6 – The Guardian of the Genome

For the series of entries so far, I realise I have concentrated on fully developed cancers or their causes. But this leaves an important aspect of the field uncovered, what stops the potential tumour cells that don’t become fully fledged cancers? Today’s entry is about the body’s defences, focusing on the protein P53, also known as the Guardian of the Genome.

But what is p53? To put it simply, it controls what genes your body is making use of, almost like a teacher instructing a student on what to read to benefit them most. It kicks in when the cell detects DNA damage (which you’ll remember is what causes cancer-generating mutations), and activates a host of responses to try and prevent that damage resulting in mutations. P53 itself is made up of 4 identical but separate proteins joined as one. This type of structure is called a homotetramer.

p53, the homotetramer shield protecting the DNA of almost every cell.

It responds to quite a few cancer indicators, which include:

• UV radiation, the reason sunlight causes skin cancer.
• Ionising radiation, such as X-rays and the gamma rays given off by certain radioactive material.
• Hypoxia, a lack of oxygen, which if you think back to the hallmarks could indicate cancer as cells in the centre of a tumour have little oxygen until a blood supply is established.
• A lack of nucleotides, which are the building blocks that make up DNA, a rapidly dividing cancer cell must also copy its DNA very quickly, which eventually causes supplies of this chemical to dwindle.

P53 responds to these events with the help of a molecule called MDM-2, which ironically, stops p53 working. While this sounds counter-intuitive, it is in fact part of a clever ‘reverse switch’. If one of the trigger events above occurs, this MDM-2 protein is inactivated, allowing p53 to do its job.

MDM-2 binds to each of the four p53 subunits, inactivating it, but separates when any of the DNA damage signals are detected.

To prevent the uncontrolled growth exhibited by cancer cells, p53 causes a number of molecules involved in growth arrest to be produced. An example is p21, which stop growth by interfering with many systems.

P53 also activates the process of apoptosis, which is where (rather nobly) the cell kills itself because of irreparable damage. This is a complicated process which would require another post to explain in full, but essentially three processes are involved. P53 causes the production of: a molecule called Bax that causes the cell mitochondria to release lethal substances, a molecule called IGFBP-3 that blocks signals that keep the cell alive, and a molecule called Fas that sits on the surface of the cell and relays signals for the cell to kill itself from elsewhere in the body.

The three major ways p53 causes apoptosis. The intrinsic pathway (Bax), the extrinsic pathway (Fas) and by blocking cell survival signals.

P53 also targets the sustained angiogenesis hallmark, causing more of molecules such as thrombospondin-1 to be produced, this blocks the signals required to attract blood vessels to the cell, depriving it of much needed oxygen.

As well as interfering with several hallmarks, p53 increases the amount of proteins involved in DNA repair present in the cell. An example would be the XPC, XPE AND XPG proteins involved in the process of nucleotide excision repair (or NER). This is the system by which the body repairs the damage caused to DNA by UV light (so sunbed users, be grateful p53 is watching over each of your cells!). ⁽¹⁰⁾

As a result of its many functions, any mutation causing the loss of p53 function can be catastrophic for a cell. Indeed, studies with mice show that a lack of p53 function leads to a lifespan of only 4.5 months compared to a normal mouse’s 27-month lifespan. Studies with mice have also shown that those with no p53 activity also show much reduced apoptosis, ⁽¹²⁾ which highlights just how important this protein is for certain cancer defences. In humans, a mutation in p53 is most prevalent in ovarian, oesophagus (food tube in neck) and colorectal cancers. In ovarian cancers almost 50% display this mutation. It is least common in cancers of the testis, thyroid gland and uterus/cervix. Appearing in only 5% of cases of the latter.

Many of these mutations make it more difficult for the four parts of the p53 tetramer to stay together, causing it to be broken down and stop functioning.  Many therapies for this type of mutation stop the mutated p53 from coming apart, an example of this is the PRIMA-1 treatment, that has restored the activity of p53 in cells displaying this type of mutation.

Cancer is an awfully scary disease, but that doesn’t mean you should live your life in fear of it, defence mechanisms such as p53 work tirelessly to prevent the development of Cancer and most of the time, they are very good at their job.

5 – Viruses – who’s side are they on?

It is believed that up to 15-20% of Cancer cases can be linked to infection by some sort of pathogen. For example, studies have shown the bacteria Helicobacter Pylori is partially responsible for the development of gastric cancer. However, as covering every pathogen would make this post the same size as a small book, I have decided here to focus on a specific group of pathogens, the viruses.

