April 30, 2003
Cancer-Proof Mouse With Anti-Cancer Immune System Discovered

Normally if a cancer cell line is injected into a mouse the cancer cells grow. Some scientists at Wake Forest University discovered a mouse that was immune to injected cancer and have bred it and produced many generations of cancer-proof mice.

A cancer-proof mouse, which can survive being injected with any number of cancer cells, has been discovered by US scientists. The discovery of the resistant mouse could pave the way for future gene or drug therapies if the mechanism by which it fights cancer can be understood

This is amazing for a few different reasons. First, it is amazing that it is possible at all. An immune system that can kill such a large variety of types of cancer which does not appear to cause auto-immune disorders is not something I would have expected to be possible. Cancer cells look too much like normal cells and most cancers (perhaps virally caused cancers are an exception) are probably expressing only genes that naturally are expressed in human cells. So where does the specificity come from that lets an immune system knock out a large variety of cancers? Just figuring it out will reveal very useful knowledge.

What is also amazing about it is that the mutation happened and someone noticed. It is hard to say what the odds are for the occurrence of a mutant that would have the resistance to cancer.until it is discovered how the mechanism works and how many mutations had to happen for a mouse to have cancer resistance. Still, it seems amazing to me.

Here are more details.

WINSTON-SALEM, N.C. Scientists at the Comprehensive Cancer Center of Wake Forest University have developed a colony of mice that successfully fight off virulent transplanted cancers.

"The mice are healthy, cancer-free and have a normal life span," the 10-member team reported in the Proceedings of the National Academy of Sciences online edition to be published the week of April 28.

The transplantation of the cancer cells in these special mice provokes a massive infiltration of white blood cells that destroy the cancer, said Zheng Cui, M.D., Ph.D., associate professor of pathology at Wake Forest University Baptist Medical Center and the lead scientist

"The destruction of cancer cells by these leukocytes is rapid and specific without apparent damage to normal cells," Cui said. "These observations suggest a previously unrecognized mechanism by which the body can fight off cancer."

The discovery of a genetic protection from cancer in mice "may have potential for better therapy or prevention of cancer in people," the team said. It also could help explain why some people are protected against cancer despite prolonged and intense exposure to carcinogens..

The discovery also could help solve another mystery. For years, scientists have been searching for the mechanism that permits spontaneous regression of human cancers without treatment. Cui said these cases are well-documented, but occur rarely. The new mouse colony gives the team the opportunity to study the mechanism in an animal model.

Cui and his colleagues began the mouse colony almost by serendipity. As part of ongoing cancer studies, they were injecting a virulent type of cancer cell that forms highly aggressive cancers in all strains of laboratory mice and rats. When injected into the abdomen, the tumor grows exponentially, causing the abdomen to fill with fluid within two weeks. The cancer can then progress by metastasizing into the liver, kidney, pancreas, lung, stomach and intestine.

But, said Cui, one male mouse unexpectedly remained free of the cancer despite repeated injections. The Wake Forest team was able to show this was genetic and to develop a colony from that single mouse. The colony, now about 700 mice, remains exclusively at Wake Forest. Meantime, the original mouse "remained healthy, cancer-free and eventually died of old age after a normal lifespan."

When the cancer-resistant mice were bred with normal partners, the researchers found that about half of their offspring were resistant to cancer cells, indicating that this genetic protection is dominant and is likely due to a change in one gene. The resistance continued in future generations.

Depending on the age of the mouse, some had complete resistance -- the cancer never got started -- while others displayed spontaneous regression -- the cancer started developing over a period of a couple of weeks, but then it rapidly disappeared in less than 24 hours.

"The mice became healthy and immediately resumed normal activities including mating," Cui said. They tested them again with another injection of the cancer cells. He said that once the mice developed the protection, they never again developed the cancer.

The researchers said the mouse model "represents a unique opportunity to examine cancer/host interactions."

Cui said the new mouse model also may help in solving another medical mystery -- why cancer becomes more common when people age. The usual explanation is that mutations accumulate in the body, leading to precancerous conditions that eventually become cancer.

But, he said, the mouse model suggests that the body's natural protection -- which scientists call host resistance -- declines with age.

Note that this result suggests another reason why the aging of the immune system is a significant problem. Luckily, it will probably be easier to develop rejuvenating cell therapy treatments for the immune system (also see this post) than for many other systems of the body.

How would a mutation that is found in a laboratory mouse strain be usable to create an anti-cancer therapy for humans? Well, the human and mouse genomes have both been sequenced and they have corresponding sections that can be lined up for 90% of their regions. Once the mutation location(s) responsible for this are found in mice then it is likely there will be a corresponding regions in the human genome. It may be possible to introduce equivalent mutations into the DNA of human leucocyte stem cell lines using gene therapy and then inject those stem cells into humans suffering from cancer. Then the cells would multiply and turn into immune cells that fight cancer. Many parts of the transfer of blood stem cells between humans is routinely done as part of leukemia treatments and for other disease treatments..

This mutation (or set of mutations - the capability may the result of a combination of mutations) is likely to have previously occurred in the wild. The fact that the mutation does not normally occur in wild type mice or naturally in other mammalian species suggests that either protection against cancer was not selected for by evolution because other things were killing mammals first or that the mutation has some cost in terms of reproductive fitness. It will be interesting to see how that shakes out.

Even if the mutation turns out to have some downsides it might still be useful as part of a therapeutic treatment. After all, when the downside of not getting treated is death then the side-effects (whatever they might be) of a revved up immune system may be worth it. Also, it might even be possible to add the mutation in a way that can be turned on and off. Attach the relevant gene to a regulatory region that can be switched on and off by a drug. Then even if there was a side-effect to this capability in the immune system it could be activated only long enough to wipe out a cancer.

Another thing that is great about this discovery is that it provides a model to figure out. Here's an immune system that can wipe out a large assortment of cancers. How? The detective work that will be done to figure that out will yield information that is useful by itself. It is even possible that the discovery of the knowledge of how these mice attack cancer will point the way to how to train an immune system to fight cancer with a method less drastic than gene therapy. Perhaps a vaccine could be developed that would train a human immune system to do the same.

Share |      Randall Parker, 2003 April 30 10:02 PM  Biotech Cancer

Stephen Gordon said at May 2, 2003 2:32 PM:

I hope this is not cold-fusion-too-good-to-be-true story.

chalmers means said at November 8, 2003 4:34 PM:

i am looking for any information or leads to crp as it relates to periodontal disease, especially in other mammals (particularly canines). Doesa inflammation in the gums of humans and dogs correlate with the presence of elevated levels of crp in the blood?

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