Newswise Researchers at Moffitt Cancer Center have discovered that the micro ribonucleic acid miR-214 plays a critical role in regulating ovarian cancer stem cell properties. This knowledge, said the researchers, could pave the way for a therapeutic target for ovarian cancer.

The study appears in a recent issue of the The Journal of Biological Chemistry.

According to the studys lead author, Jin Q. Cheng, Ph.D., M.D., senior member of the Molecular Oncology Department and Molecular Oncology and Drug Discovery Program at Moffitt, certain miRNAs can cause therapeutic resistance and cancer metastasis by regulating multiple gene targets. Previous work has shown that one microRNA miR-214 is elevated in cancer. In ovarian cancer, up-regulated miR-214 has been associated with late-stage and high-grade tumors. In past research, miR-214 has also been associated with resistance to the chemotherapy drug cisplatin, but the role played by miR-214 in cancer stem cells had not been determined.

Evidence suggests that cancer stem cells are responsible for cancer initiation, progression, metastasis, chemoresistance and relapse, Cheng said. Data are emerging to support the role of both miRNAs and transcription factor p53 in cancer stem cell regulation.

Their current study found that miR-214 regulates ovarian cancer stem cell properties by direct repression of p53, which led to induction of a stem cell transcription factor (Nanog). The researchers demonstrated that p53 mediated miR-214-induced Nanog in ovarian cancer stem cells and also induced chemoresistance.

It is plausible that miR-214 has an important influence on stem cells through its capacity to modulate p53, explained Cheng. Our study demonstrates direct evidence that miR-214 plays a critical role in maintaining ovarian cancer stem cells.

Given that knowledge, the researchers concluded that miR-214 is a potential therapeutic target for treating ovarian cancer.

The research was supported in part by the National Cancer Institute, part of the National Institutes of Health (grant numbers CA135328 and CA114343) and the U.S. Army (W81XWH-11-1-0223).

About Moffitt Cancer Center Located in Tampa, Moffitt is one of only 41 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitts excellence in research, its contributions to clinical trials, prevention and cancer control. Since 1999, Moffitt has been listed in U.S. News & World Report as one of Americas Best Hospitals for cancer. With more than 4,200 employees, Moffitt has an economic impact on the state of nearly $2 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, twitter and YouTube.

Media release by Florida Science Communications

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Researchers Find Possible Molecular Key to Regulation of Ovarian Cancer Stem Cells

Thursday, September 27, 2012

ROCHESTER, Minn. Mayo Clinic researchers have found a way to detect and eliminate potentially troublemaking stem cells to make stem cell therapy safer. Induced Pluripotent Stem cells, also known as iPS cells, are bioengineered from adult tissues to have properties of embryonic stem cells, which have the unlimited capacity to differentiate and grow into any desired types of cells, such as skin, brain, lung and heart cells. However, during the differentiation process, some residual pluripotent or embryonic-like cells may remain and cause them to grow into tumors.

MULTIMEDIA ALERT: Video resources, including an interview with Dr. Nelson will be available for journalists at the Mayo Clinic News Network.

"Pluripotent stem cells show great promise in the field of regenerative medicine; however, the risk of uncontrolled cell growth will continue to prevent their use as a therapeutic treatment," says Timothy Nelson, M.D., Ph.D., lead author on the study, which appears in the October issue of STEM CELLS Translational Medicine.

Using mouse models, Mayo scientists overcame this drawback by pretreated stem cells with a chemotherapeutic agent that selectively damages the DNA of the stem cells, efficiently killing the tumor-forming cells. The contaminated cells died off, and the chemotherapy didn't affect the healthy cells, Dr. Nelson says.

"The goal of creating new therapies is twofold: to improve disease outcome with stem cell-based regenerative medicine while also ensuring safety. This research outlines a strategy to make stem cell therapies safer for our patients while preserving their therapeutic efficacy, thereby removing a barrier to translation of these treatments to the clinic," says co-author Alyson Smith, Ph.D.

Stem cell therapies continue to be refined and improved. Researchers are finding that stem cells may be more versatile than originally thought, which means they may be able to treat a wider variety of diseases, injuries and congenital anomalies. Stem cell therapy is an emerging regenerative strategy being studied at Mayo Clinic.

