Nerve cells transplanted into brain-damaged rats helped them to fully recover their ability to learn and remember, probably by promoting nurturing, protective growth factors, according to a new study.

Building on previous investigation of transplants in the nervous system, this critical study confirms that cell transplants can help the brain to heal itself. Ultimately, it may lead to new therapies to help dementia patients. More generally, scientists can now develop and test new ways to help repair an injured nervous system — whether through new drugs, genetically modified cells, transplanted neural (nerve) and non-neural brain cells, or other means.

The discovery was announced in the December issue of Behavioral Neuroscience, published by the American Psychological Association. The findings, according to the authors, confirm the potential of cell grafts to stimulate the release of growth factors for neurons, regenerate or reorganize a part of the brain, and restore cognitive function, in a process called neural plasticity.

This study focused on the hippocampus, considered to be the seat of learning and memory, whose shrinkage in Alzheimer’s disease causes steadily worsening symptoms. The study’s authors targeted a key player in the hippocampal “learning system,” which includes the hippocampus itself, the subiculum (the major output structure connected to the cortex, the self-aware “thinking” part of the brain), and the adjacent entorhinal cortex.

Previously, these scientists had demonstrated that damage to the subiculum in rats led to deterioration of the hippocampus, and problems with learning. The next question was obvious: Could researchers do the opposite, repair the hippocampus and restore the memory functions?

They sought the answer at India’s National Institute for Mental Health and Neuro Sciences and National Centre for Biological Sciences (Tata Institute for Fundamental Research), both in Bangalore. First, the scientists injected a neuron-destroying chemical into the subiculum area of 48 adult rats.

Next, again using precise micro-injections, the scientists transplanted hippocampal cells that had been taken from newborn transgenic mice and cultured in an incubator into the hippocampi of about half the rats. These special cells had a green fluorescent protein used to “label” and track them after transplantation. (Transgenic mice are bred with a little extra DNA that allows their cells to be grown in glass plates in incubators.)

Two months later, the scientists measured how well both the transplant and non-transplant rats learned and remembered, using two well-established maze tests of spatial learning. The rats given cell transplants had recovered completely: On both mazes, they performed as well as those rats which had not had their subiculums damaged. The rats without transplants did not recover: They had many problems learning their way through the mazes.

After studying behavior, the scientists examined what happened in the brain. Under the microscope, it appeared that the transplanted cells had settled mainly in a sub-area of the hippocampus called the dentate gyrus. There, the transplants appeared to promote the secretion of two types of growth factors, namely brain-derived neurotrophic factor and fibroblast growth factor, which boost the growth and survival of the cells that give rise to neurons. In the hippocampi of rats with cell transplants, the expression of brain-derived growth factor went up threefold.

It is significant that transplants can provide more neural growth factors in the hippocampus, because the formation of new neurons there may be critical for cognitive function.

Neural growth factors, also called neurotrophic factors, hold great promise for treating neurological problems. These specialized chemicals “provide an ideal micro-environment for making new neurons,” said co-author Bindu Kutty, PhD. “They also protect existing brain cells, especially following an injury or other neurological insult.”

Further study is needed, especially to understand the underlying repair mechanism and the apparent starring role of growth factor in brain health. Although the current study shows in the lab that brain-cell transplants can restore function, “more studies along these lines using appropriate animal models are required to find definitive answers about the safety and efficacy of such approaches,” said Kutty. “We are still some way from achieving a new therapy based on these findings.”

Results of a preliminary study by scientists at the National Institutes of Health and Johns Hopkins show that “mini” stem cell transplantation may safely reverse severe sickle cell disease in adults.

The phase I/II study to establish safety of the procedure, published December 10 in the New England Journal of Medicine, describes 10 patients with severe sickle cell disease who received intravenous transplants of blood-forming stem cells. The transplanted stem cells came from the peripheral blood of healthy related donors matched to the patients’ tissue types.

Using this procedure, nine of 10 patients treated have normal red blood cells and reversal of organ damage caused by the disease.

