It’s All You

Well, to celebrate my return to the blogosphere (don’t pretend you’re not celebrating) and to welcome in the new year, I thought I’d do something light-hearted. So I’m going to talk about cancer. Yay!

This is a topic I’ve been thinking about writing on for some time. It’s a topic close to my heart both personally and professionally. But I’m not unique in that. Virtually everyone will have been affected by cancer somehow, whether directly or indirectly. Various environmental and age-related factors have seen cancer rising through the charts to become the number killer in the country. We’re still waiting for Gazza to turn up with some beer and fried chicken to try to reason with it…

These are all Bad Things(tm). Should be avoided. Image credit: I stole this from the Guardian.

It seems that most people understand at least a bit about cancer in very general terms. But do people really understand what they’re saying when they use phrases like “the cure for cancer”? Or when they say “so and so has cancer x”? The honest answer is I don’t know but I suspect there are a lot of misconceptions.

The first thing that I think needs to be said is that talking about “the cure for cancer” is like saying “the cure for… erm… stuff”. Cancer is not a single disease. Cancer, as a word, is an umbrella term that describes a broad range of diseases that have a similar theme. That theme is out-of-control cell replication. Just as epilepsy is a word that indicates a general seizure disorder that can manifest in a number of different ways and for a number of different reasons, cancer is a broad term that basically means some of your cells have stopped doing what they’re told. But there are over 200 different types of cancer. Many of these will be distinct in their effect and causation. Essentially being completely different diseases that present in similar ways.

There is one unifying factor though in all cancers. The cancer is not an alien intruder. It is not an external cancer bug that has taken root in your body and grows at the expense of the host. Unfortunately, the cancer comes from you. Ultimately it is your DNA, your genome, that has become destabilised that has led to a cascade of events that has led to cancer. This is part of the reason that I want to stress the point that to think of all cancers as a single thing is not the right way to approach the topic. Everybody accepts that we are all unique, despite having largely identical genomes. Well, broadly speaking, this uniqueness is potentially reflected in cancer. How a patient responds to treatment or to the cancer itself and the progression of the disease can be very different between people who ostensibly suffer the same disease. Patient A and Patient B may both present with what is essentially breast cancer. But depending on all of these factors, the outcome is not guaranteed to be the same for the two patients. They might both have “breast cancer” but they may have very different sub-types. Even if they have the same sub-type, they may respond very differently to the actual tumour or to the treatment that is given to them.

The processes the underlie the development of cancer (known as carcinogensis – hence known cancer-causing agents being called carcinogens) are also processes that are absolutely essential to life itself, certainly multicellular life. Which is what you are. A seminal paper on the hallmarks of cancer was published in 2000 by Hanahan and Weinberg and followed up 10 years later in a paper to mark the anniversary of this important publication. These hallmarks provide an interesting insight into cancer, and make it apparent that “cancer” is more of a general process, rather than a specific disease.

The original 6 hallmarks of cancer. Although the second paper added to these, this is an excellent tool to understand the key concepts.

1) Sustaining proliferative signaling – Cells are in constant communication with each other and monitoring their own internal signals. This communication and signaling is in the form of chemical signals and the flow of electrically charged atoms and molecules. Cells communicate with their immediate neighbours but also receive signals about the overall environment they’re in (i.e. the tissue). The can also be affected by signals from far away in the body, which is what hormones do. The constant cellular chatter is vital to a number of processes. So individual cells don’t just do their own thing. They respond to the needs and demands of the system as well as providing feedback about their environment. Sometimes it is necessary for cells to replicate, for example to repair injury or replace old cells with new ones. In these instances, chemical signals are released which bind to the membrane of the cell and tell it to go ahead and reproduce. In cancer, this signal is essentially bypassed. This can be due to faults in the receivers of the signal on the membrane on the cell. Alternatively it could be that the cell has started mimicking these growth factors. Either way the result is that the cell now thinks it is being told to replicate. Its “daughter” cell will more than likely carry the same error, resulting from damage to the genome. So this too will go on to replicate erroneously.

Cell proliferation is essential and has a lot of complex pathways to regulate it. Normal cell replication takes place billions of times a day in your body, so just cutting it off would be lethal quicker than any cancer could be.

2)Evading growth suppressors – In just the same way that cells receive signals that actively tell them to go forth and multiply, there are also lots of inhibitory signals as well that tell them not to replicate. Again, these work through molecular pathways that are genetically determined. Disruption to any part of these pathways can result in the whole pathway failing. Cell pathways can be incredibly complex so I’ll try to illustrate with a simple example.

Molecule A activates Molecule B.  Molecule B changes the shape of Molecule C. Molecule C activates cell replication. You could write this pathway as A->B->C->Replication.

Now lets say Molecule P comes along and acts on Molecule A to make it inactive. Now you have disruption to that replication pathway. It never gets beyond Molecule A, meaning there is no replication. Molecule P in this instance is acting as a growth suppressor as it is effectively blocking that pathway. If any of the things in that pathway are altered then it could have the effect of making it insensitive to growth suppressors. Maybe B changes and no longer requires A to become active. Maybe A changes and is no longer silenced by P and so on.

3)Activating invasion and metastasis – One of the most devastating and unusual aspects of cancers is the ability most have to eventually travel round the body and set up shop in another organ. This is an extremely unusual property. We don’t, for example, expect to find gut cells living in the brain. And yet cancers are very often associated with this very phenomenon. The act of breaking away from the original affected tissue, moving round the body and settling down in another tissue is called metastasis. Invasion refers to the ability to penetrate through tissue and take up more and more space relative to non-cancer cells. In fact, most cancer deaths are actually the result of these metastatic tumours, not the initial primary tumour. In many ways this is the most alien aspect of cancer.

