Regulation of Telomerase in Stem Cells and Cancer Cells

Source: Max-Planck-Gesellschaft
Date: June 27, 2012

Summary:

Scientists at the Max Planck Institute of Immunobiology and Epigenetics have gained important insights for stem cell research which are also applicable to human tumours and could lead to the development of new treatments. Researchers discovered a molecular link exists between the telomerase that determines the length of the telomeres and a signalling pathway known as the Wnt/β-signalling pathway.

The researchers demonstrated that β-catenin regulates the telomerase gene directly, and has explained the molecular mechanism at work here. Embryonic stem cells with mutated β-catenin generate more telomerase and have extended telomeres, while cells without β-catenin have low levels of telomerase and have shortened telomeres. This regulation mechanism can also be found in human cancer cells. These discoveries could lead to the development of a new approach to the treatment of human tumours.

Cancer Stem Cell Vaccine in Development Shows Antitumor Effect

Source: American Association for Cancer Research
Date: April 2, 2012

Summary:

PHILADELPHIA — Scientists may have discovered a new paradigm for immunotherapy against cancer by priming antibodies and T cells with cancer stem cells, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.

In the study, the researchers extracted cancer stem cells from two immunocompetent mouse models and used them to prepare the vaccine. They discovered that the enriched cancer stem cells were immunogenic and much for effective more effective as an antigen source compared with the unselected tumor cells normally used in previous immunotherapy trials. The researchers also found that cytotoxic T lymphocytes harvested from cancer stem cell-vaccinated hosts were capable of killing cancer stem cells in vitro.

Single antibody shrinks variety of human tumors transplanted into mice, study shows

Source: Stanford University School of Medicine
Date: March 26, 2012

Summary:

Human tumors transplanted into laboratory mice disappeared or shrank when scientists treated the animals with a single antibody, according to a new study from the Stanford University School of Medicine. The antibody works by masking a protein flag on cancer cells that protects them from macrophages and other cells in the immune system. The scientists achieved the findings with human breast, ovarian, colon, bladder, brain, liver and prostate cancer samples.

It is the first antibody treatment shown to be broadly effective against a variety of human solid tumors, and the dramatic response — including some overt cures in the laboratory animals — has the investigators eager to begin phase-1 and –2 human clinical trials within the next two years. The antibody treatment also significantly inhibited the ability of the tumors to metastasize throughout the animals’ bodies. The research was published online March 26 in the Proceedings of the National Academy of Sciences.

Key to Aging? Key Molecular Switch for Telomere Extension by Telomerase Identified

Source: University of Illinois at Chicago
Date: November 23, 2011

Summary:

Researchers at the University of Illinois at Chicago College of Medicine describe for the first time a key target of DNA damage checkpoint enzymes that must be chemically modified to enable stable maintenance of chromosome ends by telomerase, an enzyme thought to play a key role in cancer and aging. Their findings are reported online in Nature Structural and Molecular Biology.

Discovery may eliminate potentially lethal side effect of stem cell therapy

Source: Stanford University Medical Center
Date: August 14, 2011

Summary:

Like fine chefs, scientists are seemingly approaching a day when they will be able to make nearly any type of tissue from human embryonic stem cells. You need nerves or pancreas, bone or skin? With the right combination of growth factors, skill and patience, a laboratory tissue culture dish promises to yield therapeutic wonders. But within these batches of newly generated cells lurks a big potential problem: Any remaining embryonic stem cells -- those that haven't differentiated into the desired tissue -- can go on to become dangerous tumors called teratomas when transplanted into patients.

Now researchers at the Stanford University School of Medicine have developed a way to remove these pluripotent human embryonic stem cells from their progeny before the differentiated cells are used in humans. ("Pluripotent" describes cells that are able to become all types of adult tissue.)

The scientists believe the technique could also be used to remove residual tumor-initiating cells from populations of cells derived from induced pluripotent stem, or iPS, cells. These cells may also be useful for therapy but, unlike embryonic stem cells, iPS cells are created in the laboratory from adult tissue.

The research will be published online Aug. 14 in Nature Biotechnology.

A Patient's Own Skin Cells May One Day Treat Multiple Diseases

Source: University of California - Davis Health System
Date: August 4, 2011

Summary:

The possibility of developing stem cells from a patient's own skin and using them to treat conditions as diverse as Parkinson's disease, Alzheimer's disease and cancer has generated tremendous excitement in the stem cell research community in recent years. Such therapies would avoid the controversial need for using stem cells derived from human embryos, and in theory, also bypass immunological problems inherent in using cells from one person to treat another.

