Stem Cell Treatment May Restore Cognitive Function In Patients With Brain Cancer

Stem cell therapy may restore cognition in patients with brain cancer who experience functional learning and memory loss often associated with radiation treatment, according to a laboratory study published in Cancer Research, a journal of the American Association for Cancer Research.

Charles Limoli, Ph.D., a professor in the department of radiation oncology at the University of California, Irvine, said radiation therapy is the standard of care for most brain cancers, but the side effects can be devastating.

"In almost every instance, people experience severe cognitive impairment that is progressive, debilitating and adversely impacts quality of life," he said. "Pediatric cancer patients can experience a drop of up to three IQ points per year."

In the current study, Limoli and colleagues subjected rats to cranial irradiation and followed up two days later with human neural stem cell transplants. A significant proportion of these cells survived and turned into brain cells found at one- and four-month evaluations. Cognitive function significantly improved compared with control rats.

Limoli said the findings of this study were significant, and may help pave the way for a human safety trial to be conducted within a few years if appropriate funding can be secured. Neural stem cells like those used in this study do not present the same ethical questions as embryonic stem cells.

Source: American Association for Cancer Research (AACR)

Stem Cells Restore Cognitive Abilities Impaired By Brain Cancer Treatment

Human neural stem cells are capable of helping people regain learning and memory abilities lost due to radiation treatment for brain tumors, a UC Irvine study suggests.

Research with rats found that stem cells transplanted two days after cranial irradiation restored cognitive function, as measured in one- and four-month assessments. In contrast, irradiated rats not treated with stem cells showed no cognitive improvement.

"Our findings provide solid evidence that such cells can be used to reverse radiation-induced damage of healthy tissue in the brain," said Charles Limoli, a UCI radiation oncology professor.

Study results appear in the July 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

Radiotherapy for brain tumors is limited by how well the surrounding tissue tolerates it. Patients receiving radiation at effective levels suffer varying degrees of learning and memory loss that can adversely affect their quality of life.

"In almost every instance, people experience severe cognitive impairment that's progressive and debilitating," Limoli said. "Pediatric cancer patients can experience a drop of up to three IQ points per year."

For the UCI study, multipotent human neural stem cells were transplanted into the brains of rats that had undergone radiation treatment. They migrated throughout the hippocampus - a region known for the growth of new neurons - and developed into brain cells.

Researchers assessed the rats one month and four months after transplantation, noting enhanced learning and memory abilities at both intervals.

Additionally, they found that transplanting as few as 100,000 human neural stem cells was sufficient to improve cognition after cranial irradiation. Of cells surviving the process, about 15 percent turned into new neurons, while another 45 percent became astrocytes and oligodendrocytes - cells that support cerebral neurons.

Most notably, Limoli said, he and his colleagues discovered that about 11 percent of the engrafted cells expressed a behaviorally induced marker of learning, indicating the functional integration of those cells into memory circuits in the hippocampus.

"This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments," Limoli said. "While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years, most likely with patients afflicted with glioblastoma multiforme, a particularly aggressive and deadly form of brain cancer."

Munjal Acharya, Lori-Ann Christie, Mary Lan and Erich Giedzinski of UCI and John Fike and Susanna Rosi of UC San Francisco contributed to the study, which was funded by the California Institute for Regenerative Medicine, the National Institutes of Health and the U.S. Department of Energy.

Source:
Tom Vasich
University of California - Irvine

The Complexity Of Glue Molecule's Role In Cancer Revealed By Stem Cell Study

A protein molecule that 'glues' cells together and so has a key role in cancer is also responsible for many other important functions of cells, a new study has found.

University of Manchester scientists say their unexpected findings are important because they could lead to a better understanding of why some cancer cells are difficult to eradicate in patients and lead to new cancer treatments.

The research - published in PLoS One - looked at the role of the cell-adhesion molecule E-cadherin in embryonic stem (ES) cells. As well as the expected findings associated with changes in adhesion, the team found that the protein may also regulate up to 25% of the genes within cells.

"E-cadherin is a 'glue' that keeps cells together in the body - without it we would not develop beyond a bundle of cells a few days after conception," said Dr Chris Ward, who led the study in the University's School of Dentistry.

"E-cadherin is also important during cancer progression from benign to malignant states, with loss of this molecule leading to increased movement of the cells which can lead to secondary tumours within the body.

"Whilst E-cadherin has been studied intensively there has been no research that has identified all of the genes that E-cadherin regulates. Our lab has carried out profiling of ES cells lacking E-cadherin and found this protein is responsible for regulating up to 25% of the genes within cells.

"As well as the expected findings associated with changes in cell adhesion, we found that E-cadherin exerts an effect on a diverse range of biological functions within the cell. This unexpected result demonstrates that E-cadherin, often viewed as no more than a cell 'glue', is an important part of regulating the biology of ES cells."

The group found that E-cadherin regulates genes associated with, amongst other things, cell proliferation, cell death, metabolism of fats and sugars and the deciphering of messages received by cells from outside.

