A Cancer primer
© R.J.Walters 1999 A Cancer primer
© R.J.Walters 1999
Cancer is the uncontrolled invasive growth and division of cells in the body (hyperplasia);
"The `non-altruistic' mutation, competition and natural selection of cells within a community leads to the
destruction of the entire community."
Mutations are alterations in the sequence and structure (and therefore information content) of a DNA sequence.
20% of individuals in the prosperous world are expected to die of cancer.
Cancers result from the chance occurrence in one cell of several independent accidents - A SINGLE MUTATION IS INSUFFICIENT TO CAUSE CANCER.
Generally 3-7 random and independent mutations are required to cause a cancer, and the probability of developing a cancer therefore increases with age.
WHAT FACTORS PROMOTE CANCER ?
WHAT CELL REGULATORY MECHANISMS ARE AFFECTED ?
CAN CANCER BE INHERITED ?
WHAT STRATEGIES ARE USED TO TREAT CANCER ?
WHAT FACTORS PROMOTE CANCER ?
CHEMICAL CARCINOGENS:
Cause local changes in the nucleotide sequence of DNA; e.g. 2-napthylamine, used in the chemical industry in early 20th century, increased incidence of bladder cancer in distillers after prolonged exposure.
IONISING RADIATION:
X-rays and ultraviolet light cause mutations; e.g. UV-light causes dimerisation of adjacent pyrimidine (nucleotide) bases.
VIRUSES:
Alter gene expression; import mutated cellular genes into host cell DNA; inactivate genes by inserting into them.
SPONTANEOUS: Deamination of the nucleotide base cytosine to uracil.
CANCER PROMOTERS: include hormones, steroid hormones and growth factors.
There is often a long incubation period from between tumour initiation and cancer formation:
e.g.LUNG CANCERS usually develop between 10 and 20 years after smoking starts.
BLADDER CANCER 10 to 20 years after first exposure to 2-napthylamine.
LEUKEMIAS were not frequent until 5 years after Nagasaki and Hiroshima.
Defects in genes responsible for DNA REPAIR and SYNTHESIS increase the frequency of mutations.
e.g. The overactivation of genes that regulate cell division (e.g. c-src protein tyrosine kinase).
Inactivation of tumour (cancer) SUPPRESSOR genes (e.g. inactivation of the Rb1 tumour suppressor gene initiates tumour formation in growing retina of eye).
PROTO-ONCOGENES are genes that have the potential to cause cancer.
ONCOGENES are altered versions of normal cellular regulatory PROTO-ONCOGENES that control cell growth and division:
Viruses insert powerful (viral) promoters in front of regulatory genes causing significant alterations in their level of gene expression.
(PROTO-ONCOGENES) causing over-expression of the gene product or protein.
Retroviruses often acquire proto-oncogenes by accident, sometimes altering their structure and/or activity to produce ONCOGENES that are inserted into the DNA of infected cells.
| Oncogene | Retrovirus | Tumour | Location | Function |
|---|---|---|---|---|
|
src |
Rous sarcoma |
- |
cell membrane |
Tyrosine kinase |
|
sis |
Monkey sarcoma |
- |
secreted |
Growth factor |
|
Ha-ras |
Rat sarcoma |
Human/ rat sarcoma |
cell membrane |
cell signal transduction |
|
myc |
Chicken leukemia |
Human lymphoma |
Nucleus |
DNA binding |
In conventional treatments (1-3) not all cancer cells are destroyed
No drugs are selectively toxic for cancer cells, cancer cell populations are heterogeneous and therefore can become resistant to drugs through mutation.
Associated with widespread tissue damage.
Injection of cell-surface antigen DNA (HLA-B7) into tumours helps T-cells to recognise cancer cells.
`Superantigens' fused to tumour-specific antibodies can be used to direct T-cells to attack cancer cells.
Bowel (colon) cancer is world's 3rd most common cancer:
60,000 deaths in US alone every year.
Ras oncogene mutations are found in 50% of bowel cancers.
The amplification of DNA from colonic cells can be probed for ras mutations to provide cancer early warning to allow intervention before cancer is untreatable.
Breast cancer is commonest cancer amongst women in industrialised world.
In UK there are 15,000 deaths from breast cancer and 4,500 from ovarian cancer each year.
Overall 10% of women will develop breast cancer.
82% of women who have a mutation in the BRCA1 gene will develop breast or ovarian cancer by the age of 70.
As many as 1 in 150 of the population may carry a mutant allele and 600,000 women in the US may be carriers.
Two copies of the altered BRCA1 gene (`tumour suppressor gene'?) is a first link in the chain that leads to cancer cell formation.
Screening of population for BRCA1 gene defect possible. Unethical to withhold test?
Screening, counselling of carriers and treatment will be expensive.
He who finds, profits. A patented commercial screening test will be lucrative for the producer and expensive for the consumer.
Why terminate a pregnancy for a disease that might not strike at all or later on in life.
Who wants the burden of the knowledge anyway? The life insurance companies?