CARCINOGENESIS

CARCINOGENS
• IDENTIFIED FROM
– EPIDEMIOLOGICAL STUDIES
– ASSESSMENT OF OCCUPATIONAL RISKS
– DIRECT ACCIDENTAL EXPOSURE
– EFFECTS IN LABORATORY ANIMALS
– TRANSFORMING EFFECTS ON CELL CULTURES
– MUTAGENICITY TESTING IN BACTERIA
– PHYLOGENETIC ANALYSIS OF BACTERIA (GENOMICS, PROTEOMICS)
CLASSES OF CARCINOGENS
• CHEMICALS
• VIRUSES
• IONISING & NON-IONISING RADIATION
• HORMONES
• BACTERIA, FUNGI & PARASITES
• MISCELLANEOUS AGENTS
CHEMICAL CARCINOGENS
• POLYCYCLIC AROMATIC HYDROCARBONS – SMOKING
• AROMATIC AMINES – BLADDER Ca; RUBBER & DYE WORKERS
• NITROSAMINES – GIT; ANIMALS
• AZO DYES – BLADDER & LIVER Ca; ANIMALS
• OTHER ORGANIC COMPNDS: VINYL CHLORIDE
• ARSENIC – SKIN Ca
ONCOGENIC VIRUSES
• TUMOURS MORE COMMON IN YOUTH
• IMMUNOSUPPRESSION FAVOURS VIRAL ONCOGENESIS
• ONCOGENIC DNA VIRAL GENOME DIRECTLY INCORPORATED INTO HOST CELL
DNA
• ONCOGENIC RNA VIRAL GENOME TRANSCRIBED INTO DNA BY REVERSE
TRANSCRIPTASE PRIOR TO INCORPORATION INTO HOST CELL DNA (ONCOGENIC
RETROVIRUS)
EXAMPLES OF ONCOGENIC VIRUSES
• HPV Types 16 & 18 – COMMON WART & CERVICAL CARCINOMA
• EBV – NEEDS A COFACTOR (MALARIA) BURKITT’S LYMPHOMA &
NASOPHARYNGEAL CARCINOMA
• HBV & HCV – HEPATOCELLULAR CARCINOMA
RADIANT ENERGY
• UV – XERODERMA PIGMENTOSUM
• IONISING RADIATION – LONG TERM EFFECTS & SENSITIVE TISSUES INCLUDE
THYROID, BREAST, BONE & HAEMOPOIETIC TISSUE
HORMONES
• OESTROGENS EXPTALLY →MAMMARY & ENDOMETRIAL CARCINOMAS
• BREAST Ca & ORAL CONTRACEPTIVES CONTAINING OESTROGEN UNPROVEN
• ANDROGENIC & ANABOLIC STEROIDS INDUCE HEPATOCELLULAR CANCER
BACTERIA, FUNGI & PARASITES
• HELICOBACTER PYLORI – GASTRITIS & PEPTIC ULCERATION → MALT
LYMPHOMAS
• ASPERGILLUS FLAVUS → AFLATOXIN B1- A POTENT CARCINOGEN FOR
HEPATOCELLULAR CARCINOMA (EASTERN CAPE, SOUTH AFRICA)
• SCHISTOSOMA – BILHARZIA → BLADDER CANCER (TRANSITIONAL / SQUAMOUS
CELL CARCINOMA)
CELLULAR & MOLECULAR EVENTS IN CARCINOGENSIS
• MULTISTEP PROCESS
• MAY REQUIRE INITIATING & PROMOTING AGENTS
• GROWTH PERSISTS IN THE ABSENCE OF CAUSATIVE AGENTS
• GENETIC ALTERATIONS OF ONCOGENES & TUMOUR SUPPRESSOR GENES
GENETIC ABNORMALITIES IN TUMOURS
• CHROMOSOMAL ABNORMALITIES COMMON eg PHILADELPHIA CHROMOSOME IN
CHRONIC MYELOID (GRANULOCYTIC) LEUKAIMIA
• ONCOGENES, GENES DIRECTING CELL GROWTH & DIFFERENTIATION
ABNORMALLY EXPRESSED IN TUMOURS
• INHERITED OR MUTATIONAL LOSS OF TUMOUR SUPPRESSOR GENES PERMITS
TUMOUR DEVELOPMENT
• ONCOGENE EXPRESSION RESULTS IN AUTOCRINE GROWTH STIMULATION