"By harnessing the potential of regenerative medicine, we'll be able to provide more definitive solutions to patients," says Andre Terzic, M.D., Ph.D., co-author and director of Mayo Clinic's Center for Regenerative Medicine.

Other members of the Mayo research team included Clifford Folmes, Ph.D., Katherine Hartjes, Natalie Nelson and Saji Oommen, Ph.D. The research was supported by the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome, National Institutes of Health New Innovator Award OD007015-01, and a Mayo Clinic Center for Regenerative Medicine accelerated research grant.

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Mayo Clinic Finds Way to Weed Out Problem Stem Cells, Making Therapy Safer

Scientists find new way to up safety factor of stem cell therapy by causing contaminated cells to purge themselves.

Pluripotent stem cells show great potential in treating various debilitating diseases, but at a risk: during the process of reprogramming the cells so they will grow (differentiate) into the desired tissue, some of their DNA may be damaged causing them to develop into tumors. Researchers have been scrambling to find a way to overcome this huge drawback to an otherwise highly promising therapeutic candidate.

Now, researchers at the Mayo Clinic in Rochester, Minnesota, think they might have found an answer. Reporting in the October issue of STEM CELLS Translational Medicine, they detail a low-cost, highly-effective way to detect and then purge at-risk cells during an early stage in the differentiation process.

Strategies to improve the safety of stem cell therapy have generally focused on separating or depleting damaged cells after the cells have differentiated. However, while this method was able to diminish the number of tumors formed as well as significantly reduce their size, the technical burdens and cost of specialized reagents and equipment needed to do so remain a challenge for widespread clinical applications, says lead investigator Timothy J. Nelson, M.D., Ph.D. He directs the cell biology group within the clinics Regenerative Strategies team.

Instead, the Mayo team turned to a relatively simple protocol that involves pre-treating cultured stem cells with a genotoxin an agent that sniffs out gene mutations or chromosomes changes in contaminated cells and kills them after first priming the cells through the up-regulation of Puma protein, which can be activated to send a series of signals leading to cell suicide. They tested their theory using stem cells taken from a mouse model.

The results showed that not only did the contaminated cells die off, At the same time, it didnt affect the remaining healthy cells capability to differentiate nor did it have any negative consequence on their genomic stability, Nelson says. And it worked on stem cells derived from both natural and bioengineered sources.

This novel strategy, based on innate mechanisms of pluripotent stem cells, is primed for high-throughput and cost-effective clinical translation.

The potential for tumor formation has been a significant drawback to therapeutic use of certain cell populations, said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. The strategy outlined in this manuscript shows promise for avoiding the risk of uncontrolled cell growth upon transplantation.

STEM CELLS Translational Medicine

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Tumorogenic stem cells purged

September 26, 2012

Connie K. Ho for redOrbit.com Your Universe Online

Scientists from the La Jolla, California-based Sanford-Burnham Medical Research Institute recently discovered kinase inhibitors, which could help facilitate the production of stem cells in the laboratory as well as increase the amount of cells for projects related to disease research and drug development.

Researchers were initially interested in quickening the process utilized in the production of induced pluripotent stem cells (iPSCs), a special group of stem cells that can be derived from any kind of an adult cell in the laboratory. iPSCs have been used to produce cells of all types, including cells from the brain, heart and muscles.

The team of investigators found that kinase inhibitors could limit the activity of kinase, enzymes that assist in cellular communication, growth and survival. When they combined starter cells along with kinase inhibitors, they discovered that they could produce more iPSCs than the method that has been used in the past by scientists.

Generating iPSCs depends on the regulation of communication networks within cells, remarked the studys senior author Tariq Rana, program director in Sanford-Burnhams Childrens Health Research Center, in a prepared statement. So, when you start manipulating which genes are turned on or off in cells to create pluripotent stem cells, you are probably activating a large number of kinases. Since many of these active kinases are likely inhibiting the conversion to iPSCs, it made sense to us that adding inhibitors might lower the barrier.

