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Newswise TAMPA, Fla. Glioblastomas are a highly aggressive type of brain tumor, with few effective treatment options. Moffitt Cancer Center researchers are one step closer to understanding glioblastoma development following the identification of a key protein signaling pathway involved in brain tumor stem cell growth and survival. Brain tumor stem cells are believed to play an important role in glioblastoma development and may be possible therapeutic targets.

The neurotrophin protein pathway controls nerve growth, survival and specialization. In an article published in the Feb. 6 issue of The Journal of Biological Chemistry, Moffitt researchers reported that the neurotrophin pathway is also involved in the survival and growth of brain tumor stem cells. The stem cells have high levels of neurotrophin receptors called TrkB and TrkC. Cellular signals from normal brain cells can activate TrkB and TrkC on the stem cells and stimulate cell growth. And when scientists inhibited TrkB and TrkC, they found decreased stem cell survival. This suggests that TrkB and TrkC may be possible drug targets for stem cells in gliomas and glioblastomas.

This work might be a first step in developing new treatment approaches targeting brain tumor stem cells. It may also partly explain why brain tumors can grow so quickly since proteins from the surrounding normal brain might be used by the tumor to grow even faster, said Peter A. Forsyth, M.D., chair of the Department of Neuro-Oncology at Moffitt.

Researchers also reported a potential reason why several clinical trials targeting a protein called EGFR in glioblastoma patients have failed to live up to expectations. EGFR is frequently activated in glioblastoma, but results from trials using EGFR inhibitors showed little or no patient improvement. Moffitt scientists discovered that TrkB and TrkC maintain brain stem cell survival and growth even when EGFR inhibitors are used. These observations suggest that one reason why EGFR inhibitors may be ineffective in glioblastoma is that TrkB and TrkC are active, thereby bypassing EGFR inhibition and allowing stem cells to continue to grow.

This is the first time that scientists have shown that TrkB and TrkC are involved in brain tumor stem cell growth. Currently, no drugs that target TrkB and TrkC have been used as brain cancer treatments. Researchers hope that these results might encourage the development of drugs that target both the stem cell compartment and the more differentiated parts of the brain tumor and result in more effective therapies.

The study was supported by funds The V Foundation for Cancer Research and the Moffitt Cancer Center Foundation.

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. Moffitt is the top-ranked cancer hospital in the Southeast and has been listed in U.S. News & World Reports Best Hospitals for cancer care since 1999. With more than 4,500 employees, Moffitt has an economic impact in Florida of nearly $1.6 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, Twitter and YouTube.

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Moffitt Cancer Center Researchers Identify Protein Pathway Involved in Brain Tumor Stem Cell Growth

Durham, NC (PRWEB) February 27, 2015

Several studies showing the promise of stem cells for treating patients with heart failure have made headline news recently. However, all these studies dealt with adult patients only. New research appearing in this months STEM CELLS Translational Medicine shows that stem cells may have the same potential in treating children with congenital heart diseases that can lead to heart failure.

The study, undertaken by researchers at the Mayo Clinic in Rochester, Minn., looked at the feasibility and long-term safety of injecting autologous umbilical cord blood cells directly into the heart muscle at the pediatric stage of heart development. The study was conducted on pigs, due to their hearts similarity to human hearts.

The team injected the stem cells directly into the right ventricle of groups of three- and four-week old healthy piglets, and then compared the results to a control group that did not receive any cells. Over the next three months, the animals were monitored to assess cardiac performance and rhythm to determine how safe the procedure would be for humans.

During this follow-up period, we found no significant acute or chronic cardiac injury pattern caused by the injections directly into the heart, said lead author Timothy J. Nelson, M.D., Ph.D., of the Mayo Clinics Department of Medicine, and all the animals hearts appeared to be normal and healthy.

This led us to conclude that autologous stem cells from cord blood can be safely collected and surgically delivered to children. The study also establishes the foundation for cell-based therapy for children and aims to accelerate the science toward clinical trials for helping children with congenital heart disease that could benefit from a regenerative medicine strategy, he added.

The lead author, Susan Cantero Peral, M.D., Ph.D. commented, This work highlights the importance and utility of umbilical cord blood as it can be applied to new applications. Rather than discarding this sample at birth, individuals with congenital heart disease may one day be able to have these cells collected and processed in a specialized way to make them available for cardiac regeneration.

This work was funded by the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome founded at the Mayo Clinic.