Cells don’t exist in solitary confinement. They live in a 3D world where it matters what is above them, below and so on. Tissues are organised structures of cells. Cells can stick to each other to stay in place. Additionally, in between cells is massive jumble of proteins and other molecules that form what is known as the Extra Cellular Matrix (ECM). The ECM, simply speaking, can be considered as a great lattice of molecules that form a scaffold onto which cells can attach and anchor themselves, giving them a defined location. To break away from the ECM and the neighbouring cells, the cancer cell must also have errors in the molecules on its membrane that allow it to adhere to the ECM and its cellular buddies.

4)Enabling reproductive immortality – Although a feature most people would like to experience, this is a very important part in the establishment of cancer and the formation of large tumours. In essence cells can only replicate a certain number of times. Just like making a photocopy of a photocopy, eventually errors build up and the cell is unable to replicate. One of two things generally happens (though they are not necessarily mutually exclusive): the cell can become senescent or it can die. Senescent basically means that it sits there, still alive, but not attempting to replicate. Alternatively, so many errors have accumulated that the cell undergoes programmed suicide in a process called apoptosis.

These outcomes are largely defined by damage that occurs to chromosomes during the replication process. Essentially the ends of the chromosomes, which are called telomeres, wear down and they become shorter with each replication until, eventually, they are so damaged that they can no longer sustain the cell. However, a cancerous cell must avoid this replicative dead-end. So they develop a way to avoid it. This is largely to do with mutations that alter the level of repair that is carried out on telomeres, as well as other DNA repair mechanisms. Once this bypass has been established the cell can, in principle, replicate forever.

Due to the fact that it is now no longer limited by damage to the chromosomes that occur during replication, it is also free to pick up more and more mutations. Some of these may enhance its cancerous behaviour. Others may kill the cell. So here a microcosm of evolution and survival of the fittest occurs. The more cancerous cell survive, the less cancerous cells don’t, so gradually the population becomes more and more aggressive.

5)Inducing angiogenesis – Quite simply this means hijacking the body’s blood vessels and manufacturing new ones. All tissues need a supply of oxygen, nutrients and water. Additionally they must be able to get rid of toxic products of metabolism. In other words, all tissues need a blood supply. Generally speaking, blood vessels are largely stable. They may get damaged and repaired but the architecture and “map” of blood vessels doesn’t really change.

Well, tumours have other ideas. In the early days of progression the cancerous cells can get what they need from the existing blood supply, just like the rest of the cells in the tissue. However this situation doesn’t last. As a tumour becomes larger its volume increases. The cells inside start to become deprived of oxygen and other essentials. So the way round it is to resculpt the blood supply. There are, as with most things in biology, two general directions for regulating this blood supply growth, known as angiogenesis. One is to signal to forge ahead with vessel growth. The other is to signal an end to vessel growth. So, a negative and positive regulation.

Relying on mutations that have affected the control of these two general regulatory pathways, cancers can grow their own unique blood supply which is tailored to their needs. Interestingly, tumours that limit their blood supply and so are low on oxygen, a condition called hypoxia, are much more aggressive and resistant to chemotherapy.

6)Resisting cell death – Cells die. A lot. As in billions each day. This is normal. This process is called apoptosis. Again, we’re talking about a series of regulatory networks that control this. Components of the cell are constantly on the lookout for these signals, which might come both from outside and inside the cell. Apoptosis can be induced after significant cell damage or in response to specific environmental needs. Your fingers and toes would still be webbed if it weren’t for apoptosis. The cells forming the webbing that you had as an embryo receive a signal to kill themselves: hence no webbing. Unless you’re from Stoke.

You can see the obvious advantage to a cancerous cell breaking out of this apoptotic pathway. You could have all the other hallmarks discussed above but you would not get a cancer as the cells would still respond to instructions to kill themselves.

Anyone familiar with the literature will probably be screaming that I’ve missed stuff out or over-generalised in places. But I want to just try and convey what happens, broadly in cancer. To develop cancer you need a series of events that cause mutations in crucial genes. These genes will be involved in controlling the aspects discussed above.

This is partly what makes it so hard to treat “cancer”. The combination of mutations and errors in regulation that have led up to the point of becoming a cancer patient may vary wildly. The actual “cause” of a specific cancer may be almost impossible to ascertain, and is probably actually a combination of causes. The nature of the cancer will be determined by how radical each of the changes discussed above are. You can get growths and benign tumours which aren’t cancer they may show some or all of the above to a lesser or greater degree.

So this is cancer. It isn’t alien – it stems directly from processes that are not just normal but essential. It merely reflects a loss of control over these crucial aspects of cellular living. Just because a tumour occurs in the same organ as someone else, doesn’t mean it has the same cause. It could be a completely different set of regulatory pathways that has broken down, that just happened to take place in the same organ. The actual disease may be very different.

A final note. You’ve probably heard people say that cancer is largely a side-effect of aging, which is why we the rates go up as people live longer. Hopefully this will help shed some light on why that is. The longer you have been alive, the more times your cells have replicated. The more times your cells have replicated the more chance there will be errors introduced into your genome in some cells. Add to this an increased time of exposure to carcinogens in the environment and you can see that you become gradually more and more likely to end up with a cell or two that decide to live by their own rules and ruin it for everyone.