
Normally … MYC decrease when cell Normally … MYC decrease when cell cycle begins …but ..in tumors there cycle begins …but ..in tumors there is sustained expression of MYC is sustained expression of MYC continuous proliferation continuous proliferation
E.g. Burkitt Lymphoma ; MYC is E.g. Burkitt Lymphoma ; MYC is dysregulated due to t( 8,14)dysregulated due to t( 8,14)
CarcinogenesisCarcinogenesis
5- Cyclins and cyclins- dependent kinases5- Cyclins and cyclins- dependent kinases Progression of cells through cell cycles is Progression of cells through cell cycles is
regulated by CDKs after they are activated regulated by CDKs after they are activated by binding with cyclinsby binding with cyclins
Mutations that dysregulate cyclins and Mutations that dysregulate cyclins and CDKs will lead to cell proliferation …e.g.CDKs will lead to cell proliferation …e.g. Cyclin D genes are overexpressed in breast, Cyclin D genes are overexpressed in breast,
esophagus and liver cancers.esophagus and liver cancers. CDK4 is amplified in melanoma and sarcomasCDK4 is amplified in melanoma and sarcomas
CarcinogenesisCarcinogenesis
Main changes in the cell physiology that Main changes in the cell physiology that lead to formation of the malignant lead to formation of the malignant phenotype:phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals
B- Insensitivity to growth-inhibitory B- Insensitivity to growth-inhibitory signalssignals
C- Evasion of apoptosisC- Evasion of apoptosis
D- Limitless replicative potentialD- Limitless replicative potential
E- Sustained angiogenesisE- Sustained angiogenesis
F- Ability to invade and metastsizeF- Ability to invade and metastsize
CarcinogenesisCarcinogenesis
2. Insensitivity to growth-inhibitory 2. Insensitivity to growth-inhibitory signalssignals
Tumor supressor genes control ( apply Tumor supressor genes control ( apply brakes) cells proliferationbrakes) cells proliferation
If mutation caused disruption to them If mutation caused disruption to them cell becomes insensitive to growth cell becomes insensitive to growth inhibitioninhibition uncontrolled proliferation uncontrolled proliferation
Examples: RB, TGF-Examples: RB, TGF-, APC, TP53, APC, TP53
CarcinogenesisCarcinogenesis
RB ( retinoblastoma ) gene :RB ( retinoblastoma ) gene : First tumor supressor gene discoveredFirst tumor supressor gene discovered It was discovered initially in It was discovered initially in
retinoblastomasretinoblastomas Found in other tumors, e.g. breast caFound in other tumors, e.g. breast ca RB gene is a DNA-binding protein RB gene is a DNA-binding protein RB is located on chromosome 13RB is located on chromosome 13
CarcinogenesisCarcinogenesis
RB gene exists in “ active “ and “ RB gene exists in “ active “ and “ inactive” formsinactive” forms
If activeIf active will stop the advancing will stop the advancing from G1 to S phase in cell cyclefrom G1 to S phase in cell cycle
If cell is stimulated by growth If cell is stimulated by growth factors factors inactivation of RB gene inactivation of RB gene brake is releasedbrake is released cells start cell cells start cell cycle …G1 cycle …G1 SSM …then RB gene is M …then RB gene is activated againactivated again
CarcinogenesisCarcinogenesis
Retinoblastoma is an uncommon Retinoblastoma is an uncommon childhood tumorchildhood tumor
Retinoblastoma is either sporadic (60%) Retinoblastoma is either sporadic (60%) or familial ( 40% )or familial ( 40% )
Two mutations required to produce Two mutations required to produce retinoblastomaretinoblastoma
Both normal copies of the gene should Both normal copies of the gene should be lost to produce retinoblastomabe lost to produce retinoblastoma
CarcinogenesisCarcinogenesis
Transforming Growth Factor- Transforming Growth Factor- pathway:pathway: TGF-TGF-is an inhibitor of proliferationis an inhibitor of proliferation It regulate RB pathwayIt regulate RB pathway Inactivation of TGF-Inactivation of TGF-lead to cell lead to cell
proliferationproliferation Mutations in TGF-Mutations in TGF-pathway are present pathway are present
in :in : of pancreatic cancersof pancreatic cancers of colon cancersof colon cancers
CarcinogenesisCarcinogenesis