Jonathan Powell, M.D., Ph.D., associate professor at the Johns Hopkins Kimmel Cancer Center, says the intravenous transplant approach for sickle cell disease, caused by a single mutation in the hemoglobin gene, does not replace the defective gene, but transplants blood stem cells that carry the normal gene.

Sickle cell disease, named for the “deflated” sickle-shaped appearance of red blood cells in those with the disease, hinders the cells’ ability to carry oxygen throughout the body. In severe cases, it causes stroke, severe pain, and damage to multiple organs, including the lungs, kidneys and liver.

All patients in the study, ranging in age from 16 to 45, were treated at the NIH with what researchers call a non-myeloablative or “mini” transplant, along with an immune-suppressing drug called rapamycin.

Conventional transplant methods use high doses of chemotherapy to wipe out the immune system before the transplanted cells are injected, a process that has many side effects, including serious bacterial and fungal infections, which may kill some patients. In mini-transplants, lower doses of medication and radiation are used to make room for the donor’s cells, the new source for healthy red blood cells in the patient.

According to Powell, side effects, including low white blood cell counts, were few and very mild compared with conventional bone marrow transplantation. But in nine of the 10, donor cells now coexist with the patients’ own cells. One patient was not able to maintain the transplanted cells long term.

Minitransplants for sickle cell disease were tested in patients almost a decade ago, but were unsuccessful because the patients’ immune systems rejected the transplanted cells, according to Powell, but by employing the drug rapamcyin, he says this new approach promotes the coexistence of the host and donor cells.

Powell’s earlier research in mice showed that rapamycin inhibits an enzymatic pathway that suppresses the immune system and makes the host and donor cells tolerant to each other.

The NIH/Johns Hopkins team is conducting further studies on immune cells gathered from patients in their study, and looking at a combination of rapamycin with a well-known cancer drug called cyclophosphamide.

Other teams at Johns Hopkins are studying the use of half-matched donors for transplants in sickle cell patients, helping to widen the pool of potential donors for stem cell transplantation.

Blood vessel blockage, a common condition in old age or diabetes, leads to low blood flow and results in low oxygen, which can kill cells and tissues. Such blockages can require amputation resulting in loss of limbs. Now, using mice as their model, researchers at Johns Hopkins have developed therapies that increase blood flow, improve movement and decrease tissue death and the need for amputation. The findings, published online last week in the early edition of the Proceedings of the National Academy of Sciences, hold promise for developing clinical therapies.

“In a young, healthy individual, hypoxia low oxygen levels triggers the body to make factors that help coordinate the growth of new blood vessels but this process doesn’t work as well as we age,” says Gregg Semenza, M.D., Ph.D., professor of pediatrics and genetic medicine and director of the vascular biology program at the Johns Hopkins Institute for Cell Engineering. “Now, with the help of gene therapy and stem cells we can help reactivate the body’s response to hypoxia and save limbs.”

Previously, Semenza’s team generated a virus that carries the gene encoding an active form of the HIF-1 protein, which turns on genes necessary for building new blood vessels. When injected into the hind legs of otherwise healthy mice and rabbits that had been treated to reduce blood flow, the HIF-1 virus treatment partially restored blood flow.

People with diabetes have a 40 times higher risk of losing a limb to amputation, says Semenza. To find out if HIF-1 gene therapy could improve blood flow in a diabetic animal, the team then tested the same virus in diabetic and non-diabetic mice that had blood flow cut off to one hind leg. Twenty-one days after treatment, the HIF-1 virus-treated mice had 85 percent recovery of blood flow compared with 24 percent in the mock-treated mice. And, treated, diabetic mice had much less tissue damage compared to the untreated diabetic mice. These results were reported in the Nov. 3 issue of the Proceedings of the National Academy of Sciences.