A roadmap for finding solutions to the problems identified with iPSCs, written by researchers at UC Davis, is available online and will be published in the Aug. 5 issue of the journal Cell Stem Cell. The publication suggests research strategies to advance the field more rapidly toward applications for human diseases.

Normal stem cells made to look and act like cancer stem cells

Source: University of North Carolina at Chapel Hill School of Medicine
Date: May 5, 2011

Summary:

CHAPEL HILL, NC — Researchers at the University of North Carolina at Chapel Hill School of Medicine, after isolating normal stem cells that form the developing placenta, have given them the same properties of stem cells associated with an aggressive type of breast cancer.

The scientific first opens the door for developing novel targeted therapies aimed at triple negative breast cancer. Known also as TNBC, this is a highly recurrent tumor that spreads aggressively beyond its original site in the breast and carries a poor prognosis for patients who have it. The study will be published online Friday, May 6, by the journal Cell Stem Cell.

Geron Announces Publication Demonstrating Activity of Imetelstat Against Cancer Stem Cells from Pediatric Neural Tumors

Source: Geron Corporation
Date: January 10, 2011

Summary:

MENLO PARK, Calif., - Geron Corporation today announced the publication of preclinical data demonstrating that the company's telomerase inhibitor drug, imetelstat (GRN163L), currently in Phase 2 clinical trials, selectively targets cancer stem cells in pediatric tumors of neural origin.

Telomerase activity has previously been linked to progression and poor patient survival in childhood cancers of the central and peripheral nervous system, such as gliomas and neuroblastomas. Cancer stem cells are believed to be responsible for the growth, recurrence and metastasis of tumors. Cancer stem cells are rare populations of malignant cells with the capacity for endless self-renewal found in many types of cancer including neural tumors. Their resistance to chemotherapy and conventional anti-cancer agents make them important targets for novel therapies.

The data in the current study showed that telomerase activity was confined to the cancer stem cell population in the pediatric neural tumors studied. Gliomas removed from fourteen patients showed high telomerase activity in the cancer stem cell fraction, but not in the bulk tumor cells. Glioma and neuroblastoma cancer stem cells grown in culture were also found to have high telomerase activity. These cancer stem cells were found to have extremely short telomeres, which along with high telomerase levels, might render them particularly sensitive to telomerase inhibition by imetelstat.

The stemness of cancer cells

Source: Salk Institute for Biological Studies
Date: December 13, 2010

Summary:

A close collaboration between researchers at the Salk Institute for Biological Studies and the Institute for Advanced Study found that the tumor suppressor p53, long thought of as the "Guardian of the Genome," may do more than thwart cancer-causing mutations. It may also prevent established cancer cells from sliding toward a more aggressive, stem-like state by serving as a "Guardian against Genome Reprogramming."

The new work, reported by Geoffrey M. Wahl, Ph.D., and Benjamin Spike, Ph.D., at Salk Institute and Arnold J. Levine, Ph.D., and Hideaki Mizuno, Ph.D., at IAS, Princeton, in this week's online edition of the Proceedings of the National Academy of Sciences, revealed striking parallels between the increased reprogramming efficiency of normal adult cells lacking p53, the inherent plasticity and tumorigenicity of stem cells, and the high incidence of p53 mutations in malignant cancers.

Too Much SP2 Protein Turns Stem Cells Into “Evil Twin” Tumor-forming Cancer Cells

Source: North Carolina State University
Date: October 27, 2010

Summary:

Researchers at North Carolina State University have found that the overproduction of a key protein in stem cells causes those stem cells to form cancerous tumors. Their work may lead to new treatments for a variety of cancers. The team of researchers looked at the protein SP2, which regulates the activity of other genes. They knew that elevated amounts of SP2 had been observed in human prostate-cancer patients, and that these levels only increased as the tumors became more dangerous. They then showed that precisely the same thing occurs in mouse skin tumors. The researchers’ results are published in the Nov. 3 edition of the journal Cancer Research.

Gene identified that prevents stem cells from turning cancerous

Source: Rockefeller University
Date: October 14, 2010

Summary:

Stem cells, the prodigious precursors of all the tissues in our body, can make almost anything, given the right circumstances. Including, unfortunately, cancer. Now research from Rockefeller University shows that having too many stem cells, or stem cells that live for too long, can increase the odds of developing cancer. By identifying a mechanism that regulates programmed cell death in precursor cells for blood, or hematopoietic stem cells, the work is the first to connect the death of such cells to a later susceptibility to tumors in mice. It also provides evidence of the potentially carcinogenic downside to stem cell treatments, and suggests that nature has sought to balance stem cells' regenerative power against their potentially lethal potency.