Adenomatous Polyposis Coli – Adenomatous Polyposis Coli – Catenin pathway:Catenin pathway: APC is tumor supressor geneAPC is tumor supressor gene APC gene loss is very common in colon APC gene loss is very common in colon
cancerscancers It has anti-proliferative action through It has anti-proliferative action through
inhibition of inhibition of Catenin which activate cell Catenin which activate cell proliferationproliferation
Individuals with mutant APC develop Individuals with mutant APC develop thousands of colonic polypsthousands of colonic polyps
CarcinogenesisCarcinogenesis
One or more of the polyps will One or more of the polyps will progress to colonic carcinomaprogress to colonic carcinoma
APC mutations are seen in 70% to APC mutations are seen in 70% to 80% of sporadic colon cancers80% of sporadic colon cancers
CarcinogenesisCarcinogenesis
TP53 ( P53 )TP53 ( P53 ) It has multiple functionsIt has multiple functions Mainly : Mainly :
Tumor suppressor gene ( anti-proliferative )Tumor suppressor gene ( anti-proliferative ) Regulates apoptosisRegulates apoptosis
CarcinogenesisCarcinogenesis
TP53 senses DNA damageTP53 senses DNA damage Causes G1 arrest to give chance for Causes G1 arrest to give chance for
DNA repairDNA repair Induce DNA repair genes Induce DNA repair genes If a cell with damaged DNA cannot If a cell with damaged DNA cannot
be repaired, it will be directed by be repaired, it will be directed by TP53 to undergo apoptosisTP53 to undergo apoptosis
CarcinogenesisCarcinogenesis
With loss of TP53, DNA damage goes With loss of TP53, DNA damage goes unrepairedunrepaired
Mutations will be fixed in the Mutations will be fixed in the dividing cells, leading to malignant dividing cells, leading to malignant transformationtransformation
TP53 is called the “ guardian of the TP53 is called the “ guardian of the genome”genome”
70% of human cancers have a defect in 70% of human cancers have a defect in TP53TP53
It has been reported with almost all types It has been reported with almost all types of cancers : e.g. lung, colon, breastof cancers : e.g. lung, colon, breast
In most cases, mutations are acquired, In most cases, mutations are acquired, but can be inhereted, e.g : Li-Fraumeni but can be inhereted, e.g : Li-Fraumeni syndromesyndrome
CarcinogenesisCarcinogenesis
CarcinogenesisCarcinogenesis
Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals
B- Insensitivity to growth-inhibitory signalsB- Insensitivity to growth-inhibitory signals
C- Evasion of apoptosisC- Evasion of apoptosis
D- Limitless replicative potentialD- Limitless replicative potential
E- Sustained angiogenesisE- Sustained angiogenesis
F- Ability to invade and metastsizeF- Ability to invade and metastsize
CarcinogenesisCarcinogenesis
Evasion of apoptosis:Evasion of apoptosis: Mutations in the genes regulating Mutations in the genes regulating
apoptosis are factors in malignant apoptosis are factors in malignant transformationtransformation
Cell survival is controlled by genes that Cell survival is controlled by genes that promote and inhibit apoptosis promote and inhibit apoptosis
CarcinogenesisCarcinogenesis
Reduced CD95 level inactivate death –Reduced CD95 level inactivate death –induced signaling cascade that cleaves induced signaling cascade that cleaves DNA to cause deathDNA to cause death tumor cells less tumor cells less susceptible to apoptosissusceptible to apoptosis
DNA damage induced apoptosis (with the DNA damage induced apoptosis (with the action of TP53 ) can be blocked in tumorsaction of TP53 ) can be blocked in tumors See figure 6-24 , page 189See figure 6-24 , page 189
loss of TP53 and up-regulation of BCL2 loss of TP53 and up-regulation of BCL2 prevent apoptosisprevent apoptosis
CarcinogenesisCarcinogenesis
Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals
B- Insensitivity to growth-inhibitory signalsB- Insensitivity to growth-inhibitory signals
C- Evasion of apoptosisC- Evasion of apoptosis
D- Limitless replicative potentialD- Limitless replicative potential
E- Sustained angiogenesisE- Sustained angiogenesis
F- Ability to invade and metastsizeF- Ability to invade and metastsize
CarcinogenesisCarcinogenesis
