TAG: "Cancer"

Study bucks conventional wisdom about how stress-response protein works


UCLA finding provides new insights into heat shock proteins.

Zhe Jing, UCLA

UCLA researchers, in a finding that runs counter to conventional wisdom, have discovered for the first time that a gene thought to express a stress-response protein in all cells that come under stress instead expresses the protein only in specific cell types.

The research team, from the Jules Stein Eye Institute at UCLA and the UCLA Division of Pulmonary and Critical Care Medicine, focused on αB-Crystallin, one of a class of molecules known as heat shock proteins, which are involved in the folding and unfolding of other proteins, helping them recover from stress so they can do their job.

The expression of heat shock proteins is increased when cells are exposed to taxing environmental conditions, such as infection, inflammation, exercise, exposure to toxins and other stressors.

The heat shock protein αB-Crystallin may be associated with certain cancers and could be developed into a biomarker to monitor for diseases such as multiple sclerosis, age-related macular degeneration, heart-muscle degeneration and clouding of the eye lens. Any discoveries about how this protein is regulated and its molecular biology may reveal potential targets for novel therapies, said the study’s first author, Zhe Jing, a research associate in the UCLA Division of Pulmonary and Critical Care Medicine.

“If you use a certain cell type, this protein can be induced when the cells are stressed, but that doesn’t happen in a different cell type,” Jing said. “This novel finding does conflict with what has been thought — that this protein could be induced in any cell type.”

The findings of the two-year study are published in the current issue of the journal Cell Stress and Chaperones, a peer-reviewed journal for research on cell stress response.

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In breast cancer metastasis, researchers ID possible drug target


Discovery points to control point that holds in check events required for tumor cells to spread.

Zena Werb, UC San Francisco

The spread of breast cancer to distant organs within the body, an event that often leads to death, appears in many cases to involve the loss of a key protein, according to UC San Francisco researchers, whose new discoveries point to possible targets for therapy.

In the Jan. 27 online edition of Nature Cell Biology, UCSF scientists describe for the first time how the protein, known as GATA3 — which is abnormal or absent in many cases of human breast cancer — normally acts downstream in biochemical pathways to prevent the distant spread of cancer, an event called metastasis.

The discovery points to a biochemical control point that simultaneously holds in check several key events required for tumor cells to successfully spread.

“When GATA3 is present, it turns off many genes that are active in metastasis,” said Zena Werb, Ph.D., a UCSF professor of anatomy who led the research. “We now have identified the molecular mechanisms involved.”

The key finding of the new study is that GATA3 acts downstream biochemically to activate a molecule — obscure until now — called microRNA29b. MicroRNA29b in turn stops protein production from other genes that play vital roles in metastasis.

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Low vitamin D levels linked to high risk of early breast cancer


Low levels in months prior to diagnosis may predict high risk of the disease in premenopausal women.

Cedric Garland, UC San Diego

A prospective study led by researchers from the UC San Diego School of Medicine has found that low serum vitamin D levels in the months preceding diagnosis may predict a high risk of premenopausal breast cancer.

The study of blood levels of 1,200 healthy women found that women whose serum vitamin D level was low during the three-month period just before diagnosis had approximately three times the risk of breast cancer as women in the highest vitamin D group. The study is currently published online in advance of the print edition of the journal Cancer Causes and Control.

Several previous studies have shown that low serum levels of vitamin D are associated with a higher risk of premenopausal breast cancer. “While the mechanisms by which vitamin D could prevent breast cancer are not fully understood, this study suggests that the association with low vitamin D in the blood is strongest late in the development of the cancer,” said principal investigator Cedric Garland, Dr.P.H., FACE, professor in the Department of Family and Preventive Medicine at UC San Diego.

Analyses of vitamin D levels measured more than 90 days before diagnosis have not conclusively established a relationship between serum levels and risk of premenopausal breast cancer in the present cohort. However, this new study points to the possibility of a relevant window of time for cancer prevention in the last three months preceding tumor diagnosis — a time physiologically critical to the growth of the tumor.

According to Garland, this is likely to be the point at which the tumor may be most actively recruiting blood vessels required for tumor growth. “Based on these data, further investigation of the role of vitamin D in reducing incidence of premenopausal breast cancer, particularly during the late phases of its development, is warranted,” he said.

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Novel technique reveals dynamics of telomere DNA structure


Chromosome-capping telomeres are a potential target for anti-cancer drugs.

Researchers observed the unfolding of telomere G-quadruplex structures using a combination of single-molecule FRET and magnetic tweezers, as shown in this diagram. DNA structural transitions between the folded state (far left) and unfolded state (far right) were monitored in real-time as the efficiency of energy transfer between a FRET donor dye (green) and acceptor dye (red) attached to the DNA.

Biomedical researchers studying aging and cancer are intensely interested in telomeres, the protective caps on the ends of chromosomes. In a new study, scientists at UC Santa Cruz used a novel technique to reveal structural and mechanical properties of telomeres that could help guide the development of new anti-cancer drugs.