Researchers explored the activity of a gene called Sept4, which encodes a protein, ARTS, that increases programmed cell death, or apoptosis, by antagonizing other proteins that prevent cell death. ARTS is found to be lacking in human leukemia and other cancers, suggesting it suppresses tumors. To study the role of ARTS, the experimenters bred a line of mice genetically engineered to lack the Sept4 gene.

Researchers studied cells that lacked ARTS, looking for signs of trouble relating to cell death. In mature B and T cells, she could not find any, however, so she began to look at cells earlier and earlier in development, until finally she was comparing hematopoietic progenitor and stem cells. Here she found crucial differences, to be published Friday in Genes and Development.

Two New Paths to the Dream: Regeneration

Source: New York Times
Date: August 5, 2010

Summary:

The New York Times reported a story on the discovery of new approaches to regenerating limbs using the body's own cells. The first, an announcement by researchers at Stanford University School of Medicine, the ability of newts to regenerate tissue was successfully replicated in mice:

Two research reports published Friday offer novel approaches to the age-old dream of regenerating the body from its own cells. Animals like newts and zebra fish can regenerate limbs, fins, even part of the heart. If only people could do the same, amputees might grow new limbs and stricken hearts be coaxed to repair themselves.

...In the first of the two new approaches, a research group at Stanford University led by Helen M. Blau, Jason H. Pomerantz and Kostandin V. Pajcini has taken a possible first step toward unlocking the human ability to regenerate. By inactivating two genes that work to suppress tumors, they got mouse muscle cells to revert to a younger state, start dividing and help repair tissue.

In a second experiment, a different technique to regenerating a tissue was announced by researchers at the University of California, San Francisco to regenerate heart tissue by reprogramming heart tissue cells into heart muscle cells reported in the journal Cell:

A second, quite different approach to regenerating a tissue is reported in Friday’s issue of Cell by Deepak Srivastava and colleagues at the University of California, San Francisco. Working also in the mouse, they have developed a way of reprogramming the ordinary tissue cells of the heart into heart muscle cells, the type that is irretrievably lost in a heart attack.
The Japanese scientist Shinya Yamanaka showed three years ago that skin cells could be converted to embryonic stem cells simply by adding four proteins known to regulate genes. Inspired by Dr. Yamanaka’s method, Dr. Srivastava and his colleagues selected 14 such proteins and eventually found that with only three of them they could convert heart fibroblast cells into heart muscle cells.

Irradiating brain's stem cell niche doubles survival time for patients with brain cancers

Source: University of California - Los Angeles
Date: July 26, 2010

Summary:

Patients with deadly glioblastomas who received high doses of radiation that hit a portion of the brain that harbors neural stem cells had double the progression-free survival time as patients who had lower doses or no radiation targeting the area, a study from the Radiation Oncology Department at UCLA's Jonsson Comprehensive Cancer Center has found.

Patients who underwent high doses of radiation that hit the specific neural stem cell site, known as the stem cell niche, experienced 15 months of progression-free survival, while patients receiving lower or no doses to this region experienced 7.2 months of progression-free survival, said Dr. Frank Pajonk, an associate professor of radiation oncology, a cancer center researcher and senior author of the study.

Pajonk said the study, published in the early online edition of the journal BMC Cancer, could result in changes in the way radiation therapy is given to patients with these deadly brain cancers.

New discovery brings hope to treatment of incurable blood cancer

Source: Uppsala University
Date: July 15, 2010

Summary:

Multiple myeloma is one of the most common blood cancers, and at present considered to be incurable. In a new study from Uppsala University, researchers now present a conceptually new model for the development and progression of multiple myeloma. The study was done in collaboration with Vrije Universitet Brussels and is published in the July edition of the on-line journal PLoS ONE.

Using large cohorts of myeloma patients the researchers have identified a profile of genes that are silenced by epigenetic mechanisms in the malignant plasma cell. The silenced gene profile was compared and contrasted to normal plasma cells, which are highly specialised and for which growth and lifetime is tightly controlled.

The silenced genes have a common denominator in being targets and controlled by the Polycomb repressor complex (PcG). This complex has previously been implicated in self-renewal and division of normal embryonic stem cells. In the study the researchers found that inhibitors of PcG also could decrease the growth of tumour cells in an animal model of myeloma.

Biologists Find Way to Lower Tumor Risk in Stem Cell Therapies

Source: University of California - San Diego
Date: July 2, 2010

Summary:

One of the characteristics of embryonic stem cells is their ability to form unusual tumors called teratomas. These tumors, which contain a mixture of cells from a variety of tissues and organs of the body, are typically benign. But they present a major obstacle to the development of human embryonic stem cell therapies that seek to treat a variety of human ailments such as Parkinson’s, diabetes, genetic blood disorders and spinal cord injuries.