In the current study, the team asked if the same gene therapy treatment could improve reduced blood flow associated with advanced age. Comparing 13 month old mice to 3 month old mice, blocking the femoral artery in the hind leg causes all older mice to lose their legs while only about a third of younger mice have to lose their legs. The research team treated young and old mice with the HIF-1 virus and examined blood flow and tissue health. They found that while treatment improved young mice, it did not make a noticeable difference in the older mice.

But, it was known that when HIF-1 normally activates signals in the body to build new vessels, one of the many types of cells recruited to the site of new vessel growth is a population of stem cells from the bone marrow, which are called bone marrow-derived angiogenic cells. So the team isolated these cells from mice and grew them under special conditions that would turn on HIF-1 in these cells.

When the researchers treated the mice with both the HIF-1 virus and simultaneously injected bone marrow-derived angiogenic cells, treated, older mice were less likely to lose their legs compared to their untreated counterparts.

Further study of these mice showed that activating HIF-1 in the cells appeared to turn on a number of genes that help these cells not only home to the ischemic limb, but to stay there once they arrive. To figure out how the cells stay where they’re needed, the research team built a tiny microfluidic chamber and tested the cells’ ability to stay stuck with fluid flowing around them at rates mimicking the flow of blood through vessels in the body. They found that cells under low oxygen conditions were better able to stay stuck only if those same cells had HIF-1 turned on.

“Our results are promising because they show that a combination of gene and cell therapy can improve the outcome in the case of critical limb ischemia associated with aging or diabetes,” says Semenza. “And that’s critical for bringing such treatment to the clinic.”

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.

Duke University Medical Center researchers have figured out how stem cells in the malignant brain cancer glioma may be better able to resist radiation therapy. And using a drug to block a particular signaling pathway in these cancer stem cells, they were able to kill many more glioma cells with radiation in a laboratory experiment.

The work builds off earlier research which showed that cancer stem cells resist the effects of radiation much better than other cancer cells.

The Duke team identified a known signaling pathway called Notch as the probable reason for the improved resistance. Notch also operates in normal stem cells, where it is important for cell-cell communication that controls cell growth and differentiation processes. The study was published in late November by Stem Cells journal.

“This is the first report that Notch signaling in tumor tissue is related to the failure of radiation treatments,” said lead author Jialiang Wang, Ph.D., a research associate in the Duke Division of Surgery Sciences and the Duke Translational Research Institute. “This makes the Notch pathway an attractive drug target. The right drug may be able to stop the real bad guys, the glioma stem cells.”

Stem cells in a cancer are the source of cancer cell proliferation, Wang said. Hundreds of cancer stem cells can quickly become a million tumor cells.

The Duke researchers, in collaboration with a team led by Dr. Jeremy Rich at Cleveland Clinic, used drugs called gamma-secretase inhibitors that target a key enzyme involved in Notch signaling pathway on gliomas in a lab dish. These inhibitors are being studied by other researchers for their ability to fight tumors in which Notch is abnormally activated, such as leukemia, breast and brain tumors.

“In our study, gamma-secretase inhibitors alone only moderately slowed down tumor cell growth,” said senior author Dr. Bruce Sullenger, Duke Vice Chair for Research and Joseph W. and Dorothy W. Beard Professor of Surgery. “But when we looked at these molecules combined with radiation at clinically relevant doses, the combination caused massive cell death in the tumors and significantly reduced survival of glioma stem cells. These findings often correlate with better tumor control.”

Wang said ongoing clinical trials are testing gamma-secretase inhibitors as stand-alone therapy for breast and brain tumors. “Our study suggests that Notch inhibition using these drugs would provide significant therapeutic benefits if combined with radiotherapy, and I hope that future research will study this combination therapy in this vulnerable patient population,” Wang said. “More effective radiation may be attainable if we can stop Notch signaling in the tumor stem cells.”

Adult stem cells may help repair heart tissue damaged by heart attack according to the findings of a new study to be published in the December 8 issue of the Journal of the American College of Cardiology. Results from the Phase I study show stem cells from donor bone marrow appear to help heart attack patients recover better by growing new blood vessels to bring more oxygen to the heart.

