There are different ways to answer this important and difficult question. If the underlying question is “What are the agents that can cause cancer?” then the short answer is: 1) chemical substances, 2) infectious agents, and 3) radiation. If the underlying question is “What are the molecular mechanisms that change a cell from a benign one into a malignant one?” then that’s an entirely different topic. We’ll address the first topic – cancer-causing agents – in a later post. For now, let’s take a quick look at the molecular mechanisms involved in cancer formation.
If you want to be pithy, you can summarize the underlying molecular cause of cancer in four words (and one hyphen): non-lethal genetic damage. In other words, a cell acquires (or is born with) a genetic mutation – and that mutation does not lead to cell death. Normally, if a cell’s DNA gets damaged, it will either get fixed or the cell will kill itself (by apoptosing). In cancer, the DNA damage does not get fixed, and the cell does not die – so it is able to pass that mutation down to all subsequent cells as it divides.
Four kinds of normal genes are targets
What kinds of genes tend to get damaged in most cancers? It turns out there are four classes of normal regulatory genes that seem to be good targets for genetic damage.
1. Proto-oncogenes. These are normal genes that every cell has; their function is to tell the cell to grow. If you mutate a proto-oncogene in such a way that it is always turned on, then the cell with that mutant gene will always be growing and dividing, and a tumor will develop! Such mutant proto-oncogenes are called oncogenes. They are dominant, meaning that mutation of a single allele can lead to cellular transformation.
2. Tumor suppressor genes. These are normal genes that every cell has; their function is to tell the cell to stop growing. You can think of them like brakes on a car. If you mutate a tumor suppressor gene in such a way that it does not work, then you are effectively removing the brakes on cellular proliferation, and the cell will grow like crazy. These guys are recessive, meaning that you generally need to mutate both copies of the normal allele for transformation to occur.
3. Genes involved in apoptosis. These are important, because if a cell can’t repair its DNA, it needs to be able to kill itself (otherwise, the damaged DNA will just get passed down to daughter cells). Mutate these, and a cell will become immortal – even if its DNA is damaged!
4. Genes involved in DNA repair. Obviously, these genes are critical too. We acquire as many as 100,000 spontaneous mutations every day! (If that’s not enough to keep you up at night, I don’t know what is.) You have to have ways of fixing these mutations, or you’d be getting cancers all the time.
What happens if you damage these genes?
There are 6 particularly nasty things that a cancer cell can learn how to do as a result of genetic damage.
1. Autonomous growth. Cancer cells are able to grow all by themselves, without any of the external signals normal cells need (like growth factors or hormones).
2. Insensitivity to growth-inhibitory signals. Cancer cells are able to ignore the normal signals telling cells to stop proliferating. They just keep on growing no matter what anyone tells them.
3. Evasion of apoptosis. Cancer cells can become immortal by learning to avoid the signals that normally induce apoptosis.
4. Limitless replication. Whereas normal cells possess a limited number of doublings (usually 60-70), cancer cells can learn how to renew themselves endlessly – kind of like stem cells or germ cells.
5. Sustained angiogenesis. For a tumor to survive, it needs to be able to grow a new blood supply. Blood can only diffuse so far, so this has to be an ongoing process if a tumor wants to grow.
6. Invasion and metastasis. These are particularly nasty characteristics of cancer cells. Benign tumors tend to be non-invasive, and they never metastasize (that’s one of the few times you can say “never” with confidence in pathology class). Malignant tumors, however, are generally invasive, and they most certainly can metastasize if they so choose.
We’ll talk later about some specific genes that are commonly mutated in many different kinds of cancer.
Photo credit: Runran (http://www.flickr.com/photos/runran/3358075794/), under cc license.
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