In Greek mythology, a terrifying swamp monster known as Hydra would regrow two heads for every one lost when one of the serpent's many necks was severed, making the beast nearly impossible to slay. Modern scientists think they may have discovered why cancer often behaves like Hydra, refusing to die despite every seemingly mortal blow that medicine inflicts upon it.
Current cancer therapies may attack only the equivalent of Hydra's head -- the majority of cancer cells removed by surgery or destroyed by radiation and chemotherapy. Spared is a crucial pool of mutant cells that acts as the source of the malignancy, leaving the cancer able to rise again and again.
According to this theory, which has steadily been gaining credence, the only effective strategy for defeating cancer will be found in treatments that stanch cancer's ability to regrow, such as what Hercules did when he finally slew the beast of ancient Greece by cauterizing each of the monster's necks.
In the case of cancer, the solution would lie in stamping out the highly specialized cells, known as cancer stem cells, that appear to give rise to the cancer in the first place. Such cells are largely impervious to current treatments, enabling them to lurk silently until they repeatedly spawn new tumors, either in the same part or in other parts of the body.
"What we've been doing is simply making the tumor shrink -- leaving the equivalent of the source of the head behind. So it just regrows," said Michael Clarke, a professor of medicine at the University of Michigan in Ann Arbor, who has found evidence for the existence of breast cancer stem cells. "We need to figure out how to sever the head so it doesn't grow back."
In addition to breast cancer, scientists have produced evidence for the existence of cancer stem cells in two leukemias and a variety of brain cancers.
In the most recent evidence, published in the Aug. 12 issue of the New England Journal of Medicine, researchers at Stanford University showed that among the millions of cancerous cells found in patients suffering from chronic myelogenous leukemia, only a small, discrete population had the ability to replenish the cancer.
"We showed that only certain cells have the ability to self-renew," said Irving Weissman, who directs Stanford's Institute for Cancer/Stem Cell Biology and Medicine.
These cells appear to have specific characteristics -- they are mutant versions of normal stem cells, which are the immature versions of all cells that have been the focus of attention in recent years because of their potential for treating a host of ailments.
It remains unclear how cancer stem cells originate. But they probably arise as a result of genetic defects or exposure to toxins, researchers said.
"Normal stem cells are regulated by the body to make just the amount you need," Weissman said. "But a cancer stem cell has broken out of that control. It self-renews in an unregulated fashion. Its self-renewal gets way too big."
Regardless of the cause, scientists are urgently trying to identify cancer stem cells for every type of malignancy.
"We're going to keep going through each and every human cancer to isolate each of the cancer stem cells and show what their properties are so one can look for new kinds of therapies," Weissman said.
Identifying the properties of the cancer stem cells could provide crucial information, according to Peter Dirks, a neurosurgeon at the University of Toronto who has found evidence for cancer stem cells in every form of brain cancer he has examined.
Brain cancer tumors that tend to be more aggressive appear to have higher concentrations of cancer stem cells, he said. "We're trying to apply this to patient prognosis," Dirks said. "This may identify which tumors are most likely to respond to treatment but then relapse."
Scientists trying to understand cancer better at a fundamental level should focus their efforts on cancer stem cells, he said.
"A lot of research on cancer involves the whole tumor mass," Dirks said. "If you study the expression of genes in all those cells you may not be studying the genes that are the most important."
But perhaps the most important implication is that identifying and understanding cancer stem cells could lead to more potent treatments.
"If you think about the basis for leukemia treatment, generally it is predicated on the idea that leukemia cells grow faster than the normal cells. So that's what it goes after," said John E. Dick, a professor of molecular genetics at the University of Toronto, who discovered cancer stem cells for acute myelogenous leukemia.
"But these cells aren't. These leukemia stem cells are resting. They behave just like a normal stem cell. They sit there and eventually will regrow the leukemia," Dick said. "It's critically important to understand these leukemia stem cells so we can target them.
"What we need to be able to do is identify these cancer stem cells to understand their properties so we can begin to be more strategic and kill the cancer at its source, which are these cancer stem cells."
That is exactly what Craig T. Jordan, a professor of medicine at the University of Rochester, has started to try to do. Jordan has identified a molecular switch involved in cell survival that appears to be unique to leukemia stem cells and absent from normal blood stem cells. "We don't think normal treatments would hit this target, which is why patients relapse," he said.
Jordan has begun testing drugs that, at least in the laboratory, appear highly effective at killing leukemia stem cells while sparing healthy stem cells, he said.
"It looks fantastic in the lab. In the laboratory we can very effectively kill the tumor without killing the normal stem cells," he said.
A preliminary trial involving leukemia patients has begun at the University of Kentucky, Jordan said.
"It's finally getting to the exciting point," he said.