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Newswise With the help of biomimetic matrices, a research team led by bioengineers at the University of California, San Diego has discovered exactly how calcium phosphate can coax stem cells to become bone-building cells. This work is published in the Proceedings of the National Academy of Sciences the week of Jan. 6, 2014.

UC San Diego Jacobs School of Engineering professor Shyni Varghese and colleagues have traced a surprising pathway from these biomaterials to bone formation. Their findings will help them refine the design of biomaterials that encourage stem cells to give rise to new bone. The researchers say their study may also point out new targets for treating bone defects and bone metabolic disorders such as major fractures and osteoporosis.

The materials are built to mimic the bodys own cellular niches, in which undifferentiated or blank-slate stem cells from bone marrow transform into specific bone-forming cells. We knew for years that calcium phosphate-based materials promote osteogenic differentiation of stem cells, but none of us knew why, Varghese said.

As engineers, we want to build something that is reproducible and consistent, she explained, so we need to know how building factors contribute to this end.

The researchers found that when phosphate ions gradually dissolve from these materials, they are taken up by the stem cells and used for the production of ATP, a key metabolic molecule. An ATP metabolic product called adenosine then signals the stem cells to commit to becoming bone-forming cells.

Varghese said it was a surprise to her team that the biomaterials were connected to metabolic pathways. And we didnt know how these metabolic pathways could influence stem cells commitment to bone formation.

While the PNAS findings only apply to bone building, Varghese and her students at UC San Diego are working on a variety of projects to understand how stem cells thrive and differentiate into a variety of cell types. With this information, they hope to design biomaterials that can be used to help transform stem cells into tissues that may someday replace diseased or degenerated bone, muscle, or blood vessels.

Stem cell research may seem like an unusual endeavor for engineers, but tissue construction and the development of biomaterials have become one more type of building in the engineering repertoire, Varghese said.

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Biomaterials Get Stem Cells to Commit to a Bony Future

PUBLIC RELEASE DATE:

6-Jan-2014

Contact: Sandy Van sandy@prpacific.com 808-526-1708 Cedars-Sinai Medical Center

LOS ANGELES (Jan. 6, 2014) Researchers at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute and Department of Neurosurgery identified immune system targets on cancer stem cells cells from which malignant brain tumors are believed to originate and regenerate and created an experimental vaccine to attack them.

Results of laboratory and animal studies are published in the online edition of Stem Cells Translational Medicine, and will appear in the March 2014 print edition. A Phase I safety study in human volunteers with recurrent glioblastoma multiforme, the most common and aggressive brain tumor in adults, is underway.

Like normal stem cells, cancer stem cells have the ability to self-renew and generate new cells, but instead of producing healthy cells, they create cancer cells. In theory, if the cancer stem cells can be destroyed, a tumor may not be able to sustain itself, but if the cancer originators are not removed or destroyed, a tumor will continue to return despite the use of existing cancer-killing therapies.

The researchers identified certain fragments of a protein CD133 that is found on cancer stem cells of some brain tumors and other cancers. In the laboratory, they cultured the proteins with dendritic cells, the immune system's most powerful antigen-presenting cells, which are responsible for helping the immune system recognize and attack invaders.

Studies in lab mice showed that the resulting vaccine was able to stimulate an immune response against the CD133 proteins without causing side effects such as an autoimmune reaction against normal cells or organs.

"CD133 is one of several proteins made at high levels in the cancer stem cells of glioblastoma multiforme. Because this protein appears to be associated with resistance of the cancer stem cells to treatment with radiation or chemotherapy or both, we see it as an ideal target for immunotherapy. We have found at least two fragments of the protein that can be targeted to trigger an immune response to kill tumor cells. We don't know yet if the response would be strong enough to prevent a tumor from coming back, but we now have a human clinical trial underway to assess safety for further study," said John Yu, MD, vice chair of the Department of Neurosurgery, director of surgical neuro-oncology, medical director of the Brain Tumor Center and neurosurgical director of the Gamma Knife Program at Cedars-Sinai. He is senior author of the journal article.

With standard care, which includes surgery, radiation treatment and chemotherapy, median length of survival is 15 months for patients diagnosed with glioblastoma multiforme. Cedars-Sinai researchers have studied dendritic cell immunotherapy since 1997, with the first patient human clinical trial launched in 1998.

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Cedars-Sinai researchers target cancer stem cells in malignant brain tumors

Stanford Report, January 6, 2014

Irving Weissman, director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford.

The Stanford University School of Medicine has received $90 million from Ludwig Cancer Research on behalf of its founder, Daniel K. Ludwig, to support the school's innovative work in cancer stem cells, which are believed to drive the growth of many cancers.

Stanford is one of six institutions to share in Ludwig's $540 million contribution to the field of cancer research. Announced today, the gift is one of the largest ever made to the field from an individual donor.

The funding will augment the existing endowment for the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, established in 2006, where scientists already have discovered some promising therapies that are moving into clinical trials.

"The gift from Ludwig Cancer Research is truly historic," said Stanford President John Hennessy. "Over the years, Ludwig has been a generous supporter of cancer research, and through its support changed the course of cancer treatment. But this extraordinary gift will spur innovation well into the future.Stanford is distinguished for its cancer research and has assembled a 'dream team' of dedicated scientists at the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. This gift is a tremendous vote of confidence in the work they and their colleagues at other Ludwig Centers are doing and will provide essential support as they pioneer new treatments and therapies."

The Ludwig gift will complement Stanford's Cancer Initiative, a $250 million effort to advance research and improve patient care, said Lloyd Minor, dean of the Stanford School of Medicine.

"We are very grateful to Ludwig Cancer Research for this exceptional gift, which will provide momentum for further discoveries in cancer stem cells and spur the development of new therapies," Minor said. "Together with our Cancer Initiative, it represents an opportunity to truly transform cancer research and treatment."

With his latest gift, Ludwig has now committed $150 million to Stanford. The university's Ludwig Center, the only cancer stem cell center of its kind, is directed by Irving Weissman, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research at Stanford.

The first evidence of cancer stem cells was found in acute myeloid leukemia in 1994 by Canadian scientist John Dick. Weissman and his colleagues purified human blood-forming stem cells in 1992 and human leukemia stem cells in 2000 and later identified potential therapeutic targets on them. Since then, Michael Clarke, professor of medicine at Stanford and a Ludwig Center deputy director, isolated cancer stem cells in breast cancer, pancreatic cancers and colorectal cancer, and with Weissman head and neck cancers, bladder cancer, myelomas and other cancers.

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Stanford shares in $540 million gift from Ludwig Cancer Research