Limitless replicative potential :Limitless replicative potential : Normally there is progressive Normally there is progressive
shortening of telomeres at the ends of shortening of telomeres at the ends of chromosomeschromosomes
Telomerase is active in normal stem Telomerase is active in normal stem cells but absent in somatic cellscells but absent in somatic cells
In tumor cells : activation of the enzyme In tumor cells : activation of the enzyme telomerase, which can maintain normal telomerase, which can maintain normal telomere lengthtelomere length
CarcinogenesisCarcinogenesis
Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals
B- Insensitivity to growth-inhibitory signalsB- Insensitivity to growth-inhibitory signals
C- Evasion of apoptosisC- Evasion of apoptosis
D- Limitless replicative potentialD- Limitless replicative potential
E- Sustained angiogenesisE- Sustained angiogenesis
F- Ability to invade and metastsizeF- Ability to invade and metastsize
CarcinogenesisCarcinogenesis
Sustained angiogenesisSustained angiogenesis Neovascularization has two main Neovascularization has two main
effects: effects: Perfusion supplies oxygen and nutrientsPerfusion supplies oxygen and nutrients Newly formed endothelial cells stimulate Newly formed endothelial cells stimulate
the growth of adjacent tumor cells by the growth of adjacent tumor cells by secreting growth factors, e.g : PDGF, IL-1secreting growth factors, e.g : PDGF, IL-1
Angiogenesis is required for metastasisAngiogenesis is required for metastasis
CarcinogenesisCarcinogenesis
How do tumors develop a blood How do tumors develop a blood supply?supply? Tumor-associated angiogenic factors Tumor-associated angiogenic factors These factors may be produced by These factors may be produced by
tumor cells or by inflammatory cells tumor cells or by inflammatory cells infiltrating the tumor e.g. macrophagesinfiltrating the tumor e.g. macrophages
Important factors : Important factors : Vascular endothelial growth factor( VEGF ) Vascular endothelial growth factor( VEGF ) Fibroblast growth factorFibroblast growth factor
CarcinogenesisCarcinogenesis
Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals
B- Insensitivity to growth-inhibitory signalsB- Insensitivity to growth-inhibitory signals
C- Evasion of apoptosisC- Evasion of apoptosis
D- Limitless replicative potentialD- Limitless replicative potential
E- Sustained angiogenesisE- Sustained angiogenesis
F- Ability to invade and metastsizeF- Ability to invade and metastsize
CarcinogenesisCarcinogenesis
Ability to invade and metastsize:Ability to invade and metastsize: Two phases : Two phases :
Invasion of extracellular matrixInvasion of extracellular matrix Vascular dissimenation and homing of Vascular dissimenation and homing of
tumor cellstumor cells
CarcinogenesisCarcinogenesis
Invasion of ECM:Invasion of ECM: Malignant cells first breach the Malignant cells first breach the
underlying basement membraneunderlying basement membrane Traverse the interstitial tissueTraverse the interstitial tissue Penetrate the vascular basement Penetrate the vascular basement
membrane membrane Gain access to the circulationGain access to the circulation
CarcinogenesisCarcinogenesis
Invasion of the ECM has four steps:Invasion of the ECM has four steps: Detachment of tumor cells from each Detachment of tumor cells from each
otherother Attachments of tumor cells to matrix Attachments of tumor cells to matrix
componentscomponents Degradation of ECMDegradation of ECM Migration of tumor cells Migration of tumor cells
CarcinogenesisCarcinogenesis
Vascular dissemination and homing Vascular dissemination and homing of tumor cells:of tumor cells: May form emboli May form emboli Most travel as single cellsMost travel as single cells Adhesion to vascular endotheliumAdhesion to vascular endothelium extravasationextravasation
CarcinogenesisCarcinogenesis
Main changes in the cell physiology Main changes in the cell physiology that lead to formation of the that lead to formation of the malignant phenotype:malignant phenotype:A- Self-sufficiency in growth signalsA- Self-sufficiency in growth signals
B- Insensitivity to growth-inhibitory signalsB- Insensitivity to growth-inhibitory signals
C- Evasion of apoptosisC- Evasion of apoptosis
