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The same genes that are chemically altered during normal cell differentiation, as well as when normal cells become cancer cells, are also changed in stem cells that scientists derive from adult cells, according to new research from Johns Hopkins and Harvard.

Although genetically identical to the mature body cells from which they are derived, induced pluripotent stem cells (iPSCs) are notably special in their ability to self-renew and differentiate into all kinds of cells. And now scientists have detected a remarkable if subtle molecular disparity between the two: They have distinct “epigenetic” signatures; that is, they differ in what gets copied when the cell divides, even though these differences aren’t part of the DNA sequence.

“Relatively little study has been done on the epigenetic nature of stem cells,” says Andrew Feinberg, M.D., M.P.H., a professor of medicine at the Johns Hopkins University School of Medicine. “To date, the bulk of what is known about stem cells is focused on how you create them and grow them and so forth, but not on the essence of them, and what is fundamentally different about these cells.”

To compare and contrast mature connective tissue cells called fibroblasts with the pluripotent stem cells into which they were reprogrammed, the investigators focused on a chemical change known as methylation. This chemical change which, associated with silencing genes, is classified as epigenetic because, although not part of the DNA sequence, is copied when a cell divides. They identified and then measured so-called differentially methylated regions (DMRs) of genes whose expression was changed in the process of being reprogrammed from a parent cell to a stem cell.

Building on previous research that looked at where differently methylated sites were located in cancer cells, as well as on research that had shown these same sites matching up with many of the methylated areas that had been implicated in the differentiation of normal brain, liver and spleen tissues, the team discovered that the reprogramming of a cell to become a stem cell apparently involves many of the very same DMRs and genes.

“The surprise,” says Feinberg, “is that there is such a degree of overlap between the differently methylated regions and genes that are involved in turning a fibroblast into a stem cell and turning a normal cell into a cancer cell.”

The study, done jointly with George Q. Daley, M.D., Ph.D., and colleagues from Harvard University, was published Nov. 1 in the advanced online edition of Nature Genetics. The researchers suggest in the study that certain sites throughout the genome appear to be generally involved in distinguishing DNA methylation among different cell types and cancers, and these same sites are involved in reprogramming fibroblasts back into stem cells (…)

from http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20091104.074444&time=09%2059%20PST&year=2009&public=0

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The body is a battle zone. Cells constantly compete with one another for space and dominance. Though the manner in which some cells win this competition is well known to be the survival of the fittest, how stem cells duke it out for space and survival is not as clear. A study on fruit flies published in the October 2 issue of Science by Johns Hopkins researchers describes how stem cells win this battle by literally sticking around.

“Our work exemplifies how one signal coordinately maintains two types of stem cells in a single niche, or microenvironment,” says Erika Matunis, Ph.D., associate professor of cell biology at the Johns Hopkins School of Medicine. “What we found may emerge as common themes of mammalian stem cell niches as they become better characterized.”

To tackle the stem cell competition quandary, the team looked at fruit fly testes where two different stem cells exist: germline stem cells which give rise to sperm, and somatic stem cells which develop into non-reproductive cell types.

Using genetics, the researchers grew flies lacking the SOCS protein, which controls other molecules that promote stem cell growth. SOCS normally ensures that the right numbers of stem cells are present in the stem cell niche, a region at the far end of the fly testis where new cells are born. In a normal testis, the germline stem cells are surrounded by somatic stem cells at a ratio of about one germline stem cell for every two somatic stem cells.

The researchers isolated testes from flies lacking SOCS and, under a microscope, counted the number of germline stem cells and somatic stem cells. They found that nearly half of the germline stem cells were gone and the somatic stem cells appeared to be occupying that space.

“The somatic stem cells almost look like they’ve invaded the niche area,” says Melanie Issigonis, a graduate student in the Biochemistry, Cellular, and Molecular Biology graduate program at Johns Hopkins. “I saw that image and said, ‘Wow, it’s right there. Germline stem cell loss.’”

To figure out where the lost germline stem cells went and how they lost the battle for space, the team returned to the microscope. This time, they examined the cells for whether they contained integrin, a protein that helps cells stick to each other. They found that somatic stem cells from flies lacking SOCS seemed to contain more integrin than somatic stem cells from flies with functional SOCS. According to Matunis, it’s the increase in integrin that allows somatic stem cells to gain the upper hand because they can stick to the niche better than neighboring germline stem cells can.

