THE CANCER CELL
Making a simple statement about what distinguishes a normal cell from a tumour cell is straightforward – it’s mutations. Even when the initiating factor is infection by viruses that are not directly mutagenic, the effects of their oncogenic proteins are equivalent to mutations that occur in genes that are critical regulators of proliferation and apoptosis. Similarly, mutations also arise from the effects of chronic bacterial infection. Furthermore, specific mutations or groups of mutations are often associated with some cancers. This was first established for some hereditary colon cancers and it is now possible, for example, to classify acute myelogenous leukaemia and other cancers into sub-groups reflecting their behaviour on the basis of patterns of mutations and to predict whether metastases will develop from primary breast tumours. Revealing mutational signatures may permit differentiation between cancers that are clinically indistinguishable, provide information about how tumours develop and, of course, assist in the rational design of drugs to target abnormal gene products.
The requirement to accumulate a specific hand of mutations to drive tumourigenesis is, of course, the reason why most cancers don’t appear until late in life. If this idea of cancers selecting groups of mutations, so to speak, and using them to their advantage sounds familiar it’s because it closely parallels the concept of Darwinian evolution. That is, the development of a tumour cell may be compared with the evolution of a species: the driving force for both comes from the acquisition of specific mutations and the selection of those helping survival and proliferation until the cancer cell gradually acquires a growth advantage over normal cells. Cancer always requires its host to survive (it’s a parasite) but eventually it is capable of diverting nutrients from the host to support its own uncontrolled expansion. Thus the cancer patient may continue to eat normally but nevertheless, lose weight – the observation that led Warburg to call it the ‘wasting disease’ some 80 years ago.
The extraordinarily detailed molecular picture of cancer that is now emerging derives from a massive archive of cellular information that has given us a reasonably clear picture of the phenotypic changes associated with tumour cells and their neighbours as cancers evolve (Fig. 1).
1. Eight main features of cancers.
These may be classified as follows:
- They have a reduced dependence on external signals for growth.
- They ignore external signals telling them not to grow.
- They avoid suicide, a powerful anti-cancer strategy when cellular DNA is damaged.
- They can grow indefinitely.
- They can induce the formation of their own blood supply.
- Their metabolism is perturbed relative to that of normal cells.
- They may promote inflammation and activation of an immune response.
- They can spread from their primary site to other places.
One definition of a multicellular organism is an aggregate of cells that communicate with each other so that each knows how to behave to permit the entire organism to work. One critical and recurrent question for an individual cell is whether to proliferate, that is to grow and divide into two daughter cells, or whether to remain in a quiescent, non-proliferating state. All normal cells rely on cues from the rest of the animal to make this decision. These cues come in the form of molecules that are either directly presented to the target cell by adjacent cells, or that diffuse either from nearby cells or from further afield (via the bloodstream, for example). Both positive (‘divide’) and negative (‘don’t’) signals contribute to the outcome (Fig. 2).
2. Genetic signals in cancer development.
A key feature of a cancer cell is that it has to a substantial degree become independent of these molecular cues. One of the main ways cancer cells achieve this independence is by changing their internal wiring so that they can function as if they were being told to divide when they are not. In addition, aberrant expression of cell-surface receptors may render the cell hyper-responsive to growth factors. As ever in cancer, it’s a little bit more complicated than that because, rather than completely switching off contact with the outside world, tumour cells can persuade their neighbours to change sides, so to speak; that is, normal cells adjacent to a tumour start to make factors that promote growth of a tumour itself. At the same time, as part of their re-wiring, tumour cells may even start to make their own growth-promoting factors and we’ll return to these points shortly in the tumour microenvironment.
So a critical point about cancer cells is that they change the way in which they sense the world around them and they also change the way their environment sees them. By so doing they make themselves able to grow in a way that is largely independent of that world.