THE HALLMARKS OF CANCER
In 2000, two leading cell biologists, Douglas Hanahan and Robert Weinberg, published a seminal paper entitled ‘The Hallmarks of Cancer’ summarizing the changes that are both necessary and sufficient to produce cancer. A cancer cell differs from normal cells in that it divides in an unregulated fashion. In addition, cancer cells have the ability to spread to and invade other parts of the body. Hanahan and Weinberg summarized the processes that must occur in the cell in order for it to be transformed from a normal, law-abiding member of cellular society into a dangerous outlaw. These changes, illustrated in Figure 1, are characterized as:
- Self-sufficiency in positive growth signals;
- Lack of response to inhibitory signals;
- Failure to undergo ‘programmed cell death’ to eliminate faulty cells;
- Evasion of destruction by the immune system;
- The ability to grow in and destructively invade other tissues;
- Ability to sustain growth by generating new blood vessels.The first two of these are reasonably self-explanatory and lead to unregulated growth. The third is less obvious and is linked to the development process. If all cells simply grew and divided, it would not be possible, for example, to form hollow tubular structures such as the gut or blood vessels. To do this, certain cells must be deleted from the growing organism as the needs of the growing structure dictate. This process, already mentioned, is called apoptosis, and is a key cellular function. Apoptosis is also a method that the organism uses to get rid of faulty or malfunctioning cells such as those nearing the end of their lifespan that need replacing. Cancer cells are by definition abnormal and thus should be self-deleting. Failure to undergo apoptosis is thus key to the transformation from an abnormal cell into one with limitless replicative potential. A further feature of apoptosis is that cells damaged by chemotherapy or radiotherapy are frequently not killed outright, but merely ‘mortally wounded’. The subsequent death of the cell is often by apoptosis, illustrating that the evasion mechanism is not completely shut down, even in the cancer cell. Increasing resistance to apoptosis is, however, one way in which the cancer cell evades destruction by chemotherapy or radiotherapy. Understanding apoptosis is unsurprisingly therefore one of the major areas of cancer research.Further distinguishing features of cancers are their ability to grow and to invade other tissues in the body while avoiding destruction themselves by the immune system. The immune system can be regarded as a sort of cellular police force that identifies intruders such as bacteria and eliminates them. As cancer cells are abnormal, the immune system should be able to identify and destroy them. Evasion of this process is therefore essential to cancer. As already indicated, the growth and development of cells, tissues, and organs are very finely regulated to ensure the correct sort of cell grows in the correct place and time in the organism. One key aspect of cancer growth is the acquisition of the ability to grow in the wrong place, and this is a feature that distinguishes a malignant tumour from a benign one, which can grow but not spread or invade. It should be noted that benign tumours can still present severe consequences, for example, an acoustic neuroma is a benign tumour of the auditory nerve that transmits signals from the inner ear to the brain. The tumour will progressively enlarge, causing deafness and balance problems, without ever spreading elsewhere.The final hallmark of cancer is the ability to grow a new blood supply. Any collection of cells larger than around one-tenth of a millimetre across needs a blood supply. As a new tumour grows, it must, therefore, acquire the ability to stimulate blood vessel growth. The blood vessel growth of tumours is often haphazard and turns out to use genes not involved in the maintenance of normal blood vessels. The process is known as tumour angiogenesis, and because it differs from normal angiogenesis, it has become an important target for cancer drug development. If it is possible to knock out the blood supply of cancer, further growth is prevented. One of the most successful of the new generation of targeted molecular therapies, bevacizumab (Avastin), works by targeting this process.