GENETIC MECHANISMS IN CARCINOGENESIS
• LOSS OR INACTIVATION OF RECESSIVE INHIBITORY GENES – TUMOUR
SUPPRESSOR GENES
• ENHANCED OR ABNORMAL EXPRESSION OF DOMINANT STIMULATORY GENES -
ONCOGENES
NON-RANDOM CHROMOSOMAL ABNORMALITIES
• TRANSLOCATION OF c-myc ONCOGENE FROM CHROM 8 TO an Ig GENE LOCUS
ON CHROM 14 RESULTS IN c-myc EXPRESSION & BURKITT’SLYMPHOMA
• TRANSLOCATION BTWN CHROMS 11 & 22 GIVES EWING’S SARCOMA & PNET
(DISTINGUISHING FEATURE FROM NEUROBLASTOMA
TUMOUR SUPPRESSOR GENES
• KNUDSON’S TWO-HIT HYPOTHESIS
• CARETAKERS & GATEKEEPERS
• CARETAKER GENES MAINTAIN THE INTEGRITY OF THE GENOME BY REPAIRING
DNA DAMAGE
• GATEKEEPER GENES INHIBIT PROLIFERATION OR PROMOTE DEATH OF CELLS
WITH DNA DAMAGE
GATEKEEPERS
• P53 MUTATED IN 50% OF HUMAN Cas; A TRANSCRIPTION FACTOR
• Rb1 A TRANSCRIPTIONAL REGULATOR OF FAMILIAL RETINOBLASTOMA
• APC REGULATES BETA-CATENIN FUNCTION OFTEN MUTATEDE IN SPORADIC
COLORECTAL Cas (FAP)
CARETAKERS
• BRCA1 REPAIRS DNA – BREAST & OVARIAN Ca BUT RARELY MUTATED IN
SPORADIC CASES
• BRCA2 REPAIRS DNA – BREAST Ca IN BOTH MALES & FEMALES
• MSH2 & MLH1 REPAIR DNA MISMATCHES – HEREDITARY NON-POLYPOSIS
COLORECTAL CANCER
HOW p53 LOSES ITS NORMAL FUNCTION
• MUTATIONS – NON-SENSE OR MIS-SENSE HENCE ENCODING FOR A DEFECTIVE
PROTEIN
• COMPLEXES OF NORMAL p53 AND MUTANT p53 INACTIVATES FUNCTION OF THE
NORMAL ALLELE
• BINDING OF NORMAL p53 TO PROTEINS ENCODED BY ONCOGENIC DNA
VIRUSES eg HPV & POLYOMAVIRUSES
CLASSIFICATION OF ONCOGENES – BASED ON ONCOPROTEIN
• NUCLEAR BINDING
• TYROSINE KINASE ACTIVITY
• GROWTH FACTORS
• RECEPTORS FOR GROWTH FACTORS
• CYCLIC NUCLEOTIDE BINDING activity
Effects of oncogene products in tumour growth
• No need for extrinsic growth factors
• Tumour production when injected into immunotolerant mice
• Production of plasminogen activator & proteases to assist invasion
• Reduced cell cohesiveness →metastasis
• Immortalisation
• Increased plasma membrane & cell motility
• Abnormal cellular orientation
THE METASTATIC CASCADE
• Detachment from other tumour cells
• Invasion of connective tissue to access lymphatic & blood vessels
• Intravasation
• Evasion of host defence mechanisms
• Adherence to endothelium at a remote focus
• Extravasation from vessel lumen into surrounding tissue
ROUTES OF METASTASIS
• HAEMATOGENOUS
• LYMPHATIC
• TRANSCOELOMIC - PLEURAL, PERICARDIAL & PERITONEAL →NEOPLASTIC
EFFUSION
• IMPLANTATION – ACCIDENTAL SPILLAGE DURING SURGERY