What Causes Cancer, Part II
This is a continuation on the last article on what causes cancer. In my last post we’ve seen how cancer is a multi-step disease, caused by a sequence of genetic changes, or mutations in certain genes. Here I want to look at the inherited or external factors that cause these mutations, and are thus what causes cancer. There are a couple of ways we can get these genes mutated or changed. One of them is to bring an active oncogene (a gene that helps a cell turn into a tumor cell) into a cell. If a cell has an oncogene that is not being expressed, a virus can actually bring it into the cell.
Cancer Caused By Viruses
Tumor viruses were discovered in a very interesting way, in 1910 by Peyton Rous. He got a call from chicken farmers in Long Island. The chickens were all getting these horrible tumors. So, he thought it might be an infectious disease. He went to Long Island and he showed that there was a virus that was spreading form chicken to chicken and causing these tumors (sarcoma). He isolated the virus and then infected an animal that didn’t have the tumor. The animal got the tumor, and from the tumor in that animal, he isolated the virus and repeated.
Rous was awarded the Nobel Prize in 1966, 56 years later. Why did it take that long to recognize him? Because no one really wanted to believe that cancer could be a communicable disease. People started to look at proteins and DNA, and attention shifted.
Tumor viruses, as it turns out, have actively expressed oncogenes. There is a tumor virus that has an actively expressed oncogene for that growth factor. When these active oncogenes get unto our cells, they stimulate cell division. Approximately 10% of human cancer is caused by viruses. In our society there are two major ones that are important: hepatitis B virus is associated with liver cancer, and a papillomavirus (warts), which causes cervical cancer. In both cases the good news is that antiviral vaccines are being used and developed.
Inherited Cancers
Inherited mutations in tumor suppressor genes can allow cells to divide inappropriately. It turns out that about 10% of cancers are inherited. This includes about 10% of breast and colon cancer.
Compared to non-inherited cancers (called also sporadic), inherited tumors typically occur earlier in life. For instance, inherited breast cancer would manifest in women during their 20’s, instead of in their 50’s, as it is common with sporadic cancers. These inherited tumors also appear in numerous places.
After looking at the data, Arthur Knudson proposed the “two-hit” hypothesis. From Mendelian genetics we know that most cells have two copies of every gene. Knudson proposed that for tumor-suppressor genes both copies have to be mutated. Both alleles of the tumor-suppressor gene must be off. People with inherited cancer have already in all of their cells one bad allele. So, if they later get a mutation of the second allele, they’ll get a tumor. That can happen reasonably soon. People who inherited two normal alleles, however, need two mutations, and that’s going to happen somewhat later.
Cancers Caused by External Factors
Most cancers turn out to be sporadic, so they need many mutations in order for the tumor to form. What do I mean by many mutations? Mutations must happen not only on the tumor-suppressor genes, but also on oncogenes and metastasis genes. You need all these events to occur in a sequence.
A doctor at John Hopkins University, Bert Vogelstein, and his colleagues, spent a lot of time during the 1990’s looking at the sequence of genetic changes that lead to cancer, specifically to colorectal cancer. This cancer develops first as a small group of cells. This group gets larger and larger over time. You can actually follow this. In colonoscopy, the objective is to remove the group of cells before it becomes a tumor. If you remove the cells, you have a sample of an early cancer.
What Vogelstein did was to make a survey of all the genes involved in cancer in these groups of cells as they went through the stages of development. What he found was a very dramatic series of events. First there were mutations in tumor-suppressor genes, and then there were mutations on oncogenes. Then there were mutations in metastasis genes.
Describing cancer in this amount of molecular detail is an amazing achievement of modern biology and medicine. It would lead to treatments.
So, when we are talking about something causing cancer, we mean that they cause these genetic changes. DNA can change in two ways. First, there are spontaneous mutations that occur during DNA replication. This means that people can get cancer without getting exposed to any bad stuff. This is rare event, but think of the fact that the body has trillions of cells, and cancer can come from one cell that goes bad.
The second type of mutations is induced ones. They are caused by something from the outside. Most cancer mutations are caused by the environment. Cigarette smoke, for example. The chemical compounds present in cigarette smoke damage specific tumor suppressor genes. Ultraviolet light from the sun causes skin cancer.
However, these things are obvious. For the case of most cancers, we really don’t know what’s going on. In fact, many carcinogens are natural substances in the diet. In most cases, we just haven’t identified them yet. They’re not the things you might think of. They’re natural molecules that plants make to defend themselves. How do we know this? Because there are country differences in cancer incidence. Also, when someone moves from one country to another, they and their offspring will adopt the cancer rate of their new country. When you look very carefully at it, you find that it’s probably diet.
This is probably why cancer is so difficult to treat or prevent: in most cases we don’t even know what causes it.