The scientists focused on identifying kinase inhibitors with a group of over 240 chemical compounds that limited kinase. The compounds were each added to the cell and many of the kinase inhibitors generated more iPSCs than the untreated cells. They found that the more powerful inhibitors focused on kinases AurkA, P38, and PI3K. Team members from Ranas laboratory collaborated with staff members from Stanford-Burnhams bioinformatics, animal modeling, genomics and histology core facilities to confirm the findings of the study.

We found that manipulating the activity of these kinases can substantially increase cellular reprogramming efficiency, continued Rana in the statement. But whats more, weve also provided new insights into the molecular mechanism of reprogramming and revealed new functions for these kinases. We hope these findings will encourage further efforts to screen for small molecules that might prove useful in iPSC-based therapies.

With this new finding, researchers will be able to create new treatments and examine human disease. For example, researchers can use stem cells in Alzheimers disease studies in reproducing malfunctioning brain cells from an individual. These cells can then be observed in therapeutic drug testing.

The identification of small molecules that improve the efficiency of generating iPSCs is an important step forward in being able to use these cells therapeutically. Tariq Ranas exciting new work has uncovered a class of protein kinase inhibitors that override the normal barriers to efficient iPSC formation, and these inhibitors should prove useful in generating iPSCs from new sources for experimental and ultimately therapeutic purposes, Tony Hunter, a professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies and director of the Salk Institute Cancer Center, and unaffiliated with the study, said in the statement.

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Kinase Inhibitors Quicken Stem Cell Production Process

ScienceDaily (Sep. 26, 2012) Is aging inevitable? What factors make older tissues in the human body less able to maintain and repair themselves, as in the weakening and shrinkage of aging muscles in humans? A new study from Massachusetts General Hospital (MGH) investigators and collaborators at King's College London describes the mechanism behind impaired muscle repair during aging and a strategy that may help rejuvenate aging tissue by manipulating the environment in which muscle stem cells reside.

The report will appear in the journal Nature and has received advance online release.

Rare muscle stem cells are located inside each skeletal muscle of the body. Also called satellite cells, due to their position on the surface of the muscle fibers they serve and protect, these cells are essential to maintaining the capacity of muscles to regenerate. Satellite cells are able to generate new, differentiated muscle cells while keeping their identity as stem cells, retaining the ability to maintain and repair muscle tissue. Normally in a resting or dormant state, satellite cells respond rapidly to repair injured tissues. The current study finds that aging muscle stem cells lose their ability to maintain a dormant state, so that when called upon to repair injured muscle, they are unable to mount an adequate response.

Andrew Brack, PhD, of the MGH Center for Regenerative Medicine, senior and corresponding author of the Nature paper, says, "Just as it is important for athletes to build recovery time into their training schedules, stem cells also need time to recuperate, but we found that aged stem cells recuperate less often. We were surprised to find that the events prior to muscle regeneration had a major influence on regenerative potential. That makes sense to us as humans, in terms of the need to sleep and to eat a healthy diet, but that the need to rest also plays out at the level of stem cells is quite remarkable." An assistant professor of Medicine at Harvard Medical School, Brack is also a principal faculty member at the Harvard Stem Cell Institute.

In a series of experiments in mice, the authors found that a developmental protein called fibroblast growth factor-2 (FGF2) is elevated in the aging muscle stem cell microenvironment and drives stem cells out of the dormant state. Satellite cells that are forced to replicate lose the ability to maintain their identity as stem cells, reducing the stem cell population. The authors also found that blocking the age-related increase in FGF signaling both in aged satellite cells or in the cellular microenvironment protected against stem cell loss, maintained stem cell renewal during aging and dramatically improved the ability of aged muscle tissue to repair itself. Lead author Joe Chakkalakal, PhD, a research fellow in Brack's lab, says, "This work highlights the usefulness of targeting the aged stem cell or its environment to protect stem cells and the tissues they serve from the effects of aging."

Noting that FGF2 is known for laying the foundation for muscle development, Brack adds, "At present we don't know why this developmental factor is re-expressed in the aged stem cell environment. It appears that what was beneficial for the development of muscle becomes detrimental during aging. After this proof-of-principle study, we are beginning to ask whether the lessons we have learned can be translated to improving the health of the ever-growing aged human population."

