The controversial idea that all tumors are created by cancer stem cells received a setback Wednesday.

The theory holds that a tiny percentage of cancer cells — perhaps one in a million or one in 10,000 — are responsible for creating tumors. Like evil relatives of standard organ-forming stem cells, cancer stem cells build tumors. It's an appealing idea because it provides a new, well defined target for treatment.

But a new study casts doubt on the idea that only a few cancer cells are able to generate tumors. By tweaking the experimental design other cancer researchers had been using — the new study used a different type of mice — a highly-respected stem cell oncologist found that as many as 25 percent of melanoma cells were capable of reproducing.

What makes the study particularly surprising is that its lead author was a founder of Oncomed, the leading cancer stem cell biotech startup, and comes out of the University of Michigan, where much of the early work on cancer stem cells was conducted.

"We're not trying to claim there is no merit to the field, but we think that the frequency of cancer stem cells will be much higher," said Sean Morrison, director of the Center for Stem Cell Biology at the U-M Life Sciences Institute and coauthor of the study in Nature Thursday. "And there will be some cancers like melanoma where lots of cells will be tumorigenic and it won't be possible to treat those cancers by treating a small subset of cells."

The cancer stem cell theory of tumor creation had taken the field of oncology by storm. It promised an entirely new class of cancer treatments. In fact, a raft of new drugs designed to attack cancer stem cells are just entering clinical trials. While Oncomed has been a leader in the biotech space — signing a $1.4 billion commercialization deal with GlaxoSmithKline, the largest ever biotech deal for a preclinical stage company — major pharmaceutical companies are beginning to develop their own drugs based on the research.

Now, the underlying premise of those studies and drugs is being called into question.

Long-time critics of the cancer stem cell theory like Johns Hopkins oncologist, Scott Kern, are pleased.

"The paper seems in line with what one should expect," Kern wrote in an email. "Solid tumors (the carcinomas, brain tumors, and sarcomas) will not be found to follow the stem cell theory."

But even critics like Kern, who had previously attacked the math underlying the cancer stem cell theory as "weak," and Morrison believe that the cancer stem cell model will work for some tumor types, particularly leukemia.

It's the concept's broad application to all sorts of cancers that worried both Morrison and Kern. The seductive symmetry of having

"bad" stem cells along with the standard ones could have led researchers to push the theory beyond what the science could support.

"When you look back at science, it's the theories that make the most intuitive sense that people run with before the data exists," Morrison said.

But cancer stem cell researcher Max Wicha, another cofounder of Oncomd and oncologist at the University of Michigan, countered that just because the new mouse model generated large numbers of tumorigenic cells, doesn't mean that it's necessarily a better model than the one they'd long been using.

"[Morrison's work] is very interesting and important but we need to look at the different mouse models and see which provides the best representation of what's in patients," Wicha said.

Both mouse models have been engineered to lack a high-functioning immune system because the standard mouse immune system would kill the human cancer cells that the researchers are trying to study. That necessary change, however, is also a major source of uncertainty in cancer stem cell research.

The humans that will eventually be treated have standard immune systems, so how much to tweak the mice to allow the tumor cells to grow is a major variable. Morrison's mice have even weaker immune defense systems than those used by Wicha and other cancer stem cell researchers.

"He's saying that we may have underestimated the number of tumorigenic cells," Wicha said. "I say his new model may have overestimated that number."

Wicha also points to evidence outside the mouse models that only a small number of cancer stem cells are responsible for building tumors.

Wicha noted previous studies showing that some cancer cells express many of the same genes that standard stem cells do.

"These are cells which have stem cell properties," he said.

Soon, however, some of these battles will become moot as results start to roll in from clinical trials in humans. Right now, drugs designed to combat cancer stem cells are only in phase I safety trials, but they will be heading to phase II, where their efficacy will begin to be tested, within a year or two.

"Those will really tell us whether the clinical endpoints will improve,"

Wicha said. "If we start seeing any improvement in survival and the patients doing better, it'll all take off."

Many oncologists will be watching how Oncomed's lead drug candidate OMP-21M18 does when it finishes up its first trial.

"If the therapeutic shows a benefit to patients, then all of these scientific concerns go by the wayside," Morrison said. "And even if the model is flawed in fundamental ways, if it led them to a good therapeutic, that's still worth a lot."

Morrison remains skeptical, however, that any silver bullet will ever be found for cancer, arguing that his new paper shows just how complex cancer is turning out to be.

"The reality is that cancer is an extraordinarily resourceful disease and every time there has been a new idea, people have seized on it to make it the big answer," he said. "Cancer is resourceful enough that there isn't going to be a big answer."

Citation: "Efficient tumour formation by single human melanoma cells" by Elsa Quintana, Mark Shackleton, Michael S. Sabel, Douglas R. Fullen, Timothy M. Johnson and Sean J. Morrison. Nature: doi:10.1038/nature07567

Image 1: Dr. Timothy Johnson/University of Michigan. A melanoma skin lesion on the chest of a 45-year-old male patient. The lesion measures 1.2 inches by 1.6 inches. Image 2: Mark Shackleton/University of Michigan. This microscope image shows melanoma cells from a tumor, magnified 600

times. The three large, dark-brown cells contain high levels of the pigment melanin.

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