Rush University Medical Center was the only Illinois site and one of 10 cardiac centers across the country that participated in the 53-patient, double-blind, placebo-controlled Phase I trial. Rush is now currently enrolling patients for the second phase of the study.

Researchers say it is the strongest evidence thus far indicating that adult stem cells can actually differentiate, or turn into heart cells to repair damage. Until now, it has been believed that only embryonic stem cells could differentiate into heart or other organ cells.

“The results point to a promising new treatment for heart attack patients that could reduce mortality and lessen the need for heart transplants,” said Dr. Gary Schaer, head of the Rush Cardiac Catheterization Laboratory and study principal investigator at Rush.

In phase I of the study, a group of 53 patients who had heart attacks in the previous ten days received adult mesenchymal stem cells and were kept under close study for two years.

The mesenchymal stem cells (MSC) were harvested from the bone marrow of healthy adult donors. These cells have the potential to develop into mature heart cells and new blood vessels. Similar to Blood Type O, mescenchymal stem cells have the advantage that they can be taken from the bone marrow of an unrelated donor without needing to be matched by blood type.

After the stem cells were extracted, they were purified by drug manufacturer Osiris Therapeutics into a formulation for intravenous delivery called Prochymal. Patients were administered an infusion of either Prochymal or placebo as an injection into a vein in the arm or leg. To prevent bias, neither the patient nor the physician knew who received the stem cell treatment and who received the placebo.

In the study, patients who received the adult stem cells were compared to similar patients who received inert placebo injections. Both were followed by MRI and echocardiogram.

After six months, patients who received the adult stem cells were four times as likely to have improved overall condition, were able to pump more blood with each heartbeat than untreated patients, had only one-quarter as many dangerous heart arrhythmias, and suffered no toxicity or other serious adverse side effects from the treatment.

“It is suspected that these stem cells may take part in the growth of new blood vessels to bring more oxygen to the heart and help reduce the scarring from a heart attack,” said Schaer.

Echocardiograms showed patients had improved heart function, particularly in those patients with large amounts of cardiac damage. Patients also have improvements in lung function.

According to Schaer, one reason the study results are so promising is that these stem cells can be used without tissue typing and do not trigger an immune response, and are available for every patient.

A unique benefit of the stem cell product is that it is given to patients through a standard intravenous (IV) line which is simple and easy for the patient compared to other therapies that require delivery to the site of the disease through catheterization or open surgical procedures,

Adult stem cells are designed by nature to perform tissue repair in a mature adult. It is believed that these cells can be used in patients unrelated to the donor, without rejection, eliminating the need for donor matching and recipient immune suppression. Once transplanted, the cells promote healing of damaged or diseased tissues.

“It is possible that in the future, hospitals might be able to keep frozen adult stem cells on hand for speedy use in treating heart attacks,” said Schaer.

“This study suggests that adult bone marrow derived stem cells are more flexible than previously thought,” said Schaer. “If the benefits and safety are confirmed in the oingoing Phase II trial, we may soon have a remarkable new therapy for patients with a large heart.”

Dr. Bernard Thébaud lives in two very different worlds. As a specialist in the Stollery Children’s Hospital’s Neonatal Intensive Care Unit at the Royal Alexandra Hospital, he cares for tiny babies, many of whom struggle for breath after being born weeks before they are due. Across town, in his laboratory in the Faculty of Medicine & Dentistry at the University of Alberta, Dr. Thébaud dons a lab coat and peers into a microscope to examine the precise effect of stem cells on the lungs.

With his scientific research being published in the American Journal of Respiratory and Critical Care Medicine, Dr. Thébaud has made a significant leap to bridge the gap between those two worlds.

An international team of scientists led by Dr. Thébaud has demonstrated for the first time that stem cells protect and repair the lungs of newborn rats. “The really exciting thing that we discovered was that stem cells are like little factories, pumping out healing factors,” says Dr. Thébaud, an Alberta Heritage Foundation for Medical Research Clinical Scholar. “That healing liquid seems to boost the power of the healthy lung cells and helps them to repair the lungs.”