These data help establish the foundation of a cell-based therapy for juvenile hearts by showing that injections of autologous cells from cord blood are safe and feasible, said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

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Excerpt from:
Study Shows Stem Cells Have Potential to Help Kids Hearts, Too

Manchester scientists have a developed a new method to monitor the effect of anti-cancer drugs on very rare leukemia stem cells. The approach potentially allows doctors to screen patients and personalise their treatment.

The recent development of novel agents has improved outcomes for patients with chronic myeloid leukemia (CML). These so-called tyrosine kinase inhibitors (TKIs) target abnormal proteins caused by commonly found genetic mutations in CML patients. However, the existence of treatment-resistant cancer stem cells -- cells that are able to repeatedly renew the leukemia cell population -- is one way that many patients experience disease recurrence when treatment stops.

Any new drug must therefore be tested on such stem cells, but unfortunately they are only found in very low numbers and are identified by certain cell surface markers. Now researchers at The University of Manchester -- part of the Manchester Cancer Research Centre -- have tested a way to monitor the effect of drugs on small samples of cells.

Professor Tony Whetton, head of the Stem Cell and Leukaemia Proteomics Laboratory who led the study, said: "Current techniques require greater numbers of cells in order to detect changes caused by TKIs. Our study investigated the potential of a new technology platform that can identify changes in very small cell numbers."

The research team looked at an antibody-based approach to detect structural changes in certain proteins, in order to track the effectiveness of the TKI drugs. The instrument used fixes proteins in place and holds them, there allowing for a better signal to be generated from less material. With this approach they found that they could record changes in samples of only a few thousand critically important but rare stem cells.

"This new approach will enable us to test drugs on cells taken from patients, either at presentation or in a clinical trial setting. It has great potential to allow us to implement precision medicine, where patients receive the most appropriate treatment to target their individual tumour," added Professor Whetton.

Story Source:

The above story is based on materials provided by Manchester University. Note: Materials may be edited for content and length.

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New approach to assessing effectiveness of anti-cancer drugs

H. Lee Moffitt Cancer Center & Research Institute

TAMPA, Fla. - Glioblastomas are a highly aggressive type of brain tumor, with few effective treatment options. Moffitt Cancer Center researchers are one step closer to understanding glioblastoma development following the identification of a key protein signaling pathway involved in brain tumor stem cell growth and survival. Brain tumor stem cells are believed to play an important role in glioblastoma development and may be possible therapeutic targets.

The neurotrophin protein pathway controls nerve growth, survival and specialization. In an article published in the Feb. 6 issue of The Journal of Biological Chemistry, Moffitt researchers reported that the neurotrophin pathway is also involved in the survival and growth of brain tumor stem cells. The stem cells have high levels of neurotrophin receptors called TrkB and TrkC. Cellular signals from normal brain cells can activate TrkB and TrkC on the stem cells and stimulate cell growth. And when scientists inhibited TrkB and TrkC, they found decreased stem cell survival. This suggests that TrkB and TrkC may be possible drug targets for stem cells in gliomas and glioblastomas.

"This work might be a first step in developing new treatment approaches targeting brain tumor stem cells. It may also partly explain why brain tumors can grow so quickly since proteins from the surrounding normal brain might be used by the tumor to grow even faster," said Peter A. Forsyth, M.D., chair of the Department of Neuro-Oncology at Moffitt.

Researchers also reported a potential reason why several clinical trials targeting a protein called EGFR in glioblastoma patients have failed to live up to expectations. EGFR is frequently activated in glioblastoma, but results from trials using EGFR inhibitors showed little or no patient improvement. Moffitt scientists discovered that TrkB and TrkC maintain brain stem cell survival and growth even when EGFR inhibitors are used. These observations suggest that one reason why EGFR inhibitors may be ineffective in glioblastoma is that TrkB and TrkC are active, thereby bypassing EGFR inhibition and allowing stem cells to continue to grow.

This is the first time that scientists have shown that TrkB and TrkC are involved in brain tumor stem cell growth. Currently, no drugs that target TrkB and TrkC have been used as brain cancer treatments. Researchers hope that these results might encourage the development of drugs that target both the stem cell compartment and the more differentiated parts of the brain tumor and result in more effective therapies.

###

The study was supported by funds The V Foundation for Cancer Research and the Moffitt Cancer Center Foundation.