D- Limitless replicative potentialD- Limitless replicative potential
E- Sustained angiogenesisE- Sustained angiogenesis
F- Ability to invade and metastsizeF- Ability to invade and metastsize
Genomic InstabilityGenomic Instability
Enabler of malignancyEnabler of malignancy Due to defect in DNA repair genesDue to defect in DNA repair genes Examples:Examples:
Hereditary Nonpolyposis colon Hereditary Nonpolyposis colon carcinoma(HNPCC)carcinoma(HNPCC)
Xeroderma pigmentosumXeroderma pigmentosum Familial breast cancerFamilial breast cancer
Genomic InstabilityGenomic Instability
Familial breast cancer:Familial breast cancer: Due to mutations in BRCA1 and BRCA2 Due to mutations in BRCA1 and BRCA2
genesgenes These genes regulate DNA repairThese genes regulate DNA repair Account for 80% of familial breast Account for 80% of familial breast
cancercancer They are also involved in other They are also involved in other
malignanciesmalignancies
Molecular Basis of Molecular Basis of multistep Carcinogenesismultistep Carcinogenesis
Cancer results from accumulation of Cancer results from accumulation of multiple mutationsmultiple mutations
All cancers have multiple genetic All cancers have multiple genetic alterations, involving activation of alterations, involving activation of several oncogenes and loss of two or several oncogenes and loss of two or more tumor suppressor genesmore tumor suppressor genes
Molecular Basis of Molecular Basis of multistep Carcinogenesismultistep Carcinogenesis
Tumor progressionTumor progression
Many tumors become more Many tumors become more aggressive and acquire greater aggressive and acquire greater malignant potential…this is called “ malignant potential…this is called “ tumor progression” …not increase in tumor progression” …not increase in size!!size!!
By the time, the tumor become By the time, the tumor become clinically evident, their constituent clinically evident, their constituent cells are extremely heterogeneouscells are extremely heterogeneous
Karyotypic Changes in Karyotypic Changes in TumorsTumors
Translocations: Translocations: In CML : t(9,22) …” Philadelphia In CML : t(9,22) …” Philadelphia
chromosome”chromosome” In Burkitt Lymphoma : t(8,14)In Burkitt Lymphoma : t(8,14) In Follicular Lymphoma : t(14,18)In Follicular Lymphoma : t(14,18)
DeletionsDeletions Gene amplification:Gene amplification:
Breast cancer : HER-2Breast cancer : HER-2
Carcinogenic AgentsCarcinogenic Agents
ChemicalsChemicals RadiationRadiation Microbial agentsMicrobial agents
Carcinogenic AgentsCarcinogenic Agents
Chemicals:Chemicals: Natural or syntheticNatural or synthetic Direct reacting or indirectDirect reacting or indirect Indirect Indirect need metabolic conversion need metabolic conversion
to be active and carcinogenicto be active and carcinogenic Indirect chemicals are called “ Indirect chemicals are called “
procarcinogens “ and their active end procarcinogens “ and their active end products are called “ ultimate products are called “ ultimate carcinogens”carcinogens”
Carcinogenic AgentsCarcinogenic Agents
All direct reacting and ultimate All direct reacting and ultimate chemical carcinogens are highly chemical carcinogens are highly reactive as they have electron-reactive as they have electron-deficient atomsdeficient atoms
They react with the electron rich They react with the electron rich atoms in RNA,DNA and other atoms in RNA,DNA and other cellular proteinscellular proteins
Carcinogenic AgentsCarcinogenic Agents
Examples:Examples: Alkylating agentsAlkylating agents Polycyclic hydrocarbons:Polycyclic hydrocarbons:
Cigarette smokingCigarette smoking Animal fats during broiling meatsAnimal fats during broiling meats Smoked meats and fishSmoked meats and fish
Carcinogenic AgentsCarcinogenic Agents
Aromatic amines and azo dyes:Aromatic amines and azo dyes: -naphthylamine cause bladder cancer in -naphthylamine cause bladder cancer in
rubber industries and aniline dyerubber industries and aniline dye Some azo dyes are used to color foodSome azo dyes are used to color food Nitrosamines and nitrosamides are used Nitrosamines and nitrosamides are used
as preservatives. They cause gastric as preservatives. They cause gastric cancer.cancer.
