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NEOPLASIANEOPLASIALecture 4Lecture 4
Maha Arafa,MD,KSFPMaha Arafa,MD,KSFP
Abdulmalik Alsheikh, M.D, Abdulmalik Alsheikh, M.D, FRCPCFRCPC
ObjectivesObjectives
List the various causes of neoplasmsList the various causes of neoplasms
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 P53 are common targetsRAS and P53 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 P53 geneThey cause mutations in P53 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 P53E7 protein binds to P53
facilitates degradation of P53facilitates degradation of P53
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 AgentsEpstein-Barr Virus Epstein-Barr Virus
relatedrelated 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 Epstein-Barr Virus Epstein-Barr Virus
relatedrelated 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 Epstein-Barr Virus Epstein-Barr Virus
relatedrelated 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