About Moffitt Cancer Center:

Located in Tampa, Moffitt is one of only 41 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, its contributions to clinical trials, prevention and cancer control. Moffitt is the top-ranked cancer hospital in the Southeast and has been listed in U.S. News & World Report's "Best Hospitals" for cancer care since 1999. With more than 4,500 employees, Moffitt has an economic impact in Florida of nearly $1.6 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, Twitter and YouTube.

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Moffitt researchers identify protein pathway involved in brain tumor stem cell growth

While well known for its unique electromechanical properties, graphene may also prove key in preventing cancer tumor recurrence. A drawback of traditional cancer treatment with radiation and chemotherapy is that the primary developmental source of future tumors is not eradicated. Cancer stem cells, or CSCs, can survive treatment and give rise to recurring tumors, metatasis, and drug resistance after repeated treatments. Researchers from the University of Manchester and the University of Calabria have discovered that graphene oxides targets and neutralize CSCs in a manner that is not yet fully understood.

One CSC can develop into a ball of new CSCs called a tumor-sphere, or into new tumor cells, such as what happens in metastasis. They're immortal, divide rapidly, and resist stress. A potential solution? Graphene oxide, GO, which is an oxidized form of its well-known carbon cousin and soluble in many solvents.

For a complete look at the efficacy of GO across cancers, researchers used CSCs from six types of cancer: breast, pancreatic, lung, brain, ovarian and prostate. They also used normal skin cells to confirm that GO would not be toxic to the body.

After cells were treated for 48 hours with a GO solution, the researchers found that not only did GO interrupt the ability of CSCs in all cancer types to proliferate by forming spheres, but that GO was safe to the skin cells.

Dr Aravind Vijayaraghavan of the National Graphene Institute at the University of Manchester says that GO seems to force the cancer stem cells to differentiate into non-cancer stem cells. In this way, GO effectively takes the CSC out of commission for creating future tumors. Currently the theory is that GO interferes with the signalling pathways in the cell membranes, curbing the proliferation mechanism.

Interestingly, this graphene derivative had already been researched for as a targeted delivery vehicle in tumors, but has now been found to have an important effect itself on the tumor.

While the researchers acknowledge that the mechanisms at play need to be researched more before the material can be used to treat cancers, the ability to destroy cancer stem cells is an an important component of a cancer treatment protocol that kills existing tumors as well as shuts down future metatasis.

Vijayaraghavan and the Graphene Institute have previously made headlines as a recipient of research money from the Bill and Melinda Gates Foundation towards the development of a better condom. Their proposal, of course, used graphene.

The team's research was originally published in Oncotarget on February 24, 2015.

Source: University of Manchester

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Graphene derivative interferes with seemingly invincible cancer stem cells

Bioengineers from Brigham and Women's Hospital (BWH) with collaborators at the pharmaceutical company Sanofi have identified small molecules that can be used to program stem cells to home in on sites of damage, disease and inflammation. The techniques used to find and test these small molecules may represent important tools in advancing cell-based therapy, offering a new strategy for delivering cells to the right locations in the body. The results of their work appear online this week in Cell Reports.

Through a collaborative research project, the research team tested more than 9,000 compounds, and used a multi-step approach -- including a sophisticated microfluidics set up and novel imaging technique -- to narrow in on and test the most promising compounds.

"There are all kinds of techniques and tools that can be used to manipulate cells outside of the body and get them to do almost anything we want, but once we transplant cells we lose complete control over them," said co-senior author Jeff Karp, PhD, an associate professor at BWH, Harvard Medical School, and principal faculty at the Harvard Stem Cell Institute. "Through this collaboration, we've been able to identify small molecules that can be used to treat cells outside of the body, programming them to target blood vessels in diseased or damaged tissue."

Small molecules offered the team several advantages including the ability to use a safe and relatively simple procedure to pre-treat the cells before injecting them intravenously.

"There's a great need to develop strategies that improve the clinical impact of cell-based therapies," said co-first author Oren Levy, PhD, an instructor in medicine at BWH. "If you can create an engineering strategy that is safe, cost effective and simple to apply, that's exactly what we need to achieve the promise of cell-based therapy."

Karp's team at the Brigham had previously found that it is possible to use bioengineering techniques to chemically attach molecules to the surface of a cell that act as a GPS, guiding the cell to the site of inflammation. These findings indicated that targeted delivery of cells was possible, but a scalable approach would be needed to impact patients.