Aflatoxin B: produced by aspirigillus Aflatoxin B: produced by aspirigillus growing on improperly stored grains. It growing on improperly stored grains. It cause hepatocellular carcinomacause hepatocellular carcinoma
Carcinogenic AgentsCarcinogenic Agents
Mechanism of action of chemical Mechanism of action of chemical carcinogens:carcinogens: Most of them are mutagenic. i.e. cause Most of them are mutagenic. i.e. cause
mutationsmutations RAS and TP53 are common targetsRAS and TP53 are common targets
Carcinogenic AgentsCarcinogenic Agents
Radiation carcinogenesisRadiation carcinogenesis UV rays of sunlightUV rays of sunlight X-raysX-rays Nuclear radiationNuclear radiation Therapeutic irradiationsTherapeutic irradiations
Radiation has mutagenic effects: Radiation has mutagenic effects: chromosomes breakage, chromosomes breakage, translocations, and point mutationstranslocations, and point mutations
Carcinogenic AgentsCarcinogenic Agents
UV rays of sunlight :UV rays of sunlight : Can cause skin cancers: melanoma, Can cause skin cancers: melanoma,
squamous cell carcinoma, and basal cell squamous cell carcinoma, and basal cell carcinomacarcinoma
It is capable to damage DNA It is capable to damage DNA With extensive exposure to sunlight, the With extensive exposure to sunlight, the
repair system is overwhelmedrepair system is overwhelmed skin skin cancer cancer
They cause mutations in TP53 geneThey cause mutations in TP53 gene
Carcinogenic AgentsCarcinogenic Agents
Viral and Microbial oncogenesisViral and Microbial oncogenesis
DNA virusesDNA viruses
RNA virusesRNA viruses
other organismsother organisms
Carcinogenic AgentsCarcinogenic Agents Viral oncogenes:Viral oncogenes:
carry genes that induce cell replication as part of the viral life cycle
host cell has endogenous genes that maintain the normal cell-cycle
Viral infection mimics or blocks these normal cellular signals necessary for growth regulation
Carcinogenic AgentsCarcinogenic Agents
RNA Oncogenic virusesRNA Oncogenic virusesHuman T-Cell Leukemia Virus type 1 Human T-Cell Leukemia Virus type 1
(HTLV-1)(HTLV-1)• RNA retrovirus targets / transforms T-cellsRNA retrovirus targets / transforms T-cells
• causes T-Cell leukemia/Lymphoma causes T-Cell leukemia/Lymphoma
• Endemic in Japan and CaribbeanEndemic in Japan and Caribbean
• Transmitted like HIV but only 1% of infected Transmitted like HIV but only 1% of infected
develop T-Cell leukemia/Lymphoma develop T-Cell leukemia/Lymphoma
• 20-30 year latent period20-30 year latent period
Carcinogenic AgentsCarcinogenic Agents
No cure or vaccine No cure or vaccine Treatment : chemotherapy with Treatment : chemotherapy with
common relapsecommon relapse
Carcinogenic AgentsCarcinogenic Agents
DNA Oncogenic VirusesDNA Oncogenic Viruses virus DNA forms stable association with virus DNA forms stable association with
host’s DNAhost’s DNA transcribed viral DNA transforms host celltranscribed viral DNA transforms host cell
Examples: Examples: papilloma virusespapilloma viruses
Epstein-Barr (EBV)Epstein-Barr (EBV)
Hepatitis B (HBV)Hepatitis B (HBV)
Kaposi sarcoma herpes virusKaposi sarcoma herpes virus
Carcinogenic AgentsCarcinogenic Agents
Human Papillomavirus (HPV)Human Papillomavirus (HPV)• 70 types70 types• squamous cell carcinoma of squamous cell carcinoma of
cervixcervix anogenital regionanogenital region mouth mouth larynxlarynx
Carcinogenic AgentsCarcinogenic Agents
sexually transmittedsexually transmitted Cervical cancer Cervical cancer
85% have types 16 and 1885% have types 16 and 18
Genital wartsGenital warts types 6 and 11types 6 and 11
Carcinogenic AgentsCarcinogenic Agents
HPV causing benign tumors:HPV causing benign tumors:
types 6, 11types 6, 11
HPV causing malignant tumors :HPV causing malignant tumors : types 16, 18, 31types 16, 18, 31
vDNA integrates w/ hostvDNA integrates w/ host
Carcinogenic AgentsCarcinogenic Agents