Since loss of E-cadherin is implicated in higher death rates in cancer patients and a more aggressive tumour type, the group has suggested that this molecule may have a much more important role to play in preventing tumour development.

Dr Ward added: "Essentially, abnormal regulation of E-cadherin can lead to a significant change in a cell and this may be one of the reasons why such cells are difficult to eradicate in cancer patients. Further investigation of specific changes in these cells may lead to the development of novel treatments for cancer."

Source:
Aeron Haworth
University of Manchester

14 Leading Edge Studies Shared By John Theurer Cancer Center Researchers Shared At Recent ASCO Meeting

Researchers from the John Theurer Cancer Center at Hackensack University Medical Center presented results from 14 cancer-related studies during the recently concluded American Society of Clinical Oncology (ASCO) Annual Meeting, which took place June 3 - 7, 2011 in Chicago. The studies examined new cancer treatments, ways to predict the best treatment outcomes, and patient quality of life issues.

"ASCO is a great venue for sharing best practices and learning about new treatment approaches - we are proud to help contribute by presenting our recent scientific work," said Andre Goy, M.D., M.S., Chairman and Director and Chief of Lymphoma, John Theurer Cancer Center. "Our researchers will keep working to improve oncology and help develop some of the newest approaches to treating cancer. This will remain a priority for our cancer center."

Among other promising research, John Theurer Cancer Center investigators reported on a phase II study of carfilzomib, a new proteasome inhibitor to treat advanced multiple myeloma; the first phase III trial of anti-metabolite clofarabine against acute myelogenous leukemia; application of a new statistical model to predict mantle cell lymphoma survival and guide treatment choices; and a comparison of disease status and satisfaction with care among chronic myeloid leukemia patients.

"The innovative research we conduct brings tomorrow's treatments to our patients today," said Andrew L. Pecora, M.D., F.A.C.P., C.P.E., Chief Innovations Officer and Professor and Vice President of Cancer Services, John Theurer Cancer Center. "We have recently expanded our capabilities through the opening of an extraordinary new research and patient care facility, and it is our belief that this will enable us to further speed the pace of discovery and be even more prolific in our scientific publications."

Highlights of the Theurer Center presentations include:

PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis.

David S. Siegel, M.D., Ph.D. and colleagues presented findings from a phase II, single-arm open-label study of carfilzomib (CFZ), a novel, highly selective proteasome inhibitor in development for treatment of advanced multiple myeloma. Proteasome inhibitors block the actions of certain proteins (proteasomes) that cancer cells need to survive and multiply. All patients in the study were previously unresponsive to treatment with other combination therapies. Of 257 patients completing the study, the overall response rate was 24% with a median response duration of 7.4 months. The median overall survival was 15.5 months. CFZ as a standalone treatment achieved significant responses in 36% of patients who did not previously respond to treatment with bortezomib and immunomodulatory drugs, including patients with chromosomal abnormalities. CFZ was well tolerated and adverse events were manageable with no new, unexpected, or cumulative toxicities.

Survival outcomes in elderly patients with plasma cell myeloma: The three-decade Eastern Cooperative Oncology Group (ECOG) experience.

Recent landmark papers showed significant improvement in survival rates for patients under 65 years of age with plasma cell myeloma, but not for older patients. To shed new light on progress in treating older individuals, David H. Vesole, M.D., PH.D., F.A.C.P. and colleagues examined data over the last 33 years for previously untreated patients who were treated according to standard European Cooperative Oncology Group protocols during three time periods: 1988-1993, 1994-2000 and 2001-2006. Patients receiving autologous stem cell transplantation were excluded. For patients over 65 years, there was a higher overall survival in those treated 2001-2006 (39%), than in those treated 1988-1993 and 1994-2000 (26% for both groups). These gains were far less than for patients 65 and under (63% in the 2001-2006 group, 35% for 1988-1993 and 32% for 1994-2000). The authors suggest an in-depth review of a number of variables that may contribute to worse survival for older patients, in order to improve the design of future clinical trials.

A new predictive model based on age, pretreatment LDH, and post-therapy PET-CT in patients with MCL treated with dose-intensive strategies.

Anthony Mato, M.D. and a research team from John Theurer Cancer Center conducted a retrospective study examining risk factors associated with survival of patients with mantle cell lymphoma who were treated with dose-intensive strategies and/or high dose therapy with autologous stem cell transplant. The researchers developed an algorithm that enabled them to identify distinct prognostic subgroups, based on three variables: age, levels of LDH enzymes in the blood, and presence of disease on PET scans. With a median follow up at 35 months, they found that age

Study Reveals Cancer Stem Cells Recruit Normal Stem Cells To Fuel Ovarian Cancer

Researchers at the University of Michigan Comprehensive Cancer Center have found that a type of normal stem cell fuels ovarian cancer by encouraging cancer stem cells to grow.

Cancer stem cells are the small number of cells in a tumor that drive its growth and spread. Traditional cancer treatments do not kill these cells, which is why cancer treatments often fail.