Additional co-authors of the Nature paper are Kieran Jones and Albert Basson, PhD, King's College London. The study was supported by funds from the National Institutes of Health, Harvard Stem Cell Institute, and the Biotechnology and Biological Sciences Research Council of the U.K.

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Inadequate cellular rest may explain effects of aging on muscles

Sept. 26, 2012

Stem cells are biological building blocks, the starting point of human life. But without proper direction, they're not very useful when it comes to treating disease.

"If we just take stem cells and inject them into you, they will simply become a cancerous tumor," says Randy Ashton, a University of Wisconsin-Madison assistant professor of biomedical engineering.

Ashton

Working in the Wisconsin Institute for Discovery, Ashton is seeking to instruct the development of human stem cells in the lab by using the molecules cells already use to communicate with one another.

"We are trying to understand how particular tissues arise in development," says Ashton. "Then, using human pluripotent stem cells, we can replicate the signals that allow those structures to develop in order to create tissues that would be therapeutic for different degenerative diseases and disorders."

For several years, Ashton has worked with two cellular communication molecules sonic hedgehog and ephrin ligands that factor into how a stem cell determines which blueprint to work from when it is differentiating into a specific cell type. In a paper co-authored by Ashton, Anthony Conway and other former colleagues at the University of California, Berkeley, and published on Sept. 16 in Nature Neuroscience, Ashton explains the role that ephrin ligands play in creating the proper circumstances for adult neurogenesis, the process by which stem cells can become neurons.

"Basically, a stem cell can 'sense' what's in its environment, and then it makes a decision to determine whether it's going to become a muscle cell or a brain cell," says Ashton.

Deeper understanding of stem cell instruction could yield deeper understanding of the origins of specific diseases.

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The language of stem cells, decoded

IRVINE, CA--(Marketwire - Sep 26, 2012) - Stem cell researchers are literally on the brink of developing new treatments for some of the world's most devastating diseases.Each of us is standing at the intersection of real, tangible progress and limitless possibility. We have the opportunity to help transform medicine by supporting stem cell research online.

On October 3, scientists, researchers and supporters will celebrate International Stem Cell Awareness Day. A new interactive website, http://www.StemCellsOfferHope.com, has been launched to share easily digestible factoids and colorful stem cell imagery within social networks.It also features banners and graphics for bloggers to post information and links to share with their community of followers, family and friends on Facebook, Twitter and Pinterest.Bloggers are encouraged to help drive visitors to this website through the use of entries and social media posts.

"This is a critical and historic time for stem cell research," said Peter Donovan, Ph.D., director, Sue & Bill Gross Stem Cell Research Center, UC Irvine. "The act of simply raising awareness about this research is one of the best things people can do to help accelerate the process."

Researchers have been working diligently to unlock the potential of stem cells and have made significant strides since the discovery of a method to grow and duplicate human stem cells less than 15 years ago. Their efforts to develop cures for conditions such as Alzheimer's disease, multiple sclerosis, macular degeneration, Huntington's disease, Parkinson's disease, as well as traumatic brain injuries and paralysis caused by spinal cord injuries are moving forward at a rapid pace.

For more information visit http://www.stemcellsofferhope.com.

About the Sue & Bill Gross Stem Cell Research Center, UC Irvine: The Sue & Bill Gross Stem Cell Research Center, UC Irvine is one of the largest most technologically advanced stem cell research facilities in the world. The center was established in 2010 in part through a $10 million gift from Bill Gross, founder and co-chief investment officer of international investment firm PIMCO, and his wife Sue. For more than 40 years, its team of scientists and multiple research and graduate assistants have worked to unlock the potential of stem cells for treating and curing an estimated 70 major diseases and disorders. The research center has devised new methods for growing stems cells that are 100 percent more effective than previous techniques. Other advances have led to the world's first clinical trial of a human neural stem cell-based therapy for chronic spinal cord injury and the first FDA-approved clinical trial using human embryonic stem cells. The embryonic stem cells are produced from embryos donated for research purposes during fertility treatments. These cells would otherwise be destroyed. For more information, visit stemcell.uci.edu.

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Educate, Inform & Inspire Global Awareness by Sharing 'Stem Cells Offer Hope'