HPV (types 16 and 18)HPV (types 16 and 18) over-expression of Exon 6 and 7over-expression of Exon 6 and 7
E6 protein binds to Rb tumor E6 protein binds to Rb tumor suppressor suppressor
replaces normal transcription replaces normal transcription factorsfactors
decreases Rb synthesisdecreases Rb synthesis E7 protein binds to TP53E7 protein binds to TP53
facilitates degradation of TP53facilitates degradation of TP53
Carcinogenic AgentsCarcinogenic Agents
HPV infection alone is not sufficient -HPV infection alone is not sufficient - other risk factors:other risk factors:
cigarette smokingcigarette smoking
coexisting infectionscoexisting infections
hormonal changeshormonal changes
Carcinogenic AgentsCarcinogenic Agents
Epstein-Barr VirusEpstein-Barr Virus• common virus worldwidecommon virus worldwide• Infects B lymphocytes and epithelial cells Infects B lymphocytes and epithelial cells
of oropharynxof oropharynx
• causes infectious mononucleosiscauses infectious mononucleosis• EBV infection may cause malignancy EBV infection may cause malignancy
Burkitt’s LymphomaBurkitt’s Lymphoma B cell lymphoma in immunosuppressedB cell lymphoma in immunosuppressed Nasopharyngeal carcinomaNasopharyngeal carcinoma
Carcinogenic AgentsCarcinogenic Agents
Nasopharyngeal carcinoma Nasopharyngeal carcinoma Cancer of nasopharygeal epitheliumCancer of nasopharygeal epithelium
Endemic in South China, parts of AfricaEndemic in South China, parts of Africa 100% of tumors contain EBV genome in 100% of tumors contain EBV genome in
endemic areasendemic areas
Carcinogenic AgentsCarcinogenic Agents
Burkitt LymphomaBurkitt Lymphoma
highly malignant
B cell tumor
sporadic rare
occurrence worldwide
most common
childhood tumor in
Africa
all cases have
t(8:14))
Carcinogenic AgentsCarcinogenic Agents
causes B lymphocyte cell proliferationcauses B lymphocyte cell proliferation loss of growth regulationloss of growth regulation predisposes to mutation, esp. t(8:14)predisposes to mutation, esp. t(8:14)
Carcinogenic AgentsCarcinogenic Agents
Hepatitis B virus (HBV) Strong association with Liver Cancer
world-wide, but HBV infection is most common in Far East and Africa
HBV infection incurs up to 200-fold risk
Carcinogenic AgentsCarcinogenic Agents
Helicobacter Pylori• bacteria infecting stomach• implicated in:
peptic ulcers gastric lymphoma
Mucosal Associated Lymphoid Tumor (MALT)
gastric carcinoma
Host defenseHost defense
Tumor Antigens:Tumor Antigens: Tumor-specific antigens: present only Tumor-specific antigens: present only
on tumor cellson tumor cells Tumor-associated antigens: present on Tumor-associated antigens: present on
tumor cells and some normal cellstumor cells and some normal cells
Host defenseHost defense
Tumor antigens may:Tumor antigens may: Result from gene mutations: TP53, RASResult from gene mutations: TP53, RAS Be products of amplified genes: HER-2Be products of amplified genes: HER-2 Viral antigens: from oncogenic virusesViral antigens: from oncogenic viruses Be differentiation specific: PSA in prostate Be differentiation specific: PSA in prostate Oncofetal antigens: CEA, Alpha fetoprotein Oncofetal antigens: CEA, Alpha fetoprotein
normal embryonic antigen but absent in normal embryonic antigen but absent in adults….in some tumors it will be re-expressed, adults….in some tumors it will be re-expressed, e.g: colon ca, liver cancer e.g: colon ca, liver cancer
Host defenseHost defense
Antitumor mechanisms involve:Antitumor mechanisms involve: Cytotoxic T lymphocytesCytotoxic T lymphocytes Natural killer cells Natural killer cells MacrophagesMacrophages Humoral mechanisms : Humoral mechanisms :
Complement systemComplement system Antibodies Antibodies
Clinical featuresClinical features
Tumours cause problems because :Tumours cause problems because : Location and effects on adjacent structures:
(1cm pituitary adenoma can compress and destroy the surrounding tissue and cause hypopituitarism).
