How cancers use enabling characteristics to evolve

Posted by ap507 at May 13, 2016 03:30 PM |
PhD student Mohan Harihar discusses the properties that help make it easier for cells to acquire the ‘hallmarks of cancer’ that promote tumour development
How cancers use enabling characteristics to evolve

Structure of the DNA repair enzyme, Uracil-DNA glycosylase

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The ‘Hallmarks of Cancer’ have been defined as the set of underlying principles driving tumour growth, acquired through a series of steps in a process known as ‘multi-step tumourigenesis’.

Interestingly the gaining of these hallmarks can be enhanced by ‘enabling characteristics’ – additional supporting traits which cancer researchers Robert Weinberg and Douglas Hanahan stated in their revised 2011 review article entitled ‘Hallmarks of Cancer: The Next Generation’.

So what is an ‘enabling characteristic’?

It can best be described as a property a tumorous cell exhibits which makes the attainment and sustainment of the ‘hallmarks of cancer’ more straightforward.  It should be noted that these characteristics play more than just a role in causing tumour growth - they can also progress tumour growth once the tumour has been established.

The two enabling characteristics discovered to-date are referred to as ‘genomic instability’ and ‘tumour-promoting inflammation’.

1) Genomic instability

Genomic instability (GIN) describes the unstable nature of the genetic make-up of cells and the increased propensity for cells to experience unwanted genetic modifications. In most cases this arises through mutations.

Mutations can be influential at any stage of tumour development – it is responsible for starting tumour growth through a series of genetic alterations in key genes, but also occurs throughout the lifetime and evolution of a tumour. In this way mutations play a major role in progressing and making more complex tumours.

In healthy cells, genes are routinely monitored by maintenance mechanisms which recognise and repair DNA damage/defects – a process which occurs every day in all of our healthy cells. By achieving this, the rate of random mutations occurring (which naturally happens in all of our DNA molecules on a day-to-day basis) is minimal.

However during the course of tumour development the rate of mutation often rises markedly, speeding up the acquisition of faulty tumour-promoting genes. These mutations can occur in genes which mediate the maintenance mechanisms – so-called “caretaker genes”.

Such genes include those which serve to identify defects, induce repair pathways, directly repair DNA damage or combat potential cancer-causing agents before they get the chance to cause any damage.

Alternatively these mutations can occur in genes which directly govern cell proliferation – known as “gatekeeper genes”.

Regardless of where the mutation occurs, healthy cellular behaviour will be lost, leading to a “snowballing” effect over time as the genetic instability worsens and becomes more complex.

Two major forms of GIN are ‘numerical chromosomal instability (nCIN)’ and ‘structural chromosomal instability (sCIN)’. Chromosomal instability refers to the misarrangement of chromosomes (packaged structures containing the majority of DNA) in cells as a result of defective cell division.

nCIN, also known as ‘aneuploidy’, is a phenomenon characterised by an abnormal number of chromosomes (either through gain or loss of entire chromosomes) in cells and is constantly observed in multiple cancers. In this state the fine balance of genetic material required for an individual healthy cell to function is disrupted.

Alignment of chromosomes during cell divisionNormally regulatory mechanisms, termed ‘cell cycle checkpoints’, ensure an equal distribution of chromosomes are present in cells following a round of cell division. When these pathways become compromised, there can be an unequal distribution of genetic material.

On the other hand sCIN takes place when chromosomes, or regions of chromosomes, become physically altered in some way – including DNA breakages, ‘deletion’ (loss of chromosome regions), ‘duplication’ (generation of new chromosome regions), ‘inversion’ (reversal in orientation of a chromosomal segment), ‘insertion’  (addition of the individual ‘building blocks’ of DNA) and ‘translocations’ (‘cross-over’ events involving regions of different chromosomes).

For example the latter can lead to the production of a hybrid protein, known as ‘BCR-ABL’, which causes a certain cancer of the blood called ‘chronic myelogenous leukaemia’.

Collectively these processes allow certain tumour cells to acquire a selective survival advantage, allowing for tumour progression involving only the best adapted tumour cells – an occurrence which mirrors the ‘survival of the fittest’ evolutionary theory.

2) Tumour-promoting inflammation

An inflammatory response is normally observed when some form of injury or irritation to tissue is sustained, and is accompanied by the release of numerous biochemical agents as a result of activating the body’s immune system. This is usually a protective response.

However this is not always the case when a tumour is detected.

Whilst some evidence has shown that tumours can regress upon stimulation of the body’s immune system through the actions of a variety of immune cells (such as tumour-infiltrating lymphocytes), alarmingly there appears to be a great number of tumours which in fact benefit from the inflammatory response.

It has been demonstrated that this response, upon detection of a tumour, can be tumour-promoting. This has been particularly noted in early stage tumours.

Broken chromosomes
Broken chromosomes

The biochemical agents which mediate the immune response can, when delivered to the region surrounding the tumour (termed the ‘tumour microenvironment’), actively promote mutations in neighbouring cells. In doing so several of the ‘hallmarks’ may be augmented.

This occurrence can be exacerbated by the onset of chronic inflammatory diseases. For example, people with Crohn’s disease (a disorder in which the gastrointestinal tract is inflamed for long periods of time) are more susceptible to getting colon cancer.  In many cases the inflammation accompanying the disease is triggered without any injury. Moreover, the inflammation tends to remain at the point where it would usually subside.

Therefore the presence of inflammation could be thought of as a vicious cycle - the tumour initially induces inflammation, the inflammation speeds up tumour development, promoting further inflammation, and so on.

 

It is clear the tumours have adapted in such a way that their complexity remains a big problem when it comes to treatments. It would therefore be no surprise if further ‘hallmarks’ and ‘enabling characteristics’ are discovered in the future.

Research and technology will certainly be able to, at least in the first instance, hinder tumour development. However one of the real challenges, as has already been demonstrated in the field of targeted therapies, is designing treatments which can account for cancer’s capacity to adapt in order to effectively eradicate tumours for good.

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