Demystifying Cancer, Part 1: How Does Cancer Start?

Before I start today's post, I wanted to apologize in the delay between posts - I've had a very busy last few weeks, including a trip out of town. However, you can now also follow my science commentary activities on twitter, where I will post shorter science updates between posts.

Anyway, now that I'm back, I wanted to take a break from stem cells for a bit and launch into another series'topic - cancer. I'd love your comments or suggestions as to what aspects of this broad field of science you would most like to learn about; but, for now, here is the first part of my series on the basics of cancer: how does cancer start? 

What is cancer?

As I've briefly described before, cancer is the unwanted, out-of-control growth of cells in the body.  To understand how cancer develops, we first need to understand how the body usually controls cell numbers.

When operating properly, our body tightly regulates the number of cells in our body. This control is based on two opposing mechanisms: cell division and cell death.  Cell division is essential, both in order to generate the body in development, and to replace cells that die. Cell division is triggered in response to signals from their environment, and can be stopped by other signals. However, in addition to managing how often cells divide, the body also controls how long the cells live. Most cells in the body have a finite lifespan, because each time a cell divides, it has to make a copy of its DNA code. Every time the code is copied, there is a chance of introducing errors (mutations) which can cause problems in the cell - like cancer. Limiting the number of cell divisions helps prevents those errors building up over time. Also, sometimes the body ends up with too many cells, such as in case of illness, when our immune system produces a bunch of new cells to fight the infection, but no longer needs these cells once the infection has been cleared. Therefore, to allow regulation of cell survival, cells in our body have a cell death program called apoptosis. Cell death can be triggered by signals internal to the cell, such as when the cell has divided the maximum number of times, or by signals from outside, such as in response to certain immune system signals.

Using these two regulation mechanisms, the body maintains a fairly constant number of cells over time, by producing new cells as replacements or to meet a crisis, and then killing them off as they age or when the crisis is over. Cancer occurs when this balance is disrupted, and cells are dividing more frequently than they are dying. This can be caused by an increase in cell division, a loss of cell death, or, most frequently, both. Cancer cells become parasites, using the body's resources to continue to divide, and the body's circulation systems to spread throughout the body.

What causes cancer?

Cancer is, in a nutshell, caused by mutations in the genetic code of the cell. Each gene codes for a protein, which then has a function in the cell. When a gene is mutated, there are several possible effects on a protein's function: the protein could lose function, keep some functions but lose others, or gain a new function it didn't have before. (Also, in some cases, the protein can remain unchanged, but we don't talk about this as much because this isn't usually dangerous.) Other mutations can affect the expression of the gene: the protein function doesn't change, but the amount of protein does. Gene expression works similar to a dimmer switch on a light bulb: there are various levels of expression, not just on or off.  Common gene expression changes in cancer include:

• Gene Silencing: A gene is turned off. This has a similar effect to a mutation where the protein loses function.
• Gene Activation: A protein is suddenly expressed in a cell type that usually wouldn't express that gene. 
• Expression Modulation: The amount of the protein changes, such as going from low to high expression.   

Many mutations that cause cancer affect genes involved in cell division and apoptosis, to either increase cellular reproduction or to deactivate cell death. It takes more than one mutation to cause cancer, and these mutations are acquired over time. As cells acquire more mutations, they will become more efficient at cell growth; for example, cancer cells which divide out of control will be able to grow even faster if they also deactivate the cell death pathway. Therefore, another common mutation in cancer cells is the disabling of the proofreading proteins which make sure that DNA is properly copied during cell division: when we lose the proofreaders, we increase the rate of new mutations due to copying errors, which will make it more likely to acquire additional cancer-causing mutations.

Any substance capable of causing cancer is referred to as a carcinogen. Many carcinogens are genotoxic, which means they directly cause mutations in the DNA genome. A classic example of a genotoxic carcinogen is radiation, which is why exposure to radioactive substances is dangerous. However, there are also nongenotoxic carcinogens, such as many pesticides, which do not directly affect the genome, but can still promote cancer development. In order to understand the action of these two types of carcinogens, we need to consider the progressive stages of tumour development.

