Slowly, Cancer Genes Tender Their Secrets
Dr. Brian Druker, a Howard Hughes investigator at the university's Cancer Institute, who led the Gleevec study, sees Mr. Weinstein as a pioneer in a new frontier of science. His treatment was based not on blasting cancer cells with harsh chemotherapy or radiation but instead on using a sort of molecular razor to cut them out.
That, Dr. Druker and others say, is the first fruit of a new understanding of cancer as a genetic disease. But if cancer is a genetic disease, it is like no other in medicine.
With cancer, a person may inherit a predisposition that helps set the process off, but it can take decades - even a lifetime - to accumulate the additional mutations needed to establish a tumor. That is why, scientists say, cancer usually strikes older people and requires an element of bad luck.
"You have to get mutations in the wrong place at the wrong time," Dr. Druker says.
Other genetic diseases may involve one or two genetic changes. In cancer, scores of genes are mutated or duplicated and huge chunks of genetic material are rearranged. With cancer cells, said Dr. William Hahn, an assistant professor of medicine at Harvard Medical School, "it looks like someone has thrown a bomb in the nucleus."
Perhaps a bit more background may make it even clearer what's happening.
Most people now understand that one thing all cancers have in common is defects in the genes of the cancerous cells which allow the cells to proliferate without effective limits. Not all cancer cells have the same defects. Indeed, even in cancers of specific tissue types (breast, colon, prostate gland, lungs, etc.), the set of defective genes may vary from person to person having the "same" type of cancer.
The defects do not occur all at once. Instead, they accumulate slowly, over many years. A variety of different "causes" can produce gene defects. Some defects are inherited at birth, which is why predisposition to particular cancers run in a family. Other defects occur "naturally" due to errors in copying DNA when cells divide. Still other defects are caused by chemical agents, which may be either produced naturally in the body (e. g. "free radicals") or come from outside (e. g. combustion products from cigarette smoking). And the list of agents that can damage DNA goes on: certain viruses (like HPV which can lead to cervical cancer), ultraviolet light (skin cancer), other high-energy electromagnetic radiation (X-rays), and radioactive materials (such as radon gas).
Fortunately, almost all DNA damage does not lead to cancer. In the first place, most DNA is "noncoding DNA" that does not correspond to a gene. The purpose (if any) of most of this noncoding DNA is still a mystery. But damage in this area probably has little effect. The remainder of the DNA does code for genes, of which humans have about 25,000. And of these 25,000, probably only a few hundred, at most, can lead to cancer if damaged. (Cataloging all such genes is a high-priority research project, known as The Cancer Genome Atlas).
And even if a critical gene is damaged, the effect is usually nothing. Cells have several ways of checking, and possibly fixing, DNA that is damaged in the process of cell division (when a fresh copy of all the DNA must be created). There are additional mechanisms for detecting errors in DNA that occur for any reason, with the results that cells having damaged DNA usually self-destruct through a process called apoptosis.
Genes that are involved in producing proteins which handle either DNA testing and repair or apoptosis are key genes which can lead to cancer if they themselves are damaged. The result is that in cells where such genes don't function properly, there are many more errors in the DNA that go unrepaired. There may be hundreds of damaged genes, though most don't contribute directly to cancerous characteristics. Yet the cell itself, because it doesn't undergo apoptosis, may survive and continue to divide and proliferate. Many cells with DNA damage may eventually cease to divide, or even die, because they are so messed up. But in a process of evolution and natural selection, some cells with damaged genes for DNA upkeep or apoptosis will survive -- the ones that do not develop fatal abnormalities.
Normal cells have an upper limit on the number of times they can divide, which is enforced by the length of the telomere structures at the end of chromosomes. A little bit of each telomere is lost every time a cell divides. However, there is an enzyme called telomerase which is active mainly in embryonic cells. Its function is to rebuild the telomeres in the cells of young embryos so that the cells can continue to divide. But at some point in development the telomerase gene becomes switched off, so that the clock regulating cell division starts ticking. Once the telomeres become too short, the cell stops dividing. The cell doesn't necessarily die, but it enters a phase called senescence.
As a result of damage to other genes which keep the telomerase gene switched off, it is possible for the enzyme to start being produced again. Cells which produce enough telomerase are potentially immortal, and can divide without limit. In other words, they become cancerous. So another key step on the way to cancer is for production of telomerase to resume in a cell that also has compromised DNA checking/repair and apoptosis function.