In a study published online in the Journal of Clinical Investigation, researchers looked in ovarian tissue at the mesenchymal stem cells, which are normal cells found throughout the body. These cells can form different specialized cells such as fat, bone or cartilage.

Mesenchymal stem cells are known to be helpful with wound healing, which has many scientists conjecturing that they may help combat cancer. In this study, the researchers observed that mesenchymal stem cells in ovarian tumors were different than mesenchymal stem cells from healthy ovaries. And in fact, the mesenchymal stem cells in the ovarian tumors were fueling the cancer.

"Cancer is very good at tricking the mesenchymal stem cells into doing what the cancer likes. The cancer takes the cells hostage and uses them to promote the cancer's growth," says study author Ronald Buckanovich, M.D., Ph.D., assistant professor of internal medicine and of obstetrics and gynecology at the U-M Medical School.

The researchers used mouse models and human tissue samples of both normal ovaries and ovarian cancer, to look at what happened to the mesenchymal stem cells. They also noticed the cancer-associated mesenchymal stem cells increased tumor size, primarily by increasing the number of cancer stem cells.

At the same time, the researchers saw that a type of protein called BMP2 was prevalent in the cancer-associated mesenchymal stem cells. BMP2 is a so-called master regulatory protein, and is carefully regulated in normal cell function. The researchers found more than three times the amount of BMP in the cancer-associated mesenchymal stem cells than in the normal ones. When BMP was added to cancer cells, it led to an increase in cancer stem cells.

The researchers then used a known BMP inhibitor called Noggin, and found that Noggin blocked the mesenchymal stem cells from triggering this cancer stem cell growth.

"High doses of Noggin might not be tolerated in humans," Buckanovich says. "Our next step is to figure out how to target Noggin directly to the vascular niche where the mesenchymal stem cells and cancer stem cells live. This would allow us to make it safer to use Noggin as a potential treatment for ovarian cancer."

This research must continue in the laboratory before it can be advanced to clinical trials in patients. In the meantime, the U-M Comprehensive Cancer Center expects to open two new clinical trials within the next year testing other therapies aimed at attacking ovarian cancer stem cells. For information, contact the Cancer AnswerLine at 800-865-1125.

Notes:

Ovarian cancer statistics: 21,880 Americans will be diagnosed with ovarian cancer this year and 13,850 will die from the disease, according to the American Cancer Society

Additional authors: Karen McLean, Yusong Gong, Junjung Choi, Ning Deng, Kun Yang, Shoumei Bai, Lourdes Cabrera, Evan Keller, Laurie McCauley and Kathleen R. Cho, all from U-M

Funding: Damon Runyon Cancer Research Foundation, National Institutes of Health

Disclosure: None

Reference: Journal of Clinical Investigation, doi:10.1172/JCI45273

Source:
Nicole Fawcett
University of Michigan Health System

Cancer Cells And Stem Cells Share Same Origin

Oncogenes are generally thought to be genes that, when mutated, change healthy cells into cancerous tumor cells. Scientists at the Keck School of Medicine of the University of Southern California (USC) have proven that those genes also can change normal cells into stem-like cells, paving the way to a safer and more practical approach to treating diseases like multiple sclerosis and cancer with stem cell therapy.

"The reality may be more complicated than people think," said Jiang F. Zhong, Ph.D., assistant professor of pathology at the Keck School. "What is a stem cell gene? What is a cancer gene? It may be the same thing."

Zhong and colleagues at the Children's Hospital of Orange County (CHOC) in California and Good Samaritan Hospital Medical Center in New York successfully converted human skin cells into brain cells by suppressing the expression of p53, a protein encoded by a widely studied oncogene. This suggests that p53 mutation helps determine cell fate - good or bad - rather than only the outcome of cancer.

The study is slated to appear in the online edition of Proceedings of the National Academy of Sciences, a peer-reviewed scientific journal, the week of July 18, 2011.

"When you turn off p53, people think the cell becomes cancerous because we tend to focus on the bad thing," Zhong said. "Actually, the cell becomes more plastic and could do good things, too. Let's say the cell is like a person who loses his job (the restriction of p53). He could become a criminal or he could find another job and have a positive effect on society. What pushes him one way or the other, we don't know because the environment is very complicated."

Stem cells can divide and differentiate into different types of cells in the body. In humans, embryonic stem cells differentiate into three families, or germ layers, of cells. The reasons why and how certain stem cells differentiate into particular layers are not clearly understood. However, from those layers, tissues and organs develop. The endoderm, for example, leads to formation of the stomach, colon and lungs, while the mesoderm forms blood, bone and heart tissue. In its study, Zhong's team examined human skin cells, which are related to brain and neural cells from the ectoderm.

When p53 was suppressed, the skin cells developed into cells that looked exactly like human embryonic stem cells. But, unlike other man-made stem cells that are "pluripotent" and can become any other cells in the body, these cells differentiated only into cells from the same germ layer, ectoderm.

"IPSCs