The revisited hallmarks

In the 11 years since the first publication on the hallmarks of cancer, cancer research has progressed, and two emerging traits can now be added to the list of hallmarks of cancer. They are one, deregulated cell energy metabolism, and two, avoiding immune destruction. In addition, two enabling characteristics, which are not in themselves necessary for a cell to become a cancer cell but greatly hasten the process, have been described. These are one, genome instability, or increased mutation rates, and two, tumour-promoting inflammation.

The description of these features, together with the understanding that tumours are not just a mass of proliferating cells but complex tissues comprising tumour cells as well as new blood vessels, tumour associated fibroblasts, and immune cells, has shaped a new understanding of cancer development. Let’s look firstly at how the cell’s energy metabolism can be disrupted. Large scale cell proliferation requires changes in cell metabolism to provide the fuel for the large building project that is tumour growth. Normal cells use a mechanism of energy production in which glucose is used to make energy via pyruvate, in a process called mitochondrial oxidative phosphorylation.

Instead, cancer cells produce very little pyruvate and favour glycolysis, which is normally used by cells in anaerobic conditions when there is very little oxygen. The reasons for cancer cells to switch metabolism are not fully understood, as glycolysis is much less efficient at producing ATP, or energy. But it is thought that the advantage of glycolysis is that it allows cells to use glucose as a building block for amino acids and nucleic acids as well as energy. Since cancer cells are able to reprogram energy metabolism even in the presence of oxygen, it has been termed aerobic glycolysis. Cancer cells reprogram cell metabolism by changing gene expression to alter the metabolic enzymes present.

However, since aerobic glycolysis is far less efficient at producing energy, cells must adapt in other ways. For example, they upregulate transporters of glucose to increase the amount of glucose available. Furthermore, a resulting product of glycolysis is lactate. And in some tumours, cells near the vasculature utilise glycolysis, while other cells further from the vasculature use lactate as a substrate for their metabolism. The second trait mentioned was that tumour cells must avoid immune destruction. Immune surveillance is a normal process by which newly formed cancer cells are identified, targeted, and destroyed by the immune system. And it’s believed that the large majority of nascent tumours are destroyed in this way.

This is supported by the fact that certain cancers are more common in immunocompromised patients. Tumours must therefore escape immune surveillance in order to be able to keep growing. The immunogenicity of tumour cells is caused by the mutations they have acquired. Some cancer cells are naturally less immunogenic and therefore will be less obvious to the immune system. Others defend themselves from the immune system by expressing anti-inflammatory factors, which disable immune cells, or by attracting immunosuppresive immune cells, which themselves disable killer immune cells. In the recent, “Revisited Hallmarks” article, Hanahan and Weinberg have also described tumour enabling characteristics. These enabling characteristics are not absolutely necessary for cells to become cancer cells, but enable them to do so faster than they would otherwise.

As we will look at in more depth later in the course, normal cells prevent DNA damage through regular DNA maintenance; and detect DNA damage and respond either by repairing the damage, if possible, or through the induction of cell death or growth arrest such that most mutations are not propagated in healthy cells. As the cancer hallmarks are generally obtained through mutations, a deficiency in the DNA repair mechanism will increase the rate of mutations and therefore the likelihood of a cell to accumulate the above mentioned hallmarks. Cancer cells can achieve this through an increased sensitivity to DNA damaging agents or by defects in DNA damage detection and responses.

This means that mutations are not repaired, or do not lead to the death of the cell, leading to the accumulation of mutations faster than would be seen in a healthy cell. The second enabling characteristic is tumor-promoting inflammation. It has been known for a long time that tumours are infiltrated with numerous immune cells, but these were thought to be part of the attempt by the immune system to destroy the tumour. However, recent research has shown that some inflammatory cells actually help tumour cells. The inflammatory cells supply growth factors, which sustain proliferative signalling, survival factors, and proangiogenic factors. In addition, they produce extracellular matrix-modifying enzymes, which improve invasion, metastasis, and angiogenesis.

Inflammatory cells can therefore offer huge help to nascent tumour cells to become fully-fledged cancers. In summary, we have seen that for healthy cells to become cancer cells, they require the acquisition of most or all of the eight hallmarks and are helped by two enabling characteristics. These allow cancer cells to escape from the normal regulation and to recruit other non-cancer cells, which are essential in building the tumour environment.