In this study, Thébaud’s team simulated the conditions of prematurity – giving the newborn rats oxygen. The scientists then took stem cells, derived from bone marrow, and injected them into the rats’ airways. Two weeks later, the rats treated with stem cells were able to run twice as far, and had better survival rates. When Thébaud’s team looked at the lungs, they found the stem cells had repaired the lungs, and prevented further damage.

“I want to congratulate Dr. Thébaud and his team. This research offers real hope for a new treatment for babies with chronic lung disease,” says Dr. Roberta Ballard, professor of pediatrics, University of California, San Francisco. “In a few short years, I anticipate we will be able to take these findings and begin clinical trials with premature babies.”

“The dilemma we face with these tiny babies is a serious one. When they are born too early, they simply cannot breathe on their own. To save the babies’ lives, we put them on a ventilator and give them oxygen, leaving many of them with chronic lung disease,” says Dr. Thébaud. “Before the next decade is out I want to put a stop to this devastating disease.”

The research team includes physicians and scientists from Edmonton, Alberta, Tours, France, Chicago, Illinois, and Montreal, Quebec.

The team is now investigating the long-term safety of using stem cells as a lung therapy. The scientists are examining rats at 3 months, and 6 months after treatment, studying the lungs, and checking their organs to rule out any risk of cancer. Dr. Thébaud’s team is also exploring whether human cord blood is a better option than bone marrow stem cells in treating lung disease.

“We are also studying closely the healing liquid produced by the stem cells,” says Dr. Thébaud. “If that liquid can be used on its own to grow and repair the lungs, that might make the injection of stem cells unnecessary.”

The generation of new nerve cells in the brain is regulated by a peptide known as C3a, which directly affects the stem cells’ maturation into nerve cells and is also important for the migration of new nerve cells through the brain tissue, reveals new research from the Sahlgrenska Academy published in the journal Stem Cells.

Although the research has been carried out using mice and cultured cells, it could lead to a new medicine for human beings, which could be given to patients who have had a stroke or other disorders that damage or destroy the nerve cells.

“Our research findings show that it could be possible to use molecules that are similar to the peptide C3a to boost the formation of nerve cells and stimulate the replacement of nerve cells lost due to injury or illness,” says senior lecturer Marcela Pekna who headed the research group at theSahlgrenska Academy.

The peptide C3a is generated through the activation of the complement system, a group of proteins in the blood that is essential for the body’s immune defence.

“Our research group was the first in the world to show that the complement system also plays an important role in the repair and regeneration of the brain,” says Pekna. “This was a surprising discovery that opened up a whole new field of research.”

New Nerve Cells

New nerve cells are formed in the brain throughout our lives. The brain’s stem cells are formed in the hippocampus and the subventricular zone, an area next to the fluid-filled cavities (lateral ventricles). Stem cells from the subventricular zone mature into nerve cells in the olfactory bulb, but can also migrate out into the brain to replace nerve cells that have been damaged or destroyed. By finding out more about how new nerve cells are formed and what controls their migration, stem cell researchers hope to find new ways of treating stroke, Parkinson’s disease and other disorders that result from the nerve cells failing to function as they should.

A study in this week’s edition of The Lancet reports that the use of human embryonic stem-cells (hESCs) is a promising alternative for producing temporary skin substitutes for patients awaiting skin grafts after, for example, serious burn injuries. The article is the work of Dr Christine Baldeschi, INSERM and Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry Cedex, France, and colleagues.

For more than two decades, patients with serious burns have benefited from cell therapy to help them recover from their injuries. In this therapy, the patient’s own skin cells (keratinocytes) are taken. Then more are grown in the laboratory and used to replace the damaged skin. But the major disadvantage is that there is a three week period needed to grow enough cells. This puts the patients at risk of dehydration and infection. Decellularised skin from deceased persons can be used to cover wounds during this period. However, availability is limited and the tissue is often rejected by the host. To overcome the problem of accessibility, there has been active search and development for inert synthetic and biosynthetic matrices. Presently however, these substitutes have not replaced skin from deceased persons in large burns since they increase the risks of rapid graft rejection and disease transmission. This is due to the fact that they contain bovine collagen and adult allogenic skin cells.

