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Leicester Warwick Medical School. Neoplasia III Why and How do Tumours Occur? Professor Rosemary A Walker [email protected] Department of Pathology. WHY DO TUMOURS DEVELOP?. Intrinsic factors Extrinsic factors. INTRINSIC FACTORS. Inherited susceptibility Host factors age Immune status - PowerPoint PPT Presentation
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Leicester Warwick Medical School
Neoplasia IIIWhy and How do Tumours
Occur?Professor Rosemary A Walker
[email protected] of Pathology
WHY DO TUMOURS DEVELOP?
Intrinsic factors
Extrinsic factors
INTRINSIC FACTORS
Inherited susceptibility
Host factors
• age
• Immune status
• hormones
INHERITANCE
Inherited conditions which predispose to the development of tumours – relate to DNA repair.
Inherited susceptibility to development of a tumour or a group of tumours due to alteration of one or more genes.
INHERITANCE
Defects in DNA repair mechanisms
Retinitis (xeroderma) pigmentosa – photosensitivity
Ataxia telangiectasia – defectiveresponse toradiation damage
Fanconi’s anaemia – sensitivity to DNA cross-linking agents.
INHERITANCEAlteration in Gene
• Polyposis coli APC 5q21• Hereditary Non Polyposis Colon
Cancer (HNPCC) Mismatch repair eg 2p21-22
• Li Fraumeni syndrome p53 17p• Familial Breast/Ovarian
cancer BRCA1 17q21BRCA2 13q12
• Retinoblastoma Rb 13q14
EXTRINSIC FACTORS
Radiation
Chemicals
Viruses
RADIATION
Evidence
Skin cancer in radiologists (1920s)
Thyroid carcinoma in children irradiated for thymic asthma.
Hiroshima – early: leukaemia, lymphomalater: thyroid, breast
Chernobyl - thyroid carcinoma in children (ret)
RADIATION
Causes a wide range of different types of damage to DNASingle and double stranded breaksBase damageEffects depend on quality of radiation and doseDNA repair mechanisms importantIncorrect repair of DNA damage mutation
CHEMICALS
Evidence
Epidemiological studies eg. cigarette smoking and lung cancer.
Occupational eg. bladder cancer and rubber industry.
Carcinogenic effects in laboratory animals.
Mutagenicity testing.
CHEMICALS
Carcinogen interacts with DNA in one of a number of ways.
eg. causes specific base damage or single strand breaks.
Damage repaired but may be imperfect.
CHEMICALS
Some act directly.
Others require metabolic conversion to active form.
If enzyme required for conversion is ubiquitous, tumours occur at site of contact/entry.
Others require enzymes confined to certain organs.
CHEMICALS
Polycyclic aromatic hydrocarbons• coal tar, cigarette smoke
• 3,4-benzpyrene most important
• converted to active form by hydroxylation eg. aryl carbonate hydroxylase
Lung cancer,bladder cancer, skin cancer
CHEMICALS
Aromatic amines• Beta-napthylamine hydroxylated in liver to
1,hydroxy-2napthylamine, which is conjugated with glucuronic acid
• Deconjugated to active form in urinary tract
Rubber and dye workers
Bladder cancer
CHEMICALS
NitrosaminesAnimal evidence that conversion of dietary nitrates/nitrites to nitrosamines by gut bacteria lead to GI cancer.
Alkylating AgentsBind directly to DNA – Nitrogen mustard.
VIRUSES
Hepatitis B Hepatocellular carcinoma
Epstein Barr Burkitt’s lymphoma,Nasopharyngeal carcinoma
Human Papilloma Cervical carcinoma
OTHER AGENTS
Asbestos Mesothelioma
Aflatoxins Liver cancer
Schistosoma Bladder cancer
Hormones Oestrogens and breast cancer
Androgens and liver cancer
GEOGRAPHIC VARIATION
• Genetic Tight family clusters• Viruses Hepatitis B, Epstein Barr• Parasites Schistosoma• Diet Gastric cancer in Japan,
Fibre content• Other factors Reproduction and breast
cancer Carcinoma of cervix
PREDISPOSING CONDITIONS
Ulcerative colitis colorectal carcinoma
Cirrhosis liver cancer
Adenoma of large adenocarcinomaintestine
HOST FACTORS
Age - incidence of cancer increases• cumulative exposure to carcinogens• latency• accumulating genetic lesions• innate defence
Immune factors
Hormones
WHICH GENES ARE INVOLVED
The function of the genes which are modified by radiation/chemicals/viruses is critical for the development of neoplasms
GrowthDifferentiation
Proto-OncogenesTumour Suppressor genes
PROTO-ONCOGENES
Present in all normal cells, involved in normal growth and differentiation. DNA sequence identical to viral oncogenes.
Alteration (mutation, amplification, translocation) oncogene
ONCOGENES• c-myc binds to DNA, stimulates synthesis
amplified (over-expressed ) in e.g. neuroblastoma, breast cancer
translocation 8 to 14, adjacent to immunoglobulin (inappropriatetranscription) in Burkitt’s lymphoma
ONCOGENES
• Ras intracellular signalling mutation (altered function)
colon, lung cancer
• c-erbB-2 growth factor receptor(HER-2) amplification (over expression)
adenocarcinoma
TUMOUR SUPPRESSOR GENES
In normal cells the protein encoded by the gene suppresses growth
Loss/alteration to the gene results in loss of growth suppression
Retinoblastoma/p53
RETINOBLASTOMA
Tumour of retina in children. 40% of cases familial.
Familial cases occur younger ( 1yr age) and can be bilateral.
Familial cases can develop osteosarcoma in teens.
RETINOBLASTOMAFamilial
Inherit defect of Rb gene on one allele
Deletion/mutation Rb gene other allele
RETINOBLASTOMA(ONE HIT)
Sporadic
Normal Rb gene
Deletion/mutation Rb gene one allele
Deletion/mutation other allele
RETINOBLASTOMA(TWO HIT)
p53
Gene encodes a nuclear protein which binds to and modulates expression of genes important for DNA repair, cell division and cell death by apoptosis
Located on chromosome 17p
Alterations to the gene found in many cancers
p53Radiation Free Radicals Chemicals DNA
DamageIncreased p53 protein
Cell cycle inhibitor increasedGrowth
Arrest
Apoptosis
DNA Repair
MECHANISMS IN CARCINOGENESIS
Long period of time elapses between exposure to stimulus and the emergence of a clinical cancer.
Initiation
Promotion
Progression
PROMOTER
INITIATOR
MECHANISMS IN CARCINOGENISIS
Initiating Stimulus- Effect modified by genetic factors, DNA repair.
Promotion - Hormones, local tissue responses, immune responses.
Progression - Number and type of genes modified allows
development of neoplastic cell
TUMOUR DEVELOPMENT AND PROGRESSION
Not just an alteration to one gene
Accumulation of alterations
Many factors involved