Metabolism refers to the biochemical reactions that allow food and other molecules to be processed (either made or broken down) in order for our bodies to carry out vital functions. A simple example is breaking down complex sugars (for example starch in bread and pasta) to the smaller molecules of glucose which get processed in our cells to produce other molecules that can eventually be used to produce energy.
One of the fundamental differences between tumours and normal tissues is the way cancer cells carry out their metabolic activities which has led to some referring to this phenomenon as metabolic “transformation”, similar to the process of a normal cell becoming cancerous being known as cell transformation.
Why is cancer metabolism different to normal cell metabolism?
The differences in metabolic traits of cancer relative to normal cells can be attributed to several factors:
- Cancer cells have increased metabolic needs to provide the building blocks required to satisfy the demand for high rates of growth and proliferation.
- Poor and chaotic blood supply in the tumour often means that cancer cells find themselves in challenging surroundings (referred to as the tumour microenvironment) which on the one hand have insufficient amounts of key nutrients and oxygen, and on the other hand do not provide adequate clearance of toxic waste products leading to overall high metabolic stress, for example low pH.
The increased demand for growth and proliferation coupled with nutrient scarcity, low oxygen and low pH in the tumour microenvironment create a stressful milieu that cancer cells have to adapt to in order to survive.
Cancer cells do this by altering various metabolic routes, for example increasing the uptake of key nutrients like glucose and the amino acid glutamine, reducing the rate of oxygen consuming processes (like the Krebs cycle) and increasing waste clearance activities (e.g. lactate transport out of cells).
This is enabled by the genetic abnormalities in cancer cells that influence directly the expression or activity of metabolic enzymes.
Glucose metabolism in cancer explained
Glucose metabolism is a very well-studied example of altered metabolism in cancer that has been appreciated for decades. Tumour cells increase the consumption of this molecule which is then preferentially processed and broken down to lactate; this is also known as the “Warburg effect”.
This action enables several important processes that support the continuous growth and expansion of tumours, including:
- The exploitation of glucose in the tumour microenvironment for rapid production of energy (in the form of ATP) even under low oxygen supply.
- The supply of metabolic intermediates for the production of important molecules such as lipids and nucleotides (necessary for new cells to be produced).
- The provision of lactate as an alternative fuel source to tumour cells not able to access glucose in the tumour microenvironment.
For normal cells to divide and expand, growth signals have to be received which stimulate and activate special proteins on the cell surface known as receptor tyrosine kinases (or RTKs); in cancer cells RTKs are activated through genetic abnormalities leading to uncontrolled cell division.
In a similar fashion, cancer cells display constant activation of certain metabolic activities to help sustain the transformed metabolic phenotype. For example increased glucose consumption is associated with increased protein levels of the glucose transporter GLUT-1 in addition to enzymes within the downstream glycolytic pathway that enable the subsequent metabolic steps to take place. For example, the enzymes hexokinase 2 (HK-2, the 1st step in the pathway), lactate dehydrogenase (LDH-A, for lactate production) and monocarboxylic transporters (MCT, for lactate transfer in and out of cells).
Despite the fact that metabolic activity in highly proliferating cancer cells is mainly self-regulated through the action of metabolites on rate-limiting enzymes, the presence of constant RTK activation in cancer cells provides additional activation of metabolic pathway output.
This occurs through activation of downstream pathways such as PI3K/AKT/mTOR and RAS pathways, which through effects on transcription factors like MYC and hypoxia inducible factor 1 increase the protein levels of key metabolic enzymes like GLUT-1, HK-2, LDH-A, and MCT1/4.
Altered metabolism supports other vital cancer processes
The abnormal metabolism of tumours does not only enable cancer cells to survive under the harsh and stressful conditions in the tumour, it also provides a means for cancer cells to:
- Expand from the initial site of tumour growth to other parts of the body (a process known as metastasis).
- Form new blood vessels to enable further tumour growth.
- Evade immune recognition and attack, with the altered cancer metabolism negatively impacting the ability of immune cells to effectively eradicate cancer cells.
- Escape therapeutic insult, with many studies showing that altered metabolic activity is linked to drug treatment inefficacy.
Given the importance of cancer metabolism for supporting tumour survival and vital functions, it is considered not only a means for informing doctors on tumour behaviour and aggressiveness (important for diagnosing and staging cancer) but also a target for anti-cancer treatment, with many drugs aimed at metabolism now in development.