In this research, the hESC were seeded on feeder cells using a pharmacological treatment over forty days. This treatment drives hESCs towards becoming keratinocytes linage. This is done by following biological steps that lead to epidermis formation during embryonic development. The team were capable to generate a population of cells that presented the characteristics of keratinocytes. Once placed on an artificial matrix, the cells were able to form a layer of skin. Just twelve weeks after grafting onto five mice, the skin layer derived from the hESCs had a structure similar to human skin.

The authors explain: “We have shown that keratinocytes can be derived from hESCs… Growing human epidermis from hESCs could have clinical relevance as an unlimited resource for temporary skin replacement in patients with large burns awaiting autologous grafts.”

They include that future research should assess whether or not this technology could extend the time needed to grow enough cells for a permanent graft, or if keratinocyte hESCs could be used for a permanent graft in cases where a permanent graft using the patients’ own keratinocytes is not possible.

In an associated comment, Dr Holger Schlüter and Dr Pritinder Kaur, Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia, remark: “This report takes research into regenerative skin stem cells to the next level…This finding suggests that keratinocyte allografts derived from hESC keratinocytes could be transplanted onto burnt patients awaiting skin grafts with a reduced risk of rejection.”

“Human embryonic stem-cell derivatives for full reconstruction of the pluristratified epidermis: a preclinical study”

A protein abundant in embryonic stem cells is now shown to be important in cancer, and offers a possible new target for drug development, report researchers from the Stem Cell Program at Children’s Hospital Boston.

Last year, George Daley, MD, PhD, and graduate student Srinivas Viswanathan, in collaboration with Richard Gregory, PhD, also of the Stem Cell Program at Children’s, showed that the protein LIN28 regulates an important group of tumor-suppressing microRNAs known as let-7. Increasing LIN28 production in a cell prevented let-7 from maturing, making the cell more immature and stem-like. Since these qualities also make a cell more cancerous, and because low levels of mature let-7 have been associated with breast and lung cancer, the discovery suggested that LIN28 might be oncogenic.

Now, publishing Advance Online in Nature Genetics on May 31, Daley, Viswanathan and colleagues show directly that LIN28 can transform cells to a cancerous state, and that it is abundant in a variety of advanced human cancers, particularly liver cancer, ovarian cancer, chronic myeloid leukemia, germ cell tumors and Wilm’s tumor (a childhood kidney cancer). They believe that overall, LIN28 and a related protein, LIN28B, may be involved in some 15 percent of human cancers. By blocking or suppressing LIN28, it might be possible to revive the let-7 family’s natural tumor-suppressing action.

“Linking this protein to advanced cancer is a very exciting new result,” says Daley, Director of Stem Cell Transplantation at Children’s, and also affiliated with Children’s Division of Hematology/Oncology, the Dana-Farber Cancer Institute and the Harvard Stem Cell Institute. “It gives us a new target to attack, especially in the most resistant and hard-to-treat cases.”

LIN28, which is abundant in embryonic stem cells and prevents them from differentiating into specific cell types, was originally discovered to influence embryonic development in worms some 25 years ago. Development, stem cell generation and carcinogenesis are known to be closely related, but until last year’s study connected LIN28 to let-7, it hadn’t been clear how.

“LIN28 is a fascinating protein that acts both in stem cells and cancers, and is teaching us that cancer is often a disease of stem cells,” says Daley.

Viswanathan, Daley and colleagues are busily searching for ways to inhibit LIN28, which could provide promising new drugs for advanced cancer.

The study was funded by the National Institutes of Health, the NIH Director’s Pioneer Award, Burroughs Wellcome Fund, the Leukemia and Lymphoma Society and the Howard Hughes Medical Institute.
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