Deconstructing cancer: The eight principles underlying tumour growth

Posted by ap507 at Apr 20, 2016 10:20 AM |
PhD student Mohan Harihar from the Department of Molecular and Cell Biology explains the eight ‘Hallmarks of Cancer’
Deconstructing cancer: The eight principles underlying tumour growth

Image shows metastatic melanoma

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Our bodies have in place quality control mechanisms to ensure cellular behaviour remains stable – a process broadly referred to as ‘cellular homeostasis’. These mechanisms, either individually or working with others, can direct a cell to grow, divide or die.

In tumours, be it benign (non-cancerous) or malignant (cancerous), these mechanisms become compromised, often as a result of genetic mutations to critical proteins, causing things to go awry.

Abnormal functioning of these afflicted proteins leads to a change in the cell’s behaviour. These changes, exhibited in tumours, have been summarized by cancer researchers Robert Weinberg and Douglas Hanahan as the eight ‘Hallmarks of Cancer’, which must be followed for a cell to become cancerous:

1) Cancer cells can promote their own growth

Healthy cell growth requires an initial external signal, usually in the form of a ‘growth factor’ binding to a target protein on the outside of the cell. This initial signal is required to activate the relevant signalling pathways within the cell which promote growth. Once the desired outcome has been achieved the overall signal will diminish – a concept called ‘negative feedback’.

These characteristics are lost in cancer cells as they do not depend on external growth factor signals for growth. Instead they are capable of producing their own growth signals, causing the signalling pathways to remain permanently ‘switched on’ and resisting ‘negative feedback’ responses. This results in uncontrolled cell growth and division.

Epidermal growth factor receptor (EGFR) signaling pathway
Epidermal growth factor receptor (EGFR) signaling pathway
Cancer cells can resist growth-inhibiting signals

Healthy cells abide by tightly regulated mechanisms, coordinated by proteins called ‘tumour suppressors’, which can control cell division. The genes effectively clock whether or not a cell is ready to divide. If the cell is not suitable to undergo division, for example if there has been DNA damage, then these tumour suppressor proteins can prevent division until the damage has been repaired.

Cancerous cells have defects in the tumour suppressor genes which reduce or remove the ability to control cell growth/division. As a result cells will undergo growth/division regardless of whether it is necessary and whether or not the damage has been repaired.

3) Cancer cells are capable of indefinite growth

Normally human cells have a limit to the number of times they can replicate which is referred to as the ‘Hayflick limit’. This is because at the ends of chromosomes there are short sequences of DNA called ‘telomeres’ (which serve as a protective cap) and these shorten with successive rounds of cell division. Progressive telomere shortening eventually renders a cell unable to divide, at which point it would usually undergo apoptosis or enter a state of dormancy known as ‘senescence’.

Interestingly cancer cells manage to synthesise high levels of a protein, called telomerase, which can maintain the telomeres. Therefore cells can undergo division indefinitely.  Additionally cancer cells can disable certain tumour suppressor proteins which are required in establishing the ‘Hayflick limit’.

In this way cancer cells are described as being ‘immortalized’ as they can continue to grow and divide without limit.

4) Cancer cells/tissue can acquire its own blood supply

Blood vessels are required to supply all cells with oxygen and nutrients to sustain survival. Cancer cells are able to manipulate the normal blood vessel architecture to obtain a strong oxygen supply by promoting further growth of the network of blood vessels (vasculature). The term given to the normal production of new blood vessels is ‘angiogenesis’.  With regards to cancer this may be referred to as ‘neo-angiogenesis’ as the cancer cells not only manipulate the existing vascular network but they can also stimulate additional growth. In this way, cancer cells are able to feed off the oxygen within the blood supply.

5) Cancer cells can avoid ‘cell death’

All cells possess the inherent ability to undergo a form of ‘programmed cell death’ called ‘apoptosis’ in the event unrepairable damage is sustained.

In cancer cells this system is by-passed. This is achieved through deficiencies in

Mutation in DNA
Mutation in DNA
either the proteins which detect cell damage and subsequently mediate signalling, or the proteins directly involved in mediating apoptosis.

6) Cancer cells can invade surrounding tissue and spread to other parts of the body

Whilst cancers may form in a single localised region the cells can break off from the primary cancerous growth and move, in a multi-step process, to other parts of the body. This trait largely dictates whether a tumour is benign or malignant. Invasion of surrounding areas, through the synthesis of proteins which can eat away at surrounding tissue, may occur first but, once advanced, cancerous cells can enter the bloodstream and move to distant body parts. This process is known as ‘metastasis’ and is perhaps the most severe outcome when treating patients in a clinical environment.

7) Cancer cells can remain undetected from the immune system

The immune system is the body’s intrinsic means of combating a range of diseases. When possible, immune cells called ‘CD8+ cytotoxic T-cells’, and ‘CD4+ helper T1-cells’ , curtail cancer development by producing a signalling protein called ‘interferon-γ’ which can recruit other effector proteins during the immune response to the tumour . Additionally compounds which are toxic to cells, called ‘cytotoxins’, can be released by immune cells that destroy targeted cells.

However cancer cells have the capacity to adapt and develop ways of evading detection by the immune system.  Moreover tumour cells can undergo genetic alterations which make them resistant to any potential immune response. Over time these resistant tumour cells can be actively selected to grow which will eventually yield a largely immune-resistant tumour. This is a process which can span several years and is referred to as ‘immunoediting’.

8) Cancer cells possess abnormal cellular metabolism

Cellular metabolism is the process by which certain components are broken down in order to produce energy whilst other substances are generated – both of which are necessary for sustaining life.

Cancer cells, just like normal cells, require a healthy supply of energy to support a range of cellular events such as growth.  Healthy cells, in the presence of oxygen, generate energy through a particular chemical process called ‘oxidative phosphorylation’.

However during solid tumour/cancer development the environment surrounding the tumour can lack oxygen – referred to as ‘hypoxia’.  Research suggests cancer cells have adapted to be able to produce energy, regardless of the oxygen level, using a process which in healthy cells would normally only be utilised when oxygen is in short supply.

This is known as the ‘Warburg effect’.

These eight principles have been largely attributed to the onset of tumour growth. While in recent years there has been some criticism aimed towards Weinberg and Hanahan’s proposed ‘hallmarks of cancer’ - suggesting that many of them could be used to describe benign tumours also -the fact remains that these eight principles must all be followed for a healthy cell to change to a pre-cancerous intermediate and finally a cancerous cell.

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