Though the somatic stem cells were invading the niche, germline stem cells were not dying. In the microscope images, the team found that all remaining germline stem cells still looked alive and healthy, but elbowed out of their niche by somatic stem cells. Says Matunis, no matter how healthy a germline stem cell is, if it cannot stick, it will eventually be outcompeted by the somatic cells and pushed all the way out of the niche. Issigonis found the discovery remarkable: “The germline stem cells are perfectly fine,” she says. “They’re just leaving the niche and differentiating.”

The team believes this model can be applied to other stem cell niches such as cancer. Just like the somatic stem cells overrunning the fly testes, cancer stem cells in mammalian systems become a danger when they become the stickiest cell in the niche. In both cases, the important control protein, SOCS, is lost. Knowing what is necessary for some stem cells to thrive and others to dwindle could have great importance to understanding the roots of stem cell diseases.

from http://www.hopkinsmedicine.org/Press_releases/2009/12_04a_09.html

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December 4, 2009- Working with mice, scientists at Johns Hopkins publishing in the December issue of Neoplasia have shown that a protein made by a gene called “Twist” may be the proverbial red flag that can accurately distinguish stem cells that drive aggressive, metastatic breast cancer from other breast cancer cells.

Building on recent work suggesting that it is a relatively rare subgroup of stem cells in breast tumors that drives breast cancer, scientists have surmised that this subgroup of cells must have some very distinctive qualities and characteristics.

In experiments designed to identify those special qualities, the Hopkins team focused on the gene “Twist” (or TWIST1) – named for its winding shape – because of its known role as the producer of a so-called transcription factor, or protein that switches on or off other genes. Twist is an oncogene, one of many genes we are born with that have the potential to turn normal cells into malignant ones.

“Our experiments show that Twist is a driving force among a lot of other players in causing some forms of breast cancer,” says Venu Raman, Ph.D., associate professor of radiology and oncology, Johns Hopkins University School of Medicine. “The protein it makes is one of a growing collection of markers that, when present, flag a tumor cell as a breast cancer stem cell.”

Previous stem cell research identified a Twist-promoted process known as epithelial-to-mesenchymal transition, or EMT, as an important marker denoting the special subgroup of breast cancer stem cells. EMT essentially gets cells to detach from a primary tumor and metastasize. The new Hopkins research shows that the presence of Twist, along with changes in two other biomarkers – CD 24 and CD44 – even without EMT, announces the presence of this critical sub-group of stem cells.
“The conventional thinking is that the EMT is crucial for recognizing the breast cancer cell as stem cells, and the potential for metastasis, but our studies show that when Twist shows up in excess or even at all, it can work independently of EMT,” says Farhad Vesuna, Ph.D., an instructor of radiology in the Johns Hopkins University School of Medicine. “EMT is not mandatory for identifying a breast cancer stem cell.”

Working with human breast cancer cells transplanted into mice, all of which had the oncogene Twist, the scientists tagged cell surface markers CD24 and CD44 with fluorescent chemicals. Following isolation of the subpopulation containing high CD44 and low CD24 by flow cytometry, they counted 20 of these putative breast cancer stem cells. They then injected these cells into the breast tissue of 12 mice. All developed cancerous tumors.

“Normally, it takes approximately a million cells to grow a xenograft, or transplanted tumor,” Vesuna says. “And here we’re talking just 20 cells. There is something about these cells – something different compared to the whole bulk of the tumor cell – that makes them potent. That’s the acid test – if you can take a very small number of purified “stem cells” and grow a cancerous tumor, this means you have a pure population.”

Previously, the team showed that 65 percent of aggressive breast cancers have more Twist compared to lower-grade breast cancers, and that Twist-expressing cells are more resistant to radiation.
Twist is what scientists refer to as an oncogene, one that if expressed when and where it’s not supposed to be expressed, causes oncogenesis or cancer because the molecules and pathways that once regulated it and kept it in check are gone.

This finding – that Twist is integral to the breast cancer stem cell phenotype – has fundamental implications for early detection, treatment and prevention, Raman says. Some cancer treatments may kill ordinary tumor cells while sparing the rare cancer stem cell population, sabotaging treatment efforts. More effective cancer therapies likely require drugs that kill this important stem cell population.

This study was supported by the Maryland Stem Cell Research Foundation.

In addition to Vesuna and Raman, authors of the paper include Ala Lisok and Brian Kimble, also of Johns Hopkins.

fonte http://www.hopkinsmedicine.org/Press_releases/2009/12_04_09.html

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