Sunday, July 20, 2008

How is cancer formed?

All cancers start with mutations in one single cell. The mutations are located in the cell's DNA and may be inherited, although less than 10% of all cancer mutations are inherited. Usually, the mutation arises as a result of environmental factors.

The DNA mutation may be a single nucleotide change, or a deletion or duplication of the DNA sequence. A change in the genetic sequence can then lead to the production of a mutant protein.

The structure of part of a DNA double helixImage via WikipediaIn rare cases such as chronic myeloid leukemia (CML) or gastrointestinal stromal tumours (GIST) one mutation is enough, but in most cancers, it is usually an accumulation of mutations that irreversibly transforms a normal cell into a cancerous one.  As we age, we accumulate more and more mutations as we are exposed to environmental carcinogens and this explains why cancer incidence increases with age.

These mutations can disrupt the cell’s life cycle of growth, proliferation, and death. This leads to the accumulation of more “rogue” cancer cells and the development of a tumour mass.

Normal cells have a natural lifespan and eventually die, a process known as apoptosis, or programmed cell death. They are replaced by new cells and so the process is repeated. Cancer cells do not respond to the signals that regulate cell growth and division. Thus these cells grow unchecked, producing more and more cancer cells.

A cell may die because it is damaged or old. Once a cell is signaled to die, the cell makes proteases and enzymes that degrade its components. The DNA in the nucleus is fragmented, the cell membrane shrinks, and, eventually, a neighboring cell engulfs the cellular remains.

To grow beyond a certain size, tumours must transport nutrients in and excrete wastes. The cancer cells that make up a tumour attract blood vessels to grow into the tumour mass, a process known as angiogenesis. The blood vessels then nourish the tumour just like any organ in the body; because the tumour is made of your own cells, the body does not recognise it as foreign, in the way it would a virus or bacteria.

The age of a cell and its ability to divide is related to structures or telomeres. The telomeres are specialised sequences at the ends of each chromosome and they prevent end-to-end fusion of chromosomes. These telomeres protect the ends of chromosomal DNA from accidents.

As normal cells go through cycles of growth and division, their telomeric DNA gets shorter and shorter and shorter and ultimately so short it can no longer protect the ends of chromosomal DNA. Eventually, the telomeres start fusing, chromosomes start fusing in those cells, and those cells die.

Cancer cells must avoid this problem because they want to grow indefinitely. Instead of dying, they turn on an enzyme called telomerase that is normally expressed only early in embryologic development and in a small number of so-called stem cells in the body.

The telomerase enzyme is able to extend the telomeres, making them longer and longer thereby enabling the cancer cell to go through many cycles of growth and division without worrying about the imminent collapse of its telomeres. The telomerase ensures the telomeres stay very long and essentially protects them from harm.

Most of the deaths from cancer (90%) are due to cancer cells spreading and establishing colonies in other parts of the body, a process known as metastasis. To do that, inactivation of a whole series of controls that normally confines a cell to the site and the tissue where it normally grows occurs, enabling the cancer cells to move to other sites in the body.

Another interesting thing about cancer cells is that they are often different in shape and size to normal cells, and they no longer respond to signals that control normal cellular functions. Our body's immune response is constantly searching for these emerging pre-cancers or pre-tumour cells.  Successful cancers have to avoid detection long enough to grow into a tumour.

The body has two adaptive immune responses, enabling it to adapt to changes in cells in our body, whether they be by infection or other changes, such as cancer. One of these responses is making antibodies produced by B cells, which bind and direct the elimination of those cells. The other response is the T cell immune response where T cells actually kill cells that are changed in the body. The body is in constant surveillance of the cells in our body, so that emerging pre-cancers or pre-tumour cells could be eliminated by the immune response.

So how does cancer arise in the first place?

Well, a cell carries the entire set of genetic instructions, the genome, that makes an entire organism.  The instructions are encoded in DNA as genes and packaged as chromosomes in the nucleus.  DNA is not indestructable and is subject to damage and mutations.  Crucial changes in the genome affect the chance and rate of the development of a cancer cell.

A defining characteristic of cancer cells is that those cells have changes in the nature of the genes that are compared to the normal cells. These changes can be either mutations, or they can be deletion of whole genes, or they can be the addition of extra copies of genes. This is called genomic instability.

The changes in our genes that accumulate in cancer cells can be acquired by a number of mechanisms. One is that during the process of copying the genetic information, mistakes can be made. After the genetic information is copied, it has to be segregated to the two daughter cells. During that segregation process, it is often that the numbers of genes get distributed unevenly to those daughter cells. Cancer cells also have an inability to repair alterations in the DNA.

Overall, you need to acquire multiple changes in the genes or multiple genes, to get cancer, perhaps 5-7 genes on average. Those changes accumulate over a period of time. Some of those changes accelerate the rate of accumulation. A person might have inherited one gene change, for example, and others develop as we age. Developing these mutational changes will weaken the DNA and increase the risk of cancer developing.

Sources (downloadable PDF):

Hallmark of Cancer

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1 comment:

Dominus said...

Well written, Sal. Good synopsis!

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