An Essential Introduction to Cancer An Essential Introduction to CancerCancer is defined as the uncontrolled invasive growth and division of cells in the body, known in the trade as hyperplasia. "Such `non-altruistic' mutation, competition and natural selection of a population of such transformed cancer cells, within a cellular community leads eventually to the destruction of the entire community."
Mutations are alterations in the sequence and structure (and therefore information content) of a DNA sequence. This may result in the abnormal regulation of gene expression or in defective gene products or proteins. As many as 20% of individuals in the prosperous world will die of cancer. However, it is important to realise that cancers result from the chance occurrence in one cell of several independent accidents or mutations- A SINGLE MUTATION IS INSUFFICIENT TO CAUSE CANCER. Generally between 3 and 7 random and independent mutations are required to cause cancer and the risk of developing a cancer therefore increases with age.
WHAT FACTORS PROMOTE CANCER? WHAT CELL REGULATORY MECHANISMS ARE AFFECTED? CAN CANCER BE INHERITED? WHAT STRATEGIES CAN BE USED TO TREAT CANCER?Normally stem cells that continuously divide produce daughter cells that have a limited capacity to divide. Such daughter cells divide until they are inhibited by contacting neighbouring cells and/or become specialised to enable them to play a particular role in the body, a process called differentiation. Normally when a stem cell divides into two it produces one daughter cell and renews itself. When either a stem cell fails to produce a daughter cell after dividing, or the daughter cells fail to reach their final form there is excessive cell division and a cancer, or tumour results.
Some agents are called CANCER INITIATORS because they mutate the nucleotide sequence encoding the information content of DNA. CHEMICAL CARCINOGENS cause local changes in the nucleotide sequence of DNA. For example 2-napthylamine was used extensively in the chemical industry earlier in this century and increased the incidence of bladder cancer in distillers after prolonged exposure.
IONISING RADIATION such as X-rays and ultraviolet light also cause mutations. For example UV-light causes the dimerisation, or chemical coupling, of adjacent pyrimidine (nucleotide) bases. VIRUSES introduce foreign DNA into host cells which may alter the level of expression of regulatory genes, introduce mutated copies of normal cellular genes into the host cell DNA or inactivate genes by inserting into the middle of them.
Some mutations can occur SPONTANEOUSLY, for example the nucleotide base cytosine deaminates to uracil a different nucleotide base that is found in RNA.
In addition there are CANCER PROMOTING agents such as HORMONES and GROWTH FACTORS that cause growth promoting signals that may trigger tumour formation in cells which a tumour has been initiated.
Often there is a long incubation period between tumour initiation and cancer formation. For example LUNG and BLADDER CANCERS usually develop between 10 and 20 years after exposure to cigarette smoke or to 2-napthylamine, whereas LEUKEMIAS were not frequently found until 5 years after the atom bombing of Nagasaki and Hiroshima.
The next slide shows that the incidence of breast cancer in both white and black women has steadily increased over the past decade, raising the possibility that some unknown environmental or dietary factor is initiating or promoting the formation of cancers in the glandular epithelium of the breast.
Mutations that result in defects in genes that are responsible for cellular DNA REPAIR and SYNTHESIS increase the likelihood of future mutations occurring. The overactivation of genes that REGULATE CELL DIVISION such as the c-src protein tyrosine kinase also increase the likelihood of a cancer occurring. The inactivation of tumour (cancer) SUPPRESSOR genes similarly tips the balance in favour of the production of a cancerous cell. For example the inactivation of both copies of the Rb1 tumour suppressor gene very frequently initiates tumour formation in the growing retina of the eye in children.
PROTO-ONCOGENES are normal cellular regulatory genes, such as those that regulate cell division, DNA synthesis and repair and suppress tumour formation, and ONCOGENES are altered versions of these genes that have the potential to cause cell transformation.
Some viruses which encode powerful promoters in their genetic information transform cells by inserting these promoters in front of normal regulatory PROTO-ONCOGENES causing abnormally high levels of expression of the proto-oncogene product or protein in the cell. Retroviruses can acquire proto-oncogenes within their genetic information by accident, an event that is often associated with alterations in protein structure and/or activity thereby producing ONCOGENES that may be inserted into the DNA of infected cells to promote cell transformation.