Both bacteria (the rods) and viruses (the spiky structures) can potentially cause cancer. Image sourced from: https://commons.wikimedia.org/wiki/File:Cellular-virus-wallpaper.jpg

The most heavily associated pathogen with Cancer, are in fact viruses. By some estimates these are responsible for up to 15% of all cancers. Not all viruses cause cancer, but there appears to be very little in the way of characteristics that can be used to identify those that do. In fact, the most striking thing about cancer-causing viruses is how unrelated they all appear to be, they are a mix of viruses from many different families, are associated with different cancers and even differ on whether they store information as DNA or RNA. The seven viruses believed to cause 10-15% of cancer cases are: Epstein-Barr virus, Hepatitis B, Merkel cell polyomavirus (MCV), HTLV-1 (Human T-lymphotropic virus-1), HPV (Human Papillomavirus) 16 and 18, Hepatitis C and Kaposi’s sarcoma herpesvirus.

Although this is an abstract drawing (viruses are far too small to photograph) it does help illustrate how different the viruses described above really are. Image sourced from: https://pixabay.com/en/viruses-abstract-background-color-672068/

While you may have heard of some of these viruses, like me, you may not have known about their association with cancer. This is because not every virus-infected individual will develop cancer. In what is quickly becoming a blog catch phrase, cancer is complicated and one driving factor alone (in this case viral infection) is often not enough to trigger tumour formation. This is especially true in cancer-causing viruses, as they cause cancer in a very inefficient and slow manner. As a result of this there is often a latency period between viral infection and cancer development, that can sometimes last up to decades.

But if this latency period exists, where is the evidence for the role of pathogens like viruses in cancer formation? Well we can look at the effect of these viruses on the immune deficient. As cancer is primarily a genetically-mediated disease, the only cancers that these individuals would be more affected by will be pathogenic cancers. David Vetter (1971-1984), an X-SCID patient more commonly known as the ‘bubble-boy’ was killed by Burkitt’s lymphoma, a cancer caused by the Epstein-Barr virus, that was introduced into him by bone marrow transplant from his sister. By contrast, his sister was obviously not suffering from cancer.

David Vetter, the tragic ‘bubble boy’. Image sourced from Rogelio A. Galaviz C. Avaliable at: https://www.flickr.com/photos/galaxyfm/359010143

But how do these viruses cause cancer formation? Well there are two approaches. The first is direct, where the pathogen is present in every cancerous cell, releasing DNA instructions coding for cancer-maintaining proteins. Examples of this include cancers associated with the HPV, MCV, Epstein-Barr and Kaposi’s sarcoma viruses. The second is indirect, where a chronic infection or long-term inflammation of the cell caused by the pathogen causes tumorigenesis, in this case the pathogen may have converted the cell in a hit-and-run manner, and does not have to be present to maintain the cancer. While this is how the bacterium H. pylori works, this process has not been well documented with viruses yet. It is likely that many, perhaps all, viruses will exert both effects when causing cancer. It is however, difficult to tell where some viruses lie, Hepatitis B genetic material is present in the DNA of all hepatocellular (liver cell) +-cancer cells, but we don’t know if this is necessary for the spread of this type of cancer. As well as this, while HTLV-1 is present when it causes adult T-cell leukaemia/lymphoma (ATLL), the oncogene that the virus causes cancer with is not always present in mature cancer cells.  With, studies  have confirmed that both hepatitis B and C, as well as HTLV-1, all produce proteins that do transform normal cells into cancers, making it even more unclear whether viruses actively maintain malignant cancers, promote a pre-cancerous cell (leading to cancer) or instead simply promote cancer through inflammation or long-term infection.

The direct approach of cancer formation requires DNA or viral proteins to be present to maintain the cancer cell, while for the indirect approach, cancer formation happens because of the inflammation or long-term infection state the virus causes.

However, viruses appear to be playing both sides of the field, as one group, oncolytic viruses cause tumour regression. While these viruses still infect most human cells, both simple differences between healthy and cancerous cells, such as their stress response, and more complicated changes, such as cancer cells lacking some of the machinery to expel viruses from the cell, means the viruses replicate much better in the latter. Therapeutic oncolytic viruses are designed to capitalise on this, and minimise their effect in healthy cells while still reproducing in (and eventually bursting out of and killing) cancer cells. They may also kill cells by assisting in activating an immune response to the tumour, so the body can fight the cancer itself.  The first virus to be approved for human treatment was Oncorine in 2005, but the drug is limited to use in China. A more widespread example is T-Vec, which has been cleared to treat malignant melanoma in the US, Europe and Australia quite recently (2015-2016).

The method of action of the T-Vec drug. Panel 1 describes how the virus leaves healthy cells alone. Panel 2 is how the virus destroys cancer cells it is injected into. Panel 3 explains how a chemical released by the virus attracts the body’s own defences to cancer cells elsewhere in the body, causing their destruction too. Image sourced from: https://commons.wikimedia.org/wiki/File:Talimogene_laherparepvec_MOA.jpg

So, this is again, an example of how complicated every aspect of the cancer disease is. However, remember before you start cursing viruses for being another cause of cancer, that with the current rate of discovery and the correct research, that these tiny non-creatures may also represent salvation from the disease.