"At BWH, we had laid the groundwork. Our collaborators at Sanofi have complementary expertise in screening for small molecules, deep understanding of the biology and unmet needs, and an exceptional ability to bring new therapeutics to the clinic," said Karp. "Defined goals and both teams working seamlessly together created perfect synergy. We learned so much from each other."

The Sanofi team screened thousands of compounds, looking for ones that activated telltale molecules on the surface of the MSCs, as well as verified that the active compounds did not alter mesenchymal stromal cell viability or the profile of secreted immunomodulatory protein factors.

There are currently more than 450 clinical trials ongoing or completed using mesenchymal stem cells (MSCs) to treat a range of diseases including heart attacks, Crohn's disease, lupus, multiple sclerosis and more, but many trials fail to meet clinical endpoints. One of the key challenges has been getting MSCs to arrive at -- and stay at -- sites of damage.

Researchers found six promising molecules, including one known as Ro-31-8425, the most potent of the group. Karp's lab then tested these compounds further by pre-treating cells with them, and then flowed the cells onto a microfluidic device -- a glass slide with tiny channels only big enough to allow small groups of cells to flow through at a time. The channels were coated with an Intracellular Adhesion Molecule (ICAM-1), which is also found on the surface of blood vessels at inflamed tissue within the body. Cells pre-treated with Ro-31-8425 stuck -- a sign that they might be able to home in on sites of inflammation.

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Small molecule helps get stem cells to sites of disease, damage

4 hours ago

The therapeutic promise of human stem cells is indisputably huge, but the process of translating their potential into effective, real-world treatments involves deciphering and resolving a host of daunting complexities.

Writing in the February 25 online issue of the journal PLOS ONE, researchers at University of California, San Diego School of Medicine, with collaborators from The Scripps Research Institute (TSRI), have definitively shown for the first time that the culture conditions in which stem cells are grown and mass-produced can affect their genetic stability.

"Since genetic and epigenetic instability are associated with cancers, we worry that similar alterations in stem cells may affect their safety in therapeutic transplants. Certain mutations might make transplanted stem cells more likely to form tumors, introducing the risk of cancer where it didn't exist before," said co-corresponding author Louise Laurent, MD, PhD, assistant professor and director of perinatal research in the Department of Reproductive Medicine at UC San Diego School of Medicine.

"This study shows the importance of quality control," added Jeanne F. Loring, PhD, professor and director of the Center for Regenerative Medicine at TSRI, and adjunct professor in the UC San Diego Department of Reproductive Medicine and the study's other co-corresponding author. "It's almost certain these cells are safe, but we want to make sure they are free from any abnormalities."

To exploit the transformative powers of human pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, requires producing them in large numbers for transplantation into patients.

"During this culturing process, mutations can occur, and mutations that increase cell survival or proliferation may be favored, such that the cells carrying such mutations could take over the culture," said Laurent.

Human pluripotent stem cells are cultured in several different ways. Key variables are the surfaces upon which the cells are cultured, called the substrate, and the methods used to transfer cells from one culture dish into another as they grow, called the passage method.

Originally, scientists determined that stem cells grew best when cultured atop of a "feeder" layer that included other types of cells, such as irradiated mouse embryonic fibroblasts. For reasons not fully understood, these cells provide stem cells with factors that support their growth. However, concerns about the feeder cells also introducing undesirable materials into stem cells has prompted development of feeder-free cultures.

Moving cells from one culture dish to another has traditionally been done manually, with technicians physically separating the cultured cells into small clumps with an instrument. "It's very labor-intensive," said Laurent, "so new methods that use enzymes to separate individual cells were created."

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Methods to multiply pluripotent cells for potential therapies raise worries about cancer

University of Manchester scientists have used graphene to target and neutralise cancer stem cells while not harming other cells.

This new development opens up the possibility of preventing or treating a broad range of cancers, using a non-toxic material.

Writing in the journal Oncotarget, the team of researchers led by Professor Michael Lisanti and Dr Aravind Vijayaraghavan has shown that graphene oxide, a modified form of graphene, acts as an anti-cancer agent that selectively targets cancer stem cells (CSCs). In combination with existing treatments, this could eventually lead to tumour shrinkage as well as preventing the spread of cancer and its recurrence after treatment. However, more pre-clinical studies and extensive clinical trials will be necessary to move this forward into the clinic to ensure patient benefit.

