Oncogene translates as ‘cancer causing gene’². Why would the body have genes that cause cancer? There are normal genes in the body called proto-oncogenes. The products of these genes regulate the cell proliferation and growth and these genes are closely regulated. Oncogenes can be turned on because of a mutation in a proto-oncogene or a virus inserting an oncogene into the cell. Products of oncogenes behave abnormally, or are over-expressed and cause cells to divide independently of the normal body signals. Oncogene products can act in the cytoplasm of the cell to disrupt the signalling of growth factors or in the nucleus to alter the control of transcription of genes.

TUMOUR SUPPRESSOR GENES

Tumour suppressor genes are also part of the normal cell’s DNA, but they have the opposite function to proto-oncogenes in that they suppress growth. In the normal body, old cells need to be able to die to be replaced. Such cells are programmed to die which is a process called apoptosis. The products made by tumour suppressor genes (e.g., p53the Rb gene) are involved in influencing the cell cycle. For example, Rb gene products are necessary for the transition from G₁ to the S phase of the cell cycle that was discussed earlier. p53 increases if there is DNA damage and can halt the cycle to either allow DNA repair to occur or to induce apoptosis. It is clear that either loss of a tumour suppressor gene or its mutation or inactivation could result in a cell that does not die when it should, that is, it transforms the cell into a cancer cell. Furthermore, anti-cancer therapies will try to induce apoptosis. If p53 is intact, higher rates of therapy induced apoptosis would be expected.

GROWTH FACTORS

Growth factors are signals that reside outside the cell and many are products of oncogenes. To impact on cell function, growth factors have to attach to a receptor (like a key fitting into a lock) that straddles the membrane of a cell and activates transmembrane proteins called tyrosine kinases. Activation of these proteins initiates a cascade, enabling the signal to travel from the outside of the cell, through the cytoplasm of the cell to the DNA in the nucleus of the cell, where the reading of genes and the duplication of DNA are controlled. This flow of information is called signal transduction. Having a receptor activated by a growth factor can cause proliferation of a cell or differentiation, or migration of the cell, or confer protection from programmed cell death and sometimes even growth arrest. These signalling pathways are not just single events but multiple paths interacting with each other, and the outcomes can differ, depending on the duration and intensity of the signals and the cooperation between pathways ³. This creates some overlap in signalling pathways, which explains why a minimum of 4 or 5 hits on oncogenes or tumour suppressor genes (which code for the growth factors, their receptors and the signal transducers) are needed to disrupt the normal regulation of cell function which then leads to cancer.

TUMOUR GROWTH

Theoretically, a cancer cell population that keeps dividing into two daughter cells will exhibit exponential growth, with doubling of the cell population after every cycle. If this were the case, after 30 cycles from each cell, there would be 2³⁰ (10⁹) cells or 1 gram (or 1 cm³) of tissue. This is the minimal size for detection of a tumour on current scanning machines. Only ten more doublings would produce 10¹² cells or 1 kg tissue, which could be lethal. However, since some cells will die if a tumour outgrows its blood supply and some will differentiate into non-dividing cells so the rate of growth will not be as rapid. In fact, the peak growth rate of a tumour occurs just before it is clinically detectable and then slows down. This pattern produces what is known as a Gompertzian growth curve, where the growth fraction (the number of dividing cells) of the tumour declines over time ⁴.

However, when a tumour is treated, a constant percentage of cells is killed (log kill), and as the tumour shrinks, its growth fraction can increase and the rate of growth increase. The observed time in which solid tumours actually double their volumes is variable. Lymphomas usually have volume doubling times of 22 days, while a bowel cancer might be 90 days and some adenocarcinomas may double only each year. The clinical importance of this is that tumours will have started to grow months to years before they are detected, so that any event that a patient may cite as occurring immediately before the detection of a tumour (e.g., trauma), cannot be the causal factor.

Various methods are used to measure the growth of tumours. One method is radioactive labelling of a DNA base (thymidine) and measuring how much of the label is incorporated into the DNA of the tumour. The non-invasive methods involve using proteins made at various stages of the cell cycle as markers of proliferation. One example would be the cyclins mentioned earlier which appear at checkpoints in the cell cycle.

ANGIOGENESIS

A tumour could not grow beyond 2–3 mm ² without new blood vessels growing to provide it with nutrients. Angiogenesis is the growth of new blood vessels from existing vessels and occurs during processes such as the healing of wounds. Cancer cells can produce angiogenic factors (such as vascular endothelial growth factor and basic fibroblast growth factor) that stimulate the formation of new blood vessels. These are balanced with anti-angiogenic factors (such as angiostatin and endostatin)⁵.