Steps of cancer formation

• Initiation: Initiation refers to the initial mutation that makes a cancer cell susceptible to growing out of control, such as the various mutations I discussed above. Initiation is always caused by a mutation, either due to a replication error, or a genotoxic carcinogen. This mutation is permanent, and so this cell, as well as all its daughter cells, will carry this susceptibility to cancer throughout its lifespan. A good example of an initiation mutation is the inactivation of the cell death pathway. These cells are poised to become cancerous; however, they are not yet a cancer, because they aren't dividing out of control. All cells require a signal in order to divide, and most initiated cells are still lacking this signal.

• Promotion: To begin uncontrolled growth, susceptible cells need to receive a prolonged signal to divide. This is where nongenotoxic carcinogens come into play: they provide the cell with this division signal. As might be expected, these carcinogens must stick around for an extended period of time in order to effectively promote cancer, and the amount of the carcinogen affects its function - low doses are insufficient to cause cancer. These carcinogens are usually location-specific, because cells in different parts of the body use different receptor proteins and respond to different division signals. It should be noted that these carcinogens only affect cells which are already susceptible (i.e. have an initiation mutation); a normal cell would receive the promotion signal, but the other checks and balances in the body (e.g. the cell death pathway) would keep its growth under control.

At this point, we would have a tumour: the cells have divided out of control. However, tumours at this point are still benign, which means they cannot invade other tissues or spread throughout the body. These tumours are relatively safe, although they can still cause health problems by interfering with the function of the tissue around them. In order to progress into malignant cancer, the cells have to gain further mutations. This is called cancer progression. For instance, cells may gain mutations which allow them to divide without requiring an outside signal, short-circuiting the body's regulations. This is important if the cancer wants to spread to other sites in the body, since most cell division signals are specific to a certain tissue type. Cancer cells will also gain mutations which help them move through the blood or lymph, so they can colonize other sites  - this is called metastasis. Cells at this point are genetically unstable: they aren't proofreading their DNA properly, and many have large chunks of their chromosomes rearranged, which can delete or modify many genes at once.

Why do some kinds of cancers run in families?

As mentioned earlier, cancer usually requires multiple mutations to progress. This is especially true in the case where the proteins being mutated are tumour suppressor genes. We have many different tumour suppressor genes, which, as suggested by the name, act as one of the checks and balances against cancer. Tumour suppressor genes include DNA damage repair proteins, apoptosis proteins, and regulators of cell signaling. Cancer can arise when tumour suppressor genes are inactivated, either by a mutation that renders the protein non-functional, or by preventing gene expression (silencing).

Because we all have two copies of each chromosome, one from each parent, most people have two functional genes for each tumour suppressor. That means that even if one copy is rendered inactive, the protein can still be produced from the other chromosome; therefore, in order to deactivate the tumour suppressor, both genes need to be inactivated. This requires at least two mutations, in very specific locations.

However, there are some cancers which seem to be at least partly hereditary: a high proportion of people in the same family all develop the same type of cancer, often at a younger age than the population average. Most hereditary cancers are caused by an inherited inactive form of a tumour suppression gene. That means that in each cell of the body, there is only one functional copy of the tumour suppression gene. Therefore, these individuals only need to inactivate that one copy in order to lose tumour suppression, which greatly increases the probability of that cell becoming cancerous. This is also why hereditary cancers more often appear in younger individuals than do non-hereditary cancers, as it takes less time for the required mutations to accumulate.

Next up

In my next post, I hope to cover more details on cancer classification and treatment: how we classify different kinds of cancers, and how this affects treatment.  However, I also want to ask for your questions and topic suggestions. Cancer is an extremely wide-reaching topic, and also an area where most of us have some personal connection. Is there something about cancer that you've always wondered about? Or specific types of cancer and/or treatments you want to learn about? Leave suggestions in the comments, and I'll do my best to get to them over the next few weeks.