Professor Lisanti, the Director of the Manchester Centre for Cellular Metabolism within the University's Institute of Cancer Sciences, explained: "Cancer stem cells possess the ability to give rise to many different tumour cell types. They are responsible for the spread of cancer within the body -- known as metastasis- which is responsible for 90% of cancer deaths.

"They also play a crucial role in the recurrence of tumours after treatment. This is because conventional radiation and chemotherapies only kill the 'bulk' cancer cells, but do not generally affect the CSCs."

Dr Vijayaraghavan added: "Graphene oxide is stable in water and has shown potential in biomedical applications. It can readily enter or attach to the surface of cells, making it a candidate for targeted drug delivery. In this work, surprisingly, it's the graphene oxide itself that has been shown to be an effective anti-cancer drug.

"Cancer stem cells differentiate to form a small mass of cells known as a tumour-sphere. We saw that the graphene oxide flakes prevented CSCs from forming these, and instead forced them to differentiate into non-cancer stem-cells.

"Naturally, any new discovery such as this needs to undergo extensive study and trials before emerging as a therapeutic. We hope that these exciting results in laboratory cell cultures can translate into an equally effective real-life option for cancer therapy."

The team prepared a variety of graphene oxide formulations for testing against six different cancer types -- breast, pancreatic, lung, brain, ovarian and prostate. The flakes inhibited the formation of tumour sphere formation in all six types, suggesting that graphene oxide can be effective across all, or at least a large number of different cancers, by blocking processes which take place at the surface of the cells. The researchers suggest that, used in combination with conventional cancer treatments, this may deliver a better overall clinical outcome.

Dr Federica Sotgia, one of the co-authors of the study concluded: "These findings show that graphene oxide could possibly be applied as a lavage or rinse during surgery to clear CSCs or as a drug targeted at CSCs.

More:
Graphene shows potential as novel anti-cancer therapeutic strategy

February 24, 2015

Stop staring into the sun. (Credit: Thinkstock)

Shayne Jacopian for redOrbit.com @ShayneJacopian

Oculus reparo!

The incantation uttered by Hermione Granger on the train to Hogwarts in Harry Potter and the Sorcerers Stone translates to eye repair, but the spell simply fixed Harry Potters broken glasses. The actual key to repairing damaged eyeballs may lie in extracted teeth, according to research from the University of Pittsburgh.

Corneal tissue is normally transplanted from donors, and many times the body rejects the foreign matter. Growing new corneal tissue with a patients own cells could effectively eliminate these problems.

[STORY: Mice stem cells capable of regenerating bone, cartilage]

The scientists extracted dental pulp from human wisdom teeth and used stem cells to engineer corneal stromal cells, or keratocytes. They then injected the human cells into the corneas of mice, where they showed no signs of rejection.

Cells extracted from humans still worked in mice. Science: 1, Magic: 0.

Less focus on donors

See the article here:
Dental stem cells could repair eyeballs

Those pesky wisdom teeth may be useful after all.

Researchers at the University of Pittsburgh School of Medicine say the dental pulp found in wisdom teeth is rich in stem cells that someday could be used to repair injured corneas.

Wisdom teeth have a pretty powerful population of stem cells, said Fatima Syed-Picard of Pitt's Department of Ophthalmology, lead author of a paper published Monday in the journal STEM CELLS Translational Medicine. It's not just your wisdom teeth; it's all your teeth. You can get similar stem cells from baby teeth.

The findings could lead to a new source of corneal transplant tissue to repair scarring of the cornea, the clear outermost layer of the eye, the researchers said. The scarring, caused by trauma, infections or genetic diseases, can result in permanent vision loss.

The team in the laboratory of ophthalmology professor James Funderburgh used pulp tissue from adult wisdom teeth obtained in routine extractions at Pitt's School of Dental Medicine.

Scientists cultured the extracted cells and turned them into keraocytes, which are cells that can heal the corneas. They then injected the cells into healthy mice to ensure they could work in a normal environment without being rejected, Syed-Picard said.

The method has not been tested in injured animals, and it could be years away from being tested in humans.

I'm confident that this will be easy to translate to humans in the near future, Syed-Picard said.

The Pitt scientists said they are looking at the wisdom teeth stem cells as a potential treatment to prevent corneal blindness, which afflicts millions of people worldwide.

The treatment of last resort is a corneal transplant using tissue from a deceased donor. Using stem cells from the patient's own tissue could help prevent rejection, they said.

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Dental stem cells valuable for cornea repair, University of Pittsburgh researchers find