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Killing Breast Cancer Stem Cells

Janice Karin, November 29, 2009

Cancer stem cells are a very new and scary concept. Traditionally researchers tested new drugs on cancer cells in test tubes. When a drug was found that killed the cells in the test tube, it was then experimented with on animals. If there was an effect on animals, then it would be tested in humans. The concept of the cancer stem cell threatens to overturn this traditional "way of doing things" that the cancer drug development industry has been based upon practically for the last century.

Specifically, the cancer stem cell concept is that the tumor is not one population of cells that all have the same properties. The cancer stem cell concept teaches that within a tumor there is a small population of "seed cells" or "stem cells" that perpetually make copies of themselves as well as differentiate or become the bulk of the tumor. In the same way that if you cut a tree but the trunk is left, the tree will re-sprout, according to the cancer stem cell concept, if you treat the bulk of the tumor but not address the cancer stem cell, the cancer will come back. But you may ask, if this is the case, then why is it that in animal studies some drugs actually produce complete cures? The answer may be in that animal tumors are very different than naturally occurring tumors. Specifically, when one gives cancer to an animal there are two approaches that are used. The first involves giving an animal cancer "cell line" to an animal that has an immune system. The second approach is giving a human "cell line" to an animal that does not have an immune system. Both of these conventional approaches involve "cell lines", which are cancer cells that have been growing in tissue culture for a long time. When tumors grow in tissue culture, certain cells of the tumor will grow faster than others. According to the old hypothesis that tumor cells are the same throughout the tumor, the use of cell lines is acceptable because it would mean that the cell line represents the tumor. According to the tumor stem cell hypothesis, the use of cell lines is unacceptable because when the tumor cells were growing in the test tube, certain cell populations may have overgrown the cell populations that "really" represented the tumor.

Evidence of the existence of tumor "subpopulations" came originally from studies in leukemia. Work from Dr. John Dick's group at the University of Toronto, in Canada, demonstrated that of the leukemic cells in the blood of patients, only a small percentage (<0.0001&) were capable of causing leukemias in mice when freshly isolated from patients. The difference between the cells capable of causing leukemia in mice and those not having this ability, resided in whether the cells expressed markers of stem cells. Specifically, the cells that contained the stem cell associated protein CD34 were capable of causing leukemia formation, but the cells that lacked expression of this molecule could not (Lapidot, T., et al., A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 1994. 367(6464): p. 645-8)

Subsequent studies by other groups demonstrated similar cancer stem cells existed in other tumors, including in breast cancer (Al-Hajj et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8) and colon cancer (O'Brien et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007 Jan 4;445(7123):106-10).

One of the common characteristics of the "tumor stem cell" is that they all express high levels of molecular pumps that spit out chemotherapeutic drugs. This is a mechanism by which cancer stem cells protect themselves. The question is asked, "how would the cancer stem cells specifically know to express such proteins that specifically spit out the drugs we use against them?" The answer is actually associated with the fact that the cancer stem cells in many ways resemble normal stem cells. Normal stem cells also express high quantities of these "drug pumps", the reason for this is because the normal stem cell has to protect itself from DNA damage. By pumping out things that could damage the DNA (such as chemotherapeutic drugs), the stem cell protects itself.

So if cancer stem cells express pumps that make chemotherapy ineffective, how can one develop therapies against them?

Researchers at the Broad Institute and Whitehead Institute have an idea. In a recently published paper (Gupta et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-59) a novel method of keeping breast cancer stem cells alive and growing in tissue culture was reported. The scientists proved that they were able to expand cancer stem cells based on cell characteristics and ability of the cells to induce tumor growth when administered to animals. Using this system, the scientists screened thousands of compounds randomly to see which ones may inhibit the cancer stem cell.

"Evidence is accumulating rapidly that cancer stem cells are responsible for the aggressive powers of many tumors," says Robert Weinberg, a Member of Whitehead Institute for Biomedical Research and one of the authors of the study. "The ability to generate such cells in the laboratory, together with the powerful techniques available at the Broad Institute, made it possible to identify this chemical. There surely will be dozens of others with similar properties found over the next several years." "Many therapies kill the bulk of a tumor only to see it regrow," says Eric Lander, Director of the Broad Institute of MIT and Harvard, and an author of the Cell paper.

"This raises the prospect of new kinds of anti-cancer therapies."

The scientists identified one compound as particularly promising: salinomycin. This compound was 100-fold more potent than standard chemotherapeutic drugs such as paclitaxel at inhibiting tumor stem cell proliferation. Additionally, salinomycin was capable of inhibiting human tumors grown in immune deficient mice. In the studies performed salinomycin appeared to have minimal toxicity. Interestingly the mechanism of action appeared to be through induction of tumor stem cell differentiation. That is, instructing the tumor cell to become a type of cell that is still alive but has lower or absent potential for continued growth and metastasis.

Salinomycin is an ionophoric coccidiostat agent that is used as a supplement in chicken feed to control infection with coccidia and Clostridium perfringens (Bolder et al. The effect of flavophospholipol (flavocin) and salinomycin sodium (sacox) on the excretion of Clostridium perfringens, Salmonella enteritidis, and Campylobacter jejuni in broilers after experimental infection. Poult Sci. 1999;78:1681-1689). Salinomycin is commercially available for veterinary use.



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