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Screening Method for Cancer Stem Cells Developed

Cell, August 13, 2009

On the one hand, there are those scientists who believe that cancerous cells originate from specialized "cancer stem cells", that exist in small numbers and reside only in specific "niches", and a number of publications in respected medical journals substantiate such a belief with persuasive evidence. On the other hand, however, there are those scientists who insist that such evidence is inconclusive, citing equally persuasive evidence to the contrary, and insisting therefore that the "cancer stem cell theory", as it is known, will eventually be disproven.

Since different types of cancer behave very differently from each other, with each type exhibiting its own unique properties and characteristics, no doubt the truth will eventually show that the "theory" applies to some cancers but not all. In other words, it is possible that some types of cancer originate from small numbers of cancer stem cells hidden in niches, while other types of cancers do not. Meanwhile, however, a new discovery now adds further fuel to the ongoing debate.

Scientists at the Broad Institute, a collaborative Harvard-M.I.T. genomics research project, have now devised a method for the utilization of drugs that can attack and kill the putative cancer stem cells, while leaving ordinary, healthy cells unharmed. Led by Dr. Piyush Gupta, the team of researchers has successfully screened 16,000 chemical agents for their ability to target and kill breast cancer stem cells. Included in the list of screened chemicals were all those currently approved by the U.S. Food and Drug Administration, from which the scientists found that 32 of the chemicals have the ability to selectively target and kill cancer stem cells, although only one of the 32 chemicals is currently approved as an anticancer drug. In particular, salinomycin was found to destroy both the cancer stem cells that were generated in vitro, in the lab, as well as those that occur naturally, in vivo. When compared to paclitaxel, the common breast cancer drug, salinomycin was found to reduce the number of cancer stem cells by more than 100-fold, while also inhibiting breast tumor regrowth in mice.

The technique, know as "epithelial-to-mesenchymal transition", generates large numbers of cancer cells with stem-cell-like qualities. According to Dr. Tamer Onder, formerly of the Whitehead Institute for Biomedical Research but now a postdoctoral fellow at Children's Hospital in Boston, "A critical aspect of our work was to generate relatively homogeneous and stable populations of cancer stem-cell-like cells that could then be used for screening. We were able to achieve this by inducing the cancer cells into an epithelial-to-mesenchymal transition using novel reagents that we had developed in the lab."

The discovery has been met with great enthusiasm by some, and great skepticism by others.

It is a well known fact that many types of cancer are highly resistant to conventional medical treatments such as chemotherapy and radiation. Even though chemotherapy may successfully kill as much as 99% of the cells in a tumor, it is the remaining 1% that is the most virulent and is often the source of recurring cancer. Such a common, unsophisticated observation has added strong evidence to the "theory" that some types of tumors develop from specialized cancer stem cells, hidden away in specialized "niches", and it is these stem cells which are believed by some researchers to be so resistant to radiation and chemotherapy, and hence to play a prime role in metastasis. As Dr. Eric Lander of the Broad Institute explains, "If we make a drug that kills 99.9% of the cells in a tumor but fails to kill the 0.1%, that is the real problem. It's a pyrrhic victory." As he further adds, this innovative new drug screening method may allow "a potential for a real renaissance in cancer therapeutics."

Skeptics remain, however. According to Dr. Bert Vogelstein, a cancer geneticist at Johns Hopkins University, "The cancer stem cell hypothesis has in the past year been challenged on many fronts. For example, a paper on melanomas last year showed that 100% of melanoma cancer cells were cancer stem cells." However, melanomas behave very differently from, say, breast or prostate cancers, for example, and in recent years there have also been numerous discoveries of stem cells that were found in niches in many types of solid tumors, including those of the breast, the prostate, the brain, the colon and the pancreas. Earlier this month, another team of researchers, led by Dr. Irving Weissman of Stanford University, reported the additional discovery of a similar type of stem cell in bladder cancer. Offering yet another counterpoint to Dr. Vogelstein's stance is Dr. Robert Weinberg, a cancer biologist at the Whitehead Institute for Biomedical Research at M.I.T. and a coauthor with Dr. Lander of the new report, who states that, "Evidence is accumulating rapidly that cancer stem cells are responsible for the aggressive power of many tumors."

Instead of simply acknowledging that all cancers are different and that it is therefore possible for some types of cancers to originate from a small number of cancer stem cells residing in niches, while other types of cancer do not neccesarily need to match such a model, instead the experts in the field insist that there must be only one theory and one model with one explanation for all types of cancer, and thus the arguments continue to escalate over who is right and who is wrong. As Dr. Michael F. Clarke of Stanford University explains, "It's the most amazing polarity that I've seen. It's like two religions fighting."

Diplomatically offering a possible solution for both camps, Dr. Weinberg further states, "The possibility is that the non-stem-cell cells in a tumor may regenerate de novo new stem cells. If one had ways of treating both the stem cells and the non-stem cells, then the de novo generation of stem cells would be dealt with." Dr. Vogelstein further adds, in apparent agreement, that if it is true that stem cells are commonly found throughout solid tumors, rather than just in a small reservoir of "niche" cells, "then there's no difference between the stem cells and the bulk cancer, so a screen for drugs to kill melanoma cells is by definition also going to kill the melanoma's cancer stem cells." From either perspective, the new techniques developed at the Broad Institute may fall into exactly this category.

Somewhere in the middle of the debate, there are a number of scientists who believe that the new methods developed by the team of researchers at the Broad Institute have important clinical implications, regardless of whether or not the cancer stem cell niche theory is correct. As Dr. Vogelstein explains, "Because most of the compounds in use now clearly aren't doing the job we'd all like, then novel methods for screening could be extremely valuable." According to Dr. Gupta, and in reference to conventional radiation and chemotherapeutic modalities, "You could probably lower the doses considerably with a combination of drugs that attacked specific types of cells."

Along those lines, and disregarding the ultimate outcome of the debate, researchers at the Broad Institute hope that their screening methods will be of possible commercial interest to pharmaceutical companies, for the eventual development of a new class of anticancer medicine.



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