Background/Hallmarks Of Cancer
It is important first to distinguish between the terms tumour and cancer (neoplasm). A tumour refers to the abnormal growth of cells and may be characterised as benign or malignant. A benign tumour is deemed to be less severe than a malignant tumour, and treatment of such tumours is generally straight forward. Sometimes, benign tumours do not require any therapy and are simply monitored. A malignant tumour, on the other hand, is one that is capable of disseminating tumour cells throughout the body. A malignant tumour is considered to be cancerous and is requires a more complicated treatment plan.
In 2000, Weinberg and Hanahan published an article outlining six key hallmarks of cancer cells (Figure 1) . In 2011, they published a follow-up article and extended the list to include four additional hallmarks . To understand what makes a cell cancerous, this section will briefly consider each hallmark in turn.
- Self-sufficiency in growth signals: cells do not spontaneously divide (normally). Instead certain chemical messages (e.g: in the form of hormones) are required. These are typically produced by an external organ and are delivered to the target site by the blood stream. In addition, other chemicals, or a reduction in the concentration of a division-stimulating chemical may halt cell division. Cancerous cells may be capable of continuous cell division for a number of reasons:
- They may be able to produce the "division-stimulating" signals themselves. This is called autocrine signalling.
- The pathways regulating cell division may be permanently activated and not require an external stimulus.
- The "off-switch" mechanism may be dysfunctional; hence external stimuli may be required to activate cell division but this process can no longer be controlled or switch off.
- No longer sensitive to anti-growth signals:
- As mentioned, there are both on and off-switches for cell division. Tumour suppressor genes are primarily responsible for halting cell division and preventing it from getting out of control. If a mutation causes tumour suppressor genes to become dysfunctional, cell division may no longer be controllable.
- Another mechanism for controlling cell division is referred to as contact inhibition. This process will halt cell division if cells become too tightly packed together. Cancerous cells are no longer subject to contact inhibition, so cells will continue to divide irrespective of their neighbouring environment.
- Evading apoptosis: Apoptosis is a mechanism by which cells are programmed to die if they become damaged. It is a carefully controlled process and is not considered to be pathological. A number of different stimuli promote cell death, including hypoxia (deficiency in oxygen concentration in the cell surroundings) and DNA damage (as a result of mutations). Both conditions may be present in the pre-cancerous stage. Cancerous cells, however, are capable of evading apoptosis and will persist despite being highly abnormal.
- Angiogenesis: angiogenesis refers to the development of new blood vessels, to support an increased demand for oxygen and glucose. As cancer cells are dividing rapidly, their metabolic needs are higher and they require an increased oxygen supply. Normally angiogenesis is a tightly controlled process. Cancerous cells are capable of stimulating blood vessel development on their own, which is essential for their persistence and survival.
- Indefinite cell division: most DNA strands are capped with a repetitive sequence of nucleotides (TTAGGG) on either end, called telomeres. This string may be repeated up-to 2500 times. Cell division in most cells is limited because the telomeres shorten after each cell division. Once the telomeres reach a critical length, the cells will be incapable of further division and will die. The vast majority of cells are incapable of "re-growing" the telomeres. Cancer cells, however, are capable of re-growing the telomeres as they can activate an enzyme called telomerase. Telomerase will extend the telomeres and prevent them from reaching the critical length. As such, the telomere length will never shorten sufficiently to initiate cell death. Thus, cancerous cells are capable of indefinite cell division.
- Metastatic capacity: metastasis refers to the spreading of cancerous cells throughout the body. In order to metastasise, cells must be able to invade the circulatory system, and survive in the blood stream (which is very challenging for normal cells). They must also be able to deposit at a distant site and grow, and divide, there.
In recent years the following characteristics were also deemed to be properties of cancerous cells :
- Abnormal metabolism: cancer cells may struggle to obtain sufficient energy from metabolism of glucose alone. As such, cancer cells may utilise alternate metabolic pathways as a means of generating energy. For example, tumours may metabolise lactate rather than glucose to produce ATP: the energy currency of the cell .
- Evading the immune system: the immune system functions to recognise (apparently) foreign substances. Cancer cells, due to the genetic mutations present, may produce proteins that would be recognised by the immune system as foreign. In order to survive, cancerous cells must avoid tumour detection by, for example, de-activating certain components of the immune system that are programmed to destroy them. The immunology of cancer is a fairly young area of research and it is likely that much more will become known over the next few years.
- Inflammation: inflammation has long-been connected with tumours. However, recent evidence suggests that the immune cells that cause the inflammatory response, may in fact be promoting tumour development and malignant change of benign tumours.
- Genomic instability: healthy cells have an unbelievable ability to detect and fix DNA defects. A hallmark of cancerous cells is that their ability to identify and repair these defects is worse. This property arises because there is a selective advantage for cells with a lower capacity to correct genetic defects, in cancer. In addition, it is likely that cancerous cells are more sensitive to mutagenic agents; thus, the rate at which mutations develop is higher than in normal cells.
- Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell 2000;100:57–70. DOI:10.1016/S0092-8674(00)81683-9.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. DOI:10.1016/j.cell.2011.02.013.
- Kennedy KM, Dewhirst MW. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 2010;6:127–48. DOI:10.2217/fon.09.145.