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Class notes Biomedical Sciences (BSc) Molecular Biology of Cancer, ISBN: 9780198717348
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Lecture Notes BB3704 The Biology and Treatment of Cancer at Brunel University
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BB3704 The Biology and Treatment of CancerIntroduction
The hallmarks of cancer
- Self-sufficiency in growth signals
o Cancer cells are not dependent on normal growth factor signalling
o Acquired mutations during the development of cancer “short-circuit” growth factor
dependence
- Insensitivity to anti-growth signals
o Acquired mutations in tumour suppressor genes interfere with inhibitory signals.
- Tissue invasion & metastasis
o Normal cells maintain their location in the body
o Acquired mutations alter the activity of enzymes involved in cell invasion and those
proteins involved in cell-to-cell interaction
o Invasion and metastasis is the major cause of cancer death.
- Limitless replicative potential
o Normal cells display a finite number of division and senescence. Senescence is when
cells have reached their maximum amount of cell divisions
o Cancer cells maintain telomeres and divide continually
- Sustained angiogenesis
o Cancer cells can induce angiogenesis
- Evasion of immune response
- Evading apoptosis
o Normal cells are removed by apoptosis, e.g. after DNA damage. Cancer cells evade
apoptotic signals
Cancer as a genetic disease
- The key genes involved in cancer are
o Oncogene, e.g. growth inducer
Mutations in oncogenes are generally dominant mutations and cause
enhanced cell growth.
o Tumour suppressor gene, e.g. growth inhibitor
Clinical manifestations in tumour suppressor genes are caused by mutations
in both alleles → recessive
o DNA repair gene
DNA repair genes could be classified as tumour suppressor genes. The loss
of DNA repair genes increases the incidence of cancer
A mutation in one allele leads to the production of half of the DNA repair
genes → haplosufficient.
Li Fraumeni disease is when individuals have a mutation in their p53 gene.
They have a high incidence of different cancers.
Genes and mutations associated with cancer
- The retinoblastoma gene (pRB)
o Phosphorylation of RB is connected to the cell cycle. It is regulated by cyclins.
Mutation in RB changes the function of the gene.
o P16 is a tumour suppressor gene that has an impact on the function of RB.
o Too much production of a cyclin could lead to the overphosphorylation of RB.
o In tumour cells, the pRB pathway is frequently deregulated
Mutation is directly with the RB gene
Interaction with some form of oncoprotein
, o The point mutation of chromosomal deletions usually affects the pocket region of
pRB – necessary region of pRB activity. It is where other important transcription
factors bind to.
- P53
o Known as the “Guardian of the Genome”
o Four p53 proteins form a tetramer to become functional
o Is activated by DNA damage, oncogene activation and cell stress, such as hypoxia or
nucleotide depletion
o Reacts by cell cycle arrest, apoptosis, DNA repair or inhibition of angiogenesis
o Over 50% of cancers of different histological origin contain mutations in the p53
gene. It is the most commonly affected tumour suppressor gene in human cancer
o Inactivation of p53 results in a reduced ability of tumour suppression
o Mutations in p53 occurs in hotspots; between exons 5 and 9, and between codons
126 to 307
o Frequency and distribution of mutations differs in different tumour types
- One or more of these tumour suppressor genes is going to have to be inactivated for
carcinogenesis to occur:
o P53
o pRB
o P16
- Oncogenes
o Proto-oncogene
Normal cellular gene however, when altered by mutation it can contribute
to carcinogenesis
Proto-oncogene regulate cell growth and differentiation
Oncogenes:
Point mutation (Ras)
Gene amplification (myc)
Translocation (BCRabI)
Insertional mutagenesis (viral)
o There are various levels of oncogenic activation
Growth factors (overproduction)
Receptors (overproduction and change in structure)
o Intracellular cell signalling is often disrupted during cancer development.
Cancer as a multistep process
- Initiation
o Interaction of carcinogen with DNA. Exposure to carcinogens, e.g. UV light →
reversible i
- Promotion
o Selective growth advantage (free radicals) → reversible
- Progression
o Enhanced cell division (additional mutations) → reversible
- Malignant conversion
o Full blown cancer → malignant
DNA mutagenesis and carcinogenesis
- Radiation
o Gamma and X-rays → low linear energy transfer
o Particular radiation (protons, neutron, electrons) → high linear energy transfer
, - Non-ionising radiation (UV light)
o Dimers: covalent linkages between adjacent pyrimidines in DNA. Covalent linkages
are unbreakable.
100,000 genomes project
- Sequencing of 100,000 genomes from 70,000 individuals
- Aim
o Creation of new genomic medicine service for the NHS
o New diagnostics
o New treatments – individualised methods of treatment
, Discovery of tumour suppressor genes
Discovery
- The introduction of a virus into a cell added new genetic information. Therefore, it was
thought that carcinogenesis must be due to the gain of genetic information
- Biologists also believed that if malignancy was caused by somatic mutation, the nature of
malignancy implied that such mutations were dominant
o Barski & Cornefert (1962) fused a highly malignant mouse cell line with a mouse cell
line of lower malignancy → hybrid cell line retained the aggressive malignancy →
malignancy must be dominant
o Hybrids had fewer chromosomes that parent cells suggesting loss of genetic
information. Harris (1969) proposed that chromosome loss was central to
carcinogenesis
- Harris fused highly malignant Ehrlich tumour cells with mouse A9 cells which produced a few
tumours. He injected into mice and looked for development of tumours. Tumours developed
after a very long lag period compared to Ehrlich tumours. Those that did develop exhibited
chromosome loss → carcinogenesis was a recessive trait
Retinoblastoma
- Alfred Knudson studied children with eye tumours (retinoblastoma). He noticed two groups
of patients
o Familial form – early development of tumours with bilateral disease (both eyes)
o Sporadic form – late development and no family history with usually single eye
involvement
- For a tumour to develop, mutations were needed in a gene involved in this disease
(retinoblastoma gene). Normally, two copies of the gene are inherited, one from each
parent.
- In sporadic disease, mutations were needed in both copies. In familial disease, one mutated
copy is inherited from a parent, but mutation of both copies are needed for disease to
develop → more likely to develop retinoblastoma.
o Therefore, two hits are required for development of the disease → called Knudson’s
“two hit” hypothesis
o Two hit hypothesis – there must be two mutation sin order for cancer to be
initiated. One mutation taking out the first allele and another mutation taking out
the second allele.
- Loss of heterozygosity
The retinoblastoma gene
- The RB transcript is 5264bp long, encoded in 27 exons, located on chromosome 13q14 and
encodes a 105 kDa protein
- The pRB protein is constitutively expressed in most normal cycling cells.
- pRB is subject to phosphorylation during specific cell cycle phases
o Hypophosphorylated during early cell cycle
o Hyperphosphorylated as cells go into S-phase and DNA synthesis
- Principal role is to regulate transition from G1 into S-phase
- Signalling proteins such as cyclins and cyclin dependent kinases (CDKs) mediate and control
the phosphorylation of pRB. When cells begin cycling, cyclin D and cyclin E are induced in
association with CDK4 and CDK6. These complexes bind to and preferentially phosphorylate
pRB. A critical level of phosphorylation commits the cell to enter S-phase.
- The transcription factor E2F is inactive when bound to pRB. When pRB is phosphorylated,
E2F is released. Transcriptionally active E2F increases the activity of target genes required
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