Shown here are a few of the many oncogenes that have been identified and the retroviruses and tumours in which they can be found. Several of these oncogenes are related to receptor activation and signal transduction mechanisms. For example v-src is a protein tyrosine kinase found in the Rous sarcoma virus that induces transformation of chicken fibroblasts, the v-sis oncogene is found in the retrovirus that causes sarcoma in the monkey by encoding a growth factor whose excessive secretion promotes cell transformation. Ras encodes a form of G-protein that is involved in cell signal transduction and is found in human epithelial tumours or carcinomas, and myc encodes a DNA binding protein that is found in retroviruses that cause human lymphomas, which are cancers of hemopoietic cells.
The next slide shows how a retroviral DNA from the Avian Leukemia Virus can integrate into human DNA near a regulatory proto-oncogene such as the c-myc gene that encodes a DNA binding protein that is not expressed in adults, causing the gene's message to be transcribed because of the chance proximity of the powerful viral promoter present in the right LTR region to the gene. This mRNA is translated into a protein which leads to cell transformation. Alternatively the myc oncogene may be encoded within the retroviral DNA and automatically transcribed under the influence of the left LTR promoter region.
With conventional treatments not all cancer cells are destroyed: In CHEMOTHERAPY drugs such as methotrexate and vincristine are used to inhibit cell division, but these drugs are NOT selectively toxic for cancer cells, and as cancer cell populations can become resistant to chemotherapeutic drugs through mutation.
RADIOTHERAPY is associated with widespread tissue damage and as with SURGERY does not remove all tumour cells.
THE IMMUNE SYSTEM CAN BE HARNESSED TO TREAT CANCER. One such strategy involves the injection of cell-surface antigen DNA called HLA-B7 into tumours to help T-cells to recognise cancer cells and another involves using so-called `superantigens' fused to antibodies that recognise tumour antigens to direct T-cells to attack cancer cells.
This next slide shows how the cytotoxic or killer T-cell activity can be turned against tumour cells. Tumour cells usually express mutant proteins that are recognised as antigens by killer T-cell receptors, but this however is not sufficient to stimulate the destruction of the tumour cell, as the tumour cells lack the necessary costimulatory signal to promote killer T-cell activity. By injecting the cell-surface antigen DNA for HLA-B7 into tumours researchers hope to provide this necessary co-stimulatory molecule for the killer T-cell CD28 receptor and thus generate a signal that instigates the destruction of the tumour cells.
Another strategy is to couple antibodies that recognise tumour antigens to so-called superantigens that are of microbial origin and have the ability when presented by macrophages to activate a large proportion of the body's T-lymphocytes regardless of their inherent antigen specificity. Such superantigen-monoclonal antibody hybrids may therefore be used to direct the activated killer T-cells to destroy the superantigen and also the tumour cell to which it is bound.
Bowel cancer is world's 3rd most common cancer, causing 60,000 deaths in US alone every year. Mutations of the ras oncogene are found in 50% of bowel cancers. DNA amplified from the cells of the colon can be probed for ras mutations to provide an early warning of cancer formation to allow intervention before the bowel cancer becomes untreatable.
Breast cancer is the commonest cancer in women in the industrialised world. In the UK there are 15,000 deaths from breast cancer and 4,500 deaths from ovarian cancer every year. In the general population 10% of all women will eventually develop breast cancer. However, 82% of women who have a mutation in the BRCA1 gene will develop breast or ovarian cancer by the age of 70. This indicates that a mutation in this gene will predispose an individual to develop such cancers. As many as 1 in 150 of the population may carry one faulty copy of the BRCA1 gene and 600,000 women in the US alone may be carriers. Two such copies of the altered BRCA1 gene, which some believe may be a tumour suppressor gene, is a first link in the chain of transformation of normal cells to tumour cells. This raises the possibility of screening the general population for the defective BRCA1 gene, and should such a test become generally available it may be considered unethical to withhold it. This raises several concerns. The screening and counselling of carriers and health care will be expensive. He who finds, profits. The laboratory that first sequences the BRCA1 gene may develop a patented commercial screening test, which will be lucrative for the producer and expensive for the market place, a cost burden that, like AZT, the health services may be obliged to meet.
On the human side prospective mothers ask why they should consider screening or terminating a pregnancy for a disease that may strike later on in life or not at all. Many feel that they would rather not know, except perhaps the life insurance companies who of course minimise their risk in formulating policies.
