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Old 02-21-2011, 02:01 PM
Dross Dross is offline
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Default Reprogrammed stem cells hit a roadblock

It's a discordant note in the symphony of good news that usually accompanies stem cell research announcements. Stem cells hold enormous promise in regenerative medicine, thanks to their ability to regenerate diseased or damaged tissues. They have made it possible to markedly improve the effectiveness of many medical treatments – muscle regeneration in cases of dystrophy, skin grafts for treating burn victims, and the treatment of leukemia via bone marrow transplants.

The problem is obtaining them. Those that are the true source of life, in the first days of embryonic development, are of course the most highly sought after; still undifferentiated, they are "pluripotent," meaning they can evolve into liver, muscle, eye – any kind of cell. But the issue of how to obtain them clearly raises insurmountable ethical questions.

"In this regard, the recent discovery of the "reprogramming" phenomenon, by which somatic cells can be induced to convert to a pluripotent state simply by forcing the expression of a few genes, opens a phenomenal number of possibilities in regenerative medicine," says Didier Trono, Dean of the EPFL School of Life Sciences. "Imagine, for example, collecting a few cells from the hair follicle of a hemophiliac patient, reprogramming them to the pluripotentiality of their embryonic precursor, correcting the mutation responsible for the coagulation disorder that plagues the patient, and then re-administering them, genetically "cured," after having orchestrated a differentiation into fully functional progeny."

Increased risks for cancer?

But a study that has just been published in the journal Cell Death and Differentiation, to be followed by two articles in the journal Nature, is dampening those hopes. Conducted by the Department of Biochemistry at the University of Geneva and the European Institute of Oncology in Milan, with the participation of Trono's laboratory, it concludes that these reprogrammed cells exhibit a "genomic instability" that appears to be caused by the process used to return the cells to their embryonic state. Even more serious, the genetic mutations observed resemble mutations that are found in cancer cells. The scientists draw the conclusion that reprogrammed stem cells need to be extensively investigated before they can even be considered for use in regenerative medicine.

The experiments were done using mouse mammary and fibroblast cells. The researchers used three different processes for reprogramming the cells to a "stem," or embryonic, state. The first method was developed expressly for this study, and the others have already been well documented.

Yet all the processes led to the same, implacable conclusion: the genetic anomalies multiplied, in a manner that seems to indicate that they are inherent to the reprogramming process itself, which typically makes use of oncogenes. "Interestingly, oncogenes have the potential to induce genomic instability," the authors explain.

These results underline the necessity of conducting further studies. First, to see if the genetic anomalies are serious enough to compromise the function and stability of cells regenerated using the reprogrammed cells; and second, to "refine the methods used for generating induced pluripotent cells, in order to avoid this problem. These results will thus motivate scientists to come up with a solution," concludes Trono.

Last edited by gdpawel : 12-15-2012 at 08:39 PM. Reason: posted full article
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Old 02-21-2011, 02:47 PM
gdpawel gdpawel is offline
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Default Re: Reprogrammed stem cells hit a roadblock

My understanding is that it's the reintroduction of oncogenes (e.g. c-myc) which is the problem. The Holy Grail is the search for "small molecules" which re-program the cells to a more primitive state, without genomically altering the cells.

(Chemotherapy Advisor) - The Nobel laureate Jim D. Watson, PhD, has put a forth a novel hypothesis about cancer. In an article published in the journal Open Biology, Watson takes aim at an essential problem in oncology, “Although the mortality from many cancers, particularly those of hematopoietic cells, has been steadily falling, the more important statistic may be that so many epithelial cancers (carcinomas) and effectively all mesenchymal cancers (sarcomas) remain largely incurable.”

In addressing this issue, Watson emphasizes the role of the gene transcription activator Myc (c-Myc), which has been found to be a key driver of cancers of blood-forming lymphocytes, small-cell lung cancer, and possibly other late-stage cancers such as receptor-negative and ductal breast cancers. High levels of Myc (c-Myc), he says, “may turn out to be an essential feature of much of the truly incurable cancer.” Cells with high levels of Myc proceed less efficiently through the mitotic cycle and which may imply that multiple vulnerabilities with increased susceptibility to chemotherapy may exist.

Watson devotes much of the article to a discussion of reactive oxygen species (ROS), which have a double nature with regard to cancer. On one hand, they promote apoptosis, the process by which stressed or damaged cells undergo programmed death, and are thereby “a positive force for life,” Watson says. On the other, ROS have the capacity “to irreversibly damage key proteins and nucleic acid molecules (e.g., DNA and RNA).” Watson suggests that many cancer chemotherapies and ionizing radiation produce apoptosis by accelerating the synthesis of ROS.

Under normal conditions, ROS are continually neutralized by antioxidative proteins including glutathione, superoxide dismutase, catalase, and thioredoxin, the synthesis of which is controlled, in part, by the Nrf2 transcription factor. The synthesis of Nrf2 is in turn promoted by the RAS, RAF, and MYC oncogenes. Thus, Watson controversially states, “The fact that cancer cells largely driven by RAS and Myc are among the most difficult to treat may thus often be due to their high levels of ROS-destroying antioxidants.”

Watson directly challenges the many scientists who have long promoted antioxidants as the first line of defense against cancer, even suggesting that antioxidants in the diet “may have caused more cancers than they have prevented.” He writes, “Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.”

Watson makes a call for a renewed and accelerated effort to develop curative treatments for cancer. He criticizes the “never frantic” pace of work toward this goal and finds it telling that there is no influential general—“an Eisenhower or even better a Patton”—leading the war on cancer. He specifically recommends a shift in emphasis in cancer research away from drugs targeting growth-promoting molecules of signal transduction pathways (such as HER2, RAS, RAF, and others) and toward anti-Myc drugs.

[url]http://rsob.royalsocietypublishing.org/content/3/1/120144.full

Antioxidants in Cancer Therapy; Their Actions and Interactions With Oncologic Therapies

[url]http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-2346.pdf
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