Several things happen in response to an angiogenic stimulus. The cells around the outside of blood vessels shrink back and the endothelial cells that line blood vessels release proteases (such as the matrix metalloproteinases), which break down the supporting matrix around the vessels. New endothelial cells can migrate into the degraded matrix and form tubes that bud off from the blood vessels to form new blood vessels. Some of the regulation of this occurs when oncogenes in cancer cells are activated, particularly the ras oncogene. Macrophages in the extracellular matrix release angiogenic factors and the cell adhesion molecules (integrins and cadherins) are involved in the adhesion, migration and control of the endothelial cells. If the cancer grows too quickly for the new blood vessel formation, only the outer rim of the cancer will be viable and the inner and middle areas, lacking blood supply, will become necrotic.

These new blood vessels not only provide a means for nutrients to reach the cancer cells but also provide a mechanism for the cancer cells to escape from their original site of growth out into the blood stream so they can spread throughout the body. This process of new blood vessel formation also happens with these secondary deposits of cancer cells.

METASTASES

One of the features of cancer is its ability to spread from one part of the body to another ⁶. One way that tumours can cause problems is to directly invade from the primary site into surrounding tissues. Cancer cells can also travel via the blood vessels or via lymphatic vessels which are drainage channels between lymph nodes but also connect with the blood vessels. Another route of tumour invasion is transcoelomic spread, where cancer cells can invade the peritoneal cavity or pleural space.

Not all cells in a cancer are capable of spreading, but every time a cancer divides, it is more likely that it will produce a colony or clone of daughter cells with the ability to metastasise. Even if these cells reach the bloodstream, there is no guarantee that a secondary deposit will result since it appears that not only is there a need for the correct type of cells (seeds), but also to find the right organ (soil) in which to grow. The primary cancer can metastasise to different organs, but there are established patterns of spread for many cancers which means the metastases must only be able to survive in certain environments. The cells also need to be able to survive the journey, migrate to an area and be accepted by surrounding cells.

For tumours to spread, the cancer cells must be able to detach themselves from each other. This is regulated through adhesion proteins (cadherins) on the cells’ surfaces which then attach to the membrane separating them from the adjacent extracellular matrix where they want to go. This basement membrane is a scaffold with collagen fibres containing proteins such as laminins and a coating of fibronectin. The cancer cells bind to these fibres in preparation for breaking through. There are many adhesion molecules, such as immunoglobulin adhesion molecules, intergrins and selectins, which all take part in regulating the binding of cells to each other and to the extracellular matrix through which they must move. Cancer cells move through the matrix in response to chemicals in the tissues which attract them or which they produce themselves in order to move independently. The cells move by a series of adhesion and release of the surrounding tissues. They can move into blood and lymph vessels or directly into adjacent organs.

In order to invade surrounding tissues, enzymes called proteases must dissolve the tissue to create a passage. Such enzymes are the serine proteases, the matrix metallaoprotienases and the aspartyl proteinases such as cathepsin D, and there must be a balance between activating and inhibiting factors to regulate this process. Interestingly, cathepsin D concentrations are a prognostic factor in breast cancer and all of these processes are potential targets for the development of new anti-cancer agents.

When the cancer cell reaches another organ it must move from, for example, a blood vessel into the organ in a reverse process to which it escaped. There are many stages of the journey all regulated by adhesion molecules and proteases. Having looked at factors that affect the development and growth of cancer, let us look at the causes of cancer.

WHAT CAUSES CANCER?

In the chain of events that results in cancer, the initiating event may be a change in a single gene in a cell. A person can inherit a defective gene. An example is the discovery that inherited mutations in the BRCA 1 or 2 genes (breast cancer 1 and 2 genes) make women susceptible to developing breast cancer ⁷. Carcinogens can also come from the environment, such as the cancer causing agents found when tobacco is burned. In the early stages a cell may not be cancerous, but other agents may promote the process by causing the altered cells to form lumps (such as occurs with polyps in the bowel) which progressively become larger and more abnormal. The agents that promote this change may be viruses or chemicals or even hormones in the case of breast and prostate cancer. Eventually, the pre-cancerous cells will become malignant, either by loss of genes when dividing or further exposure to tumour-promoting agents. Not all damage to the DNA results in the eventual development of cancer, as sometimes, cells can repair the DNA before becoming cancerous. We see then that cancer is caused if a cell is genetically susceptible, perhaps because of inheriting a mutated gene and then, either further mistakes occur when it divides, or agents in the environment trigger the cell to become malignant over time.