Now a team of biologists at UC San Diego funded by a grant from the California Institute for Regenerative Medicine, the state’s stem-cell funding agency, has discovered a way to limit the formation of teratomas. In this week’s issue of the Proceedings of the National Academy of Sciences, the researchers report that they have identified a new signaling pathway critical for unlimited self propagation of embryonic stem cells. Using small molecule compounds that inhibit this pathway, the scientists were able to dramatically reduce the potential of embryonic stem cells to form teratomas.

Human Embryonic-Like Extracellular Matrix Significantly Inhibits Tumor Growth and Cancer Cell Proliferation

Source: Histogen, Inc.
Date: June 17, 2010

Summary:

Histogen, Inc., a regenerative medicine company developing solutions based on the products of newborn cells grown under embryonic conditions, will present findings tomorrow at the International Society for Stem Cell Research (ISSCR) Annual Meeting. Studies of the human extracellular matrix (hECM) produced under proprietary conditions of hypoxia and suspension have demonstrated its ability to diminish or eliminate tumor load in melanoma, breast cancer, colon cancer and glioma, both in vitro and in vivo.

Tumor growth was significantly inhibited across these cancer cell lines, with a 50-80% reduction in tumor weight seen in the tumor chorioallantoic membrane (tumcam) model (p<0.05) and a 70-90% reduction seen in subcutaneous mouse xenograft experiments (p<0.02). In studies of a carcinomatosis model established with a human colon carcinoma line, treatment with the hECM resulted in reduced tumor number and size, reduction of ascites, and, to date, a doubling in lifespan, as compared to untreated and cisplatin-treated mice.

City of Hope receives FDA approval for first human neural stem cell clinical trial to treat brain tumors

Source: City of Hope National Medical Center
Date: June 2, 2010

Summary:

DUARTE, Calif., — City of Hope researchers received approval from the U.S. Food and Drug Administration (FDA) to conduct the first-in-human study of a neural stem cell-based therapy targeting recurrent high-grade gliomas, the most aggressive type of brain tumor.

Stem-cell activators switch function, repress mature cells

Source: Ohio State University Medical Center
Date: December 16, 2009

Summary:

In a developing animal, stem cells proliferate and differentiate to form the organs needed for life. A new study shows how a crucial step in this process happens and how a reversal of that step contributes to cancer. The study, led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, shows for the first time that three proteins, called E2f1, E2f2 and E2f3, play a key role in the transition stem cells make to their final, differentiated, state.

These proteins help stimulate stem cells to grow and proliferate. But once stem cells begin to differentiate into their final cell type - a cell in the retina or in the lining of the intestine, for example - the same three proteins switch function and stop them from dividing any more. The research also shows how these proteins can switch course yet again in cells that have mutations in the retinoblastoma (Rb) gene. Mutated Rb genes occur in many types of cancer, suggesting that these E2f proteins might offer a safe and novel therapeutic target in these tumors. The findings are published in back-to-back papers in the Dec. 17 issue of the journal Nature.

Stem Cells That “Fool” Immune System May Provide Vaccination for Cancer

Source: University of Connecticut
Date: November 23, 2009

Summary:

University of Connecticut Health Center researchers in collaboration with scientists from China have revealed the potential for human stem cells to provide a vaccination against colon cancer, reports a study published in October in STEM CELLS. This discovery, led by immunology experts Dr. Bei Liu and Dr. Zihai Li, builds upon a century-old theory that immunizing with embryonic materials may generate an anti-tumor response. However, this theory has never before been advanced beyond the use of animal embryonic materials, and the discovery that human stem cells are able to immunize against colon cancer is both new and unexpected.

Stem cells alleviate tumor treatment side effects

Source: University of California- Irvine
Date: November 17, 2009

Summary:

Human embryonic stem cells could help people with learning and memory deficits after radiation treatment for brain tumors, suggests a new UC Irvine study. Research with rats found that transplanted stem cells restored learning and memory to normal levels four months after radiotherapy. In contrast, irradiated rats that didn't receive stem cells experienced a more than 50 percent drop in cognitive function.

"Our findings provide the first evidence that such cells can be used to ameliorate radiation-induced damage of healthy tissue in the brain," says Charles Limoli, UCI radiation oncology associate professor and senior author of the study, appearing online the week of Nov. 9 in the Proceedings of the National Academy of Sciences.