Leicester Warwick Medical School

Neoplasia IIIWhy and How do Tumours

Occur?Professor Rosemary A Walker

raw14@le.ac.ukDepartment 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