One of the biggest challenges to the treatment of cancer is overcoming the ability of cancer cells to become resistant to drugs or radiation. The problem of resistance is particularly relevant in brain cancers called gliomas. Research published in the Journal Stem Cells reports one method of overcoming this problem.

Scientists at Duke University and the Cleveland Clinic claim to have identified molecules associated with the ability of certain cells within a glioma, called tumor stem cells, to resist radiation. Specifically, they have identified a protein called "Notch", which is normally involved in embryonic development, that seems to be selectively found in resistant cells. Using genetic engineering methods they have made cells that were previously sensitive to radiation to become resistant by inducing expression of Notch.

Dr. Jialiang Wang of Duke University, who is the lead author of the study. said the finding marked the first report that Notch signaling in tumor tissue is related to the failure of radiation treatments.

"This makes the Notch pathway an attractive drug target," Wang said. "The right drug may be able to stop the real bad guys, the glioma stem cells."
The authors have also demonstrated that by inhibiting activity of the Notch protein, through administration of chemicals known as gamma-secretase inhibitors, can result in making resistant cells sensitive to radiation.

These findings are interesting in light of another very recent publication (Zhen et al. Arsenic trioxide-mediated Notch pathway inhibition depletes the cancer stem-like cell population in gliomas. Cancer Lett. 2009 Dec 3) in which the anti-leukemic drug Arsenic Trioxide was also demonstrated to alter glioma stem cells through manipulation of the Notch pathway. Notch has been found in numerous other types of tumor stem cells such as breast, colon, lung, and prostate cancer. The expression of a protein in cancer cells that is supposed to be only expressed during embryonic development supports the theory that during formation of cancer, mature cells tend to revert to an embryonic-like phenotype. This is also exemplified by the fact that adding cancer genes (oncogenes) in combination with some specific proteins can take an adult skin cell and transform it into a cell that resembles the embryonic stem cell, called an "iPS" cell. This is described in the following video:

Sickle cell anemia is a genetic disorder that affects approximately 80,000 Americans, primarily of African-American origin. It is characterized by defective production of red blood cells which makes them extremely fragile and not capable of fully transporting oxygen.

In the December 10th issue of the New England Journal of Medicine a report describing a clinical trial performed at the Clinical Center of the National Institutes of Health in Bethesda, was published that described successful treatment of 9 out of 10 adults suffering from this condition.

"This trial represents a major milestone in developing a therapy aimed at curing sickle cell disease," said NIDDK Director Griffin P. Rodgers M.D. "Our modified transplant regimen changes the equation for treating adult patients with severe disease in a safer, more effective way."

The use of stem cell transplantation for genetic conditions is now becoming increasingly commonplace. For example, cord blood stem cells have been used to treat conditions such as Krabbe Disease, which is a lethal metabolic abnormality. The reason that the current study is so important was that it used a type of "conditioning regimen" that was substantially less toxic than previously performed.

In an older study about 200 children with severe sickle cell disease were cured with bone marrow transplants after receiving high doses of chemotherapy. That protocol was too toxic for adults, whose organs are damaged from the prolonged exposure to abnormal red blood cells and their breakdown products. The current treatment method is applicable to adults.

Stem cell transplantation for conditions like leukemias require the recipient bone marrow to be destroyed prior to administration of the new stem cells. In conditions such as sickle cell, one does not need to completely destroy the recipient bone marrow but merely to replace it with enough healthy stem cells so as to produce sufficient quantities of healthy red blood cells. Although this has theoretically been discussed in sickle cell anemia, to date, the current study is the first one to actually demonstrate this. It is anticipated that future studies of this sort will be conducted to attempt treatment of other metabolic abnormalities.

The cornea is front part of the eye that is transparent and allows light to enter. The cornea is does not have a blood supply and receives its nutrients from diffusion and oxygen directly from the air. Corneal scarring is a major cause of vision loss and blindness. Today researchers at the University of Cincinnati reported a new method of reducing corneal scarring using stem cells in mice.

Mice that suffer from corneal scarring are used for assessment of possible new treatments for this condition. The researchers conducting the study, lead by Winston Whei-Yang Kao, PhD, professor of ophthalmology, at the University of Cincinnati, used a mouse that was genetically engineered to lack a protein called lumican, which is involved in maintaining a clear cornea.

At the 49th Annual Meeting of the American Society of Cell Biology in San Diego today, the researchers presented data indicating that treatment of the lumican deficient mice with stem cells derived from human umbilical cords leads to preservation of vision. The specific type of stem cells used were called mesenchymal stem cells. These cells have been previously demonstrated to be capable of becoming a variety of other tissues when exposed to specific chemicals.

Although corneal transplantation is a relatively established procedure that has saved the vision of many, researchers believe that the use of umbilical cord blood stem cells in this area still has significant potential. "Corneal transplantation is currently the only true cure for restoration of eyesight that may have been lost due to corneal scarring caused by infection, mechanical and chemical wounds and congenital defects of genetic mutations," Kao says. "However, the number of donated corneas suitable for transplantation is decreasing as the number of individuals receiving refractive surgeries, like LASIK, increases."

Dr. Kao also commented on the potential treatment applications possible with the umbilical cord stem cells. "Our results suggest a potential treatment regimen for congenital and/or acquired corneal diseases," he says, adding that the availability of human umbilical stem cells is almost unlimited. These stem cells are easy to isolate and can be recovered quickly from storage when treating patients. "These findings have the potential to create new and better treatments — and an improved quality of life — for patients with vision loss due to corneal injury."

Mesenchymal stem cells have already been demonstrated safe in clinical trials, however, to date efficacy studies are still underway for a variety of conditions. The data presented today suggests how many new possible uses of stem cells exist, and the almost limitless possibilities in the area of regenerative medicine.

After severe burn wounds patients are susceptible to infections, which unless properly managed can result in sepsis and dead. The current standard of care involves taking skin cells from the patient in an area that has not been injured, expanding the cells in tissue culture, and subsequently placing the cells on the area that has been burned. The drawback with this approach is that it takes about three weeks. In the interim many patients develop infections. Therefore new technologies are needed to create cells that can be ready to use in an expedient manner. A previous approach has been to use skin cells from the foreskin of infants after circumcision and expand these cells. However immune rejection occurs and these cells are not as protective as using the patient’s own cells.

A French team of scientists created human skin from stem cells and demonstrated that the skin was functional by placing it on the back of a mouse that was lacking an immune system (so to avoid rejection). The skin engrafted on the mouse and remained alive for the evaluation period of 3 months. Most strikingly, the skin was able to allow for healing of the mouse’s own epidermis. Since the skin cells were derived from stem cells, the scientists believe that they represent cells that are less visible to the immune system.

Dr. Marc Peschanski, research director at the French Research Institute I-Stem, stated" What our findings can provide is a way to cover the burns during those three weeks with skin epidermis … produced in that factory and sent to the physician at the moment they receive a severely burned patient," He continued "They call the factory and then, immediately, they will get a square meter of epidermis which will be a temporary way to cover the burns."

Stem cell therapies for burn wounds have been relatively underexplored. Previous studies have demonstrated that bone marrow stem cells can accelerate wound healing. While this approach is promising, it is difficult to perform bone marrow extraction in patients with severe burn wounds. Additionally, few hospitals have the facilities to process bone marrow cells in order to be administered on the skin.

The advantage of the work described in the publication (Guenou et al. Lancet. 2009 Nov 21;374(9703):1745-53) is that the cells can be used in a "universal donor" fashion. That is, they can be stockpiled and ready for application when the need arises.

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.