The sweetness of cancer

Recently, I have noticed an increase in the number of headlines that mention ‘cancer’s sweet tooth’, ‘cancer cells sugar craving’ and even ‘sugar is cancers favourite food’.  I don’t have an issue so much with the analogy but I do think that it simplifies the reality a little too much.  Metabolic regulation within a cell is extremely complex.  Just looking at this diagram should be enough to convince you.

Scientists know that as a tumour develops there are fundamental changes to the metabolic programme of cancer cells.  Being a cell is a very energetic lifestyle and in order to keep up with the relentless days and nights of manufacturing proteins, breaking down molecules and warding off toxic compounds – cells need a decent supply of energy.

Under normal conditions this is readily achieved by a process called aerobic respiration.  Here’s a quick, school biology catch-up:

Glucose + oxygen → carbon dioxide + water + ENERGY

This ‘energy’ is actually a molecule called ATP or adenosine triphosphate.  It is this molecule that is used to keep the lights on, so to speak.  Just to reiterate how incredibly simplified the above equation is – here is a fuller picture of aerobic respiration.

The problem with tumours is that as they grow they become increasingly cut off from the body’s blood supply.  This creates an environment that is very low in oxygen and as such the amount of aerobic respiration that can be done is reduced.  When this happens the cell starts kicking out a protein called HIF-1 which rapidly activates genes that control a process called glycolysis.  This is another metabolic pathway, like aerobic respiration, except that it can create ATP from glucose without the need for oxygen.  Interestingly, what happens in cancer cells exposed to this pressure is they end up permanently switching on their glycolysis programme, so that even when there is oxygen available they preferentially manufacture ATP by glycolysis (a phenomenon known as the Warburg Effect).  The problem with this is that glycolysis is massively inefficient compared to aerobic respiration – producing only 2 ATP molecules compared to 38 – from one molecule of glucose.

It is this that has led to cancer cells to be called ‘sugar addicted’.  Not only do they produce very little ATP per glucose molecule, they are also much more energetic then normal cells, so they require a lot more glucose to keep themselves going.

This might sound simple enough and warrants the simple analogy but in reality it is much more complex.  Emerging research has shown that the environment around tumour cells, called the stroma, also plays an important role in cancer metabolism.  Healthy cells within the tumour stroma have been shown to succumb to the Warburg Effect and as a result begin to ‘eat’ themselves to obtain fuel to make ATP.  This is also driven by the lack of oxygen within the tumour stroma and results in energy rich nutrients spilling out into the local environment.  It has been proposed that cancer cells take up these nutrients and use them to produce their own energy.  Interestingly, these nutrients include compounds called ‘ketones’, which are much more efficient at producing ATP when metabolised by cancer cells.

So it is not clear cut whether cancer cells are ‘addicted’ to sugar.  They definitely require a lot more ATP and so they definitely need more fuel to produce it.  But the complexity of the varied metabolic systems and the relatively unknown contribution of the tumour stroma make it difficult to establish exactly what is going on.  This is something that needs to be taken into account when establishing how the Warburg Effect can be targeted therapeutically in cancer.

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