As unlikely as it is, damage to critical genes will inevitably occur, given that there are trillions of cells in a human body. Eventually, everybody will have many cells that contain some kind or another of damage in a critical gene. But fortuntately, again, even this is not enough to produce cancer by itself. For a given cell to become cancerous, several critical genes must be damaged in the same cell -- perhaps 10 or 20 more, depending on the type of tissue involved. For example, a tumor needs to attract blood vessels (in the process called angiogenesis) in order to receive oxygen and nutrients. A potentially cancerous cell must be able to hide from the body's immune system, which could otherwise destroy it. And in order for a tumor to metastasize, its cells must acquire the ability to separate from the tumor, enter the blood stream or lymphatic system, and finally invade other organs of the body. In brief, there must be a number of genes in any given cell that must all be defective for the cell to lead to a life-threatening cancer.
So on one hand, the chance of any particular cell accumulating all the necessary damaged genes is almost vanishingly small. But on the other hand, with trillions of cells in a body, the probability that eventually one cell will have damage to enough critical genes is not insignificant. Especially since damage is cumulative: mutated genes are passed along, with their mutation, to future generations of the cell. And remember, the process is not entirely haphazard. Because of a process of natural selection of cells that have just the "right" abnormalities, cell masses that have some cancerous properties evolve towards malignancy -- even though, along the way, vast numbers of cells that don't have the "right stuff" to become dangerous fall by the wayside.
The path to effectively dealing with cancer, then, requires figuring out just what the critical defects are and then devising ways to stop or interfere with the effects of the defective genes, so that cancerous tissue cannot grow and proliferate to other locations in the body.
Kolata describes how research progressed in the case of colon cancer:
Although there were scores of mutations and widespread gene deletions and rearrangements, it turned out that the crucial changes that turned a colon cell cancerous involved just five pathways. There were dozens of ways of disabling those pathways, but they were merely multiple means to the same end.
People with inherited predispositions to colon cancer started out with a gene mutation that put their cells on one of those pathways. A few more random mutations and the cells could become cancerous.
However, this all took a great deal of time. Cancer in types of tissue other than the colon doesn't necessarily work quite the same way. Fortunately new technology has come along that makes identification of active genes easier, and also allow experimentally turning genes on and off to figure out what they do:
The turning point came only recently, with the advent of new technology. Using microarrays, or gene chips - small slivers of glass or nylon that can be coated with all known human genes - scientists can now discover every gene that is active in a cancer cell and learn what portions of the genes are amplified or deleted.
With another method, called RNA interference, investigators can turn off any gene and see what happens to a cell. And new methods of DNA sequencing make it feasible to start asking what changes have taken place in what gene.
So, suppose we can determine all of the gene abnormalities that are really necessary for a malignant cancer. What then?
In the end, all those altered genes may end up being the downfall of cancer cells, researchers say.
"Cancer cells have many Achilles' heels," Dr. Golub says. "It may take a couple of dozen mutations to cause a cancer, all of which are required for the maintenance and survival of the cancer cell."
Every normal gene produces proteins which participate in various cellular processes. Each process is sort of like a relay race. For instance, one protein (a "receptor") in the cell wall reacts in some way, as a result of something in the cell's environment. The first protein acts as a signal to another protein to do something, which in turn signals other proteins, and so on. This chain of events is called a pathway. Mutated genes produce mutated proteins, or perhaps normal proteins at a time they ought not to be around. The net result is the activation of a pathway that causes cancerous behavior in the cell.
If scientists can find chemical entities that disrupt a cancerous pathway, then the cell's abnormal behavior can be thwarted. Finding these molecules is the ultimate goal of cancer research -- if successful, these are potent anti-cancer drugs. And the beauty of this is that drugs like this (ideally) affect only the abnormal pathways in cancer cells. They should not affect normal cells, unlike chemotherapeutic drugs which poison all cells, but cancer cells more than others only because the cancer cells divide more rapidly.
The "war on cancer" may actually be finally turning a corner towards success. We are now acquiring information quite rapidly about cancer-causing gene mutations and cancer pathways, thanks to our new technologies. We can now, in principle, design drugs to deal with each pathway. It's still going to take time before we have drugs for most of the serious cancers, because every potential drug has to go through a testing process of clinical trials, which can take ten years and hundreds of millions of dollars.
Dr. Golub said he expected that new drugs would strike the Achilles' heels of particular cancers. The treatment will not depend on where the cancer started - breast, colon, lung - but rather which pathway is deranged.
"It's starting to come into focus how one might target the problem," Dr. Golub said. "Individual cancers are going to fall one by one by targeting the molecular abnormalities that underlie them."
Tags: cancer, biology, medicine
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