(0.5 cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension).
Tumors may cause bleeding and secondary infections
lesion ulcerates adjacent tissue and structures
Clinical featuresClinical features Effects on functional activity
hormone synthesis occurs in neoplasms arising in endocrine glands:
adenomas and carcinomas of β cells of the islets of the pancreas produce hyperinsulinism.
Some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids.
aldosterone induces sodium retention, hypertension and hypokalemia
Usually such activity is associated with well differentiated benign tumors more than carcinomas.
Clinical featuresClinical features
Cancer cachexia Usually accompanied by weakness, anorexia and
anemia Severity of cachexia, generally, is correlated with
the size and extend of spread of the cancer. The origins of cancer cachexia are multifactorial:
anorexia (reduced calorie intake) increased basal metabolic rate and calorie expenditure
remains high. general metabolic disturbance
Clinical featuresClinical features
Paraneoplastic syndromes
They are symptoms that occur in cancer patients and cannot be explained.
They are diverse and are associated with many different tumors.
They appear in 10% to 15% of pateints. They may represent the earliest manifestation of
an occult neoplasm. They may represent significant clinical problems
and may be lethal. They may mimic metastatic disease.
Clinical featuresClinical features
The most common paraneoplastic syndrome are: Hypercalcemia Cushing syndrome Nonbacterial thrombotic endocarditis
The most often neoplasms associated with these syndromes: Lung and breast cancers and
hematologic malignancies
Clinical FeaturesClinical Features
Grading :Grading : Grade I, II, III, IVGrade I, II, III, IV Well, moderately, poorly differentiated, Well, moderately, poorly differentiated,
anaplasticanaplastic Staging :Staging :
SizeSize Regional lymph nodes involvementRegional lymph nodes involvement Presence or absence of distant metastasisPresence or absence of distant metastasis
TNM systemTNM system
Clinical FeaturesClinical Features
T (primary tumor): T1, T2, T3, T4T (primary tumor): T1, T2, T3, T4 N (regional lymph nodes): N0, N1, N (regional lymph nodes): N0, N1,
N2, N3N2, N3 M (metastasis): M0, M1M (metastasis): M0, M1
Clinical FeaturesClinical Features
American Joint committee system American Joint committee system ( AJC )( AJC ) Stages 0 to IVStages 0 to IV Using TNM features Using TNM features
Laboratory DiagnosisLaboratory Diagnosis
Morphologic methodes Biochemical assays Molecular diagnosis
Laboratory DiagnosisLaboratory Diagnosis
Microscopic Tissue DiagnosisMicroscopic Tissue Diagnosis the gold standard of cancer diagnosis.. Several sampling approaches are available:
Excision or biopsy Frozen section
fine-needle aspiration Cytologic smears
Laboratory DiagnosisLaboratory Diagnosis
Biochemical assaysBiochemical assays:: Useful for measuring the levels of tumor
associated enzymes, hormones, and tumor markers in serum.
Useful in determining the effectiveness of therapy and detection of recurrences after excision
Elevated levels may not be diagnostic of cancer (PSA).
Only few tumor markers are proved to be clinically useful, example CEA and α- fetoprotein.
Laboratory DiagnosisLaboratory Diagnosis
Molecular diagnosisMolecular diagnosis Polymerase chain reaction (PCR) example: detection of BCR-ABL transcripts
in chronic myeloid leukemia. Fluorescent in situ hybridization (fish) it is useful for detecting chromosomes
translocation characteristic of many tumorsBoth PCR and Fish can show amplification of
oncogenes (HER2 and N-MYC)