Transcript WHY DO TUMOURS DEVELOP - University of Leicester

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
• 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
– defective
response to
radiation damage
Fanconi’s anaemia
– sensitivity to DNA
cross-linking
agents.
INHERITANCE
•
•
•
•
•
Alteration in Gene
Polyposis coli
APC
Hereditary Non Polyposis Colon
Cancer (HNPCC)
Mismatch repair
Li Fraumeni syndrome
p53
Familial Breast/Ovarian
cancer
BRCA1
BRCA2
Retinoblastoma
Rb
5q21
eg 2p21-22
17p
17q21
13q12
13q14
EXTRINSIC FACTORS
Radiation
Chemicals
Viruses
RADIATION
Evidence
Skin cancer in radiologists (1920s)
Thyroid carcinoma in children irradiated for
thymic asthma.
Hiroshima –
early:
later:
Chernobyl -
thyroid carcinoma in children (ret)
leukaemia, lymphoma
thyroid, breast
RADIATION
Causes a wide range of different types of
damage to DNA
Single and double stranded breaks
Base damage
Effects depend on quality of radiation and dose
DNA repair mechanisms important
Incorrect 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
Nitrosamines
Animal evidence that conversion of
dietary nitrates/nitrites to nitrosamines by
gut bacteria lead to GI cancer.
Alkylating Agents
Bind 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
• Viruses
• Parasites
• Diet
• Other factors
Tight family clusters
Hepatitis B, Epstein Barr
Schistosoma
Gastric cancer in Japan,
Fibre content
Reproduction and breast
cancer
Carcinoma of cervix
PREDISPOSING CONDITIONS
Ulcerative colitis
carcinoma
colorectal
Cirrhosis
liver cancer
Adenoma of large
intestine
adenocarcinoma
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
Growth
Differentiation
Proto-Oncogenes
Tumour 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 (inappropriate
transcription) in Burkitt’s lymphoma
ONCOGENES
• Ras
intracellular signalling mutation
(altered function)
colon, lung cancer
• c-erbB-2
(HER-2)
growth factor receptor
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.
RETINOBLASTOMA
Familial
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
p53
Radiation Free Radicals
Chemicals
DNA
Damage
DNA Repair
Growth
Arrest
Apoptosis
Increased
p53
protein
Cell cycle
inhibitor
increased
MECHANISMS IN CARCINOGENESIS
Long period of time elapses
between exposure to stimulus and
the emergence of a clinical cancer.
Initiation
Promotion
Progression
INITIATOR
PROMOTER
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