Telomeres are long, repetitive DNA sequences at the ends of chromosomes that serve a protective function analogous to that of the plastic tips on shoelaces. As cells divide, their telomeres get progressively shorter, until eventually the cells stop dividing. Telomeres can grow longer, however, through the action of an enzyme called telomerase, which is especially active in cells that need to keep dividing indefinitely, such as stem cells. Researchers have also found that most tumor cells show high telomerase activity.

Michael Stone, an assistant professor of chemistry and biochemistry at UC Santa Cruz, said his lab is particularly interested in the folding and unfolding of a DNA structure at the tail end of the telomere, known as a G-quadruplex, because it plays a key role in regulating telomerase activity.

“Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics,” Stone said. “The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, so we wanted to understand the mechanical stability of this structure.”

Xi Long, a graduate student in Stone’s lab, led the project, which involved integrating two techniques to manipulate and monitor single DNA molecules during the unfolding of the G-quadruplex structure. A “magnetic tweezers” system was used to stretch the DNA molecule, while a fluorescence microscopy technique was used to monitor small-scale structural changes in the DNA. The results, published in Nucleic Acids Research, showed that a relatively small structural displacement causes the G-quadruplex to unfold.

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Drug targets hard-to-reach leukemia stem cells responsible for relapses


Findings may have implications for treating solid tumor cancers.

Chronic myeloid leukemia leads to production of many abnormal white blood cells, which do not fight infection as well as normal white blood cells.

Researchers at the UC San Diego School of Medicine have discovered that hard-to-reach, drug-resistant leukemia stem cells (LSCs) that overexpress multiple pro-survival protein forms are sensitive – and thus vulnerable – to a novel cancer stem cell-targeting drug currently under development.

The findings, published in today’s (Jan. 17) online issue of Cell Stem Cell, open the possibility that diseases like chronic myeloid leukemia (CML) and some solid tumor cancers might – in  combination with other therapies – be more effectively treated  with this drug, and with a lower chance of relapse.

Led by principal investigator Catriona H. M. Jamieson, M.D., Ph.D., associate professor of medicine and director of stem cell research at UC San Diego Moores Cancer Center, the researchers found that a compound called sabutoclax appears to selectively target LSCs that express particular protein isoforms through alternatively splicing, a fundamental process in which a gene is able to code for multiple proteins.

An emerging class of drugs called tyrosine kinase inhibitors (TKI) – such as imitinib (Gleevec), gifitinib (Iressa) and sunitinib (Sutent) – has become a popular anti-cancer treatment. However, current TKIs are not 100 percent effective. In cases of CML, for example, some LSCs tucked protectively within bone marrow elude destruction, develop resistance to therapy, self-renew and eventually cause the leukemia to dramatically return.

Jamieson and colleagues found that alternative splicing of BCL2 genes, which code for proteins involved in apoptosis or programmed cell death, specifically promoted malignant transformation of dormant white blood cell precursors into “blast crisis” LSCs. The blast crisis is the final phase of CML when overabundant, abnormal white blood cells crowd out healthy cells, causing serious dysfunction.

Of clinical importance, they noted that sabutoclax, which suppresses all BCL2 anti-apoptotic proteins, renders these marrow-dwelling blast crisis LSCs sensitive – and more susceptible – to TKI-based therapeutics at doses that do not harm normal progenitor cells.

“Our findings show that pan-BCL2 inhibition will be critical for the eradication of cancer stem cells in CML and that there is an essential link between cancer stem cell dormancy, pro-survival BCL2 isoform expression and therapeutic resistance,” Jamieson said. “By using a novel pan-BCL2 inhibitor, we may be able to prevent therapeutic resistance by sensitizing malignant stem cell clones to TKIs.”

The findings may have implications for treating solid tumor cancers, such as colon, prostate, breast and brain cancers, noted Daniel J. Goff, the study’s first author. “With many of these tumor types being shown to harbor cancer stem cells, it raises the question of whether BCL2 family expression as well as isoform-switching may be crucial for the maintenance of cancer stem cells in these diseases as well,” he said. “If so, they may also be candidates for treatment with a BCL2 inhibitor like sabutoclax.”

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How cells know when it’s time to eat themselves


In autophagy, some elements of a cell are degraded and recycled to generate nutrients and energy to sustain and preserve the whole cell.

An electron microscope image of a mammalian cell with organelles depicted.

Researchers at the UC San Diego School of Medicine have identified a molecular mechanism regulating autophagy, a fundamental stress response used by cells to help ensure their survival in adverse conditions.

The findings are published online in today’s (Jan. 17) issue of Cell.

Senior author Kun-Liang Guan, Ph.D., a professor of pharmacology at UC San Diego Moores Cancer Center, and colleagues report that an enzyme called AMPK, typically involved in sensing and modulating energy use in cells, also regulates autophagic enzymes.

Autophagy, which derives from the Greek words for “self” and “eat,” is triggered to protect cells when times are tough, such as when cells are starved for nutrients, infected or suffering from damaged organelles, such as ribosomes and mitochondria. Much like the human body in freezing conditions will reduce operations in extremities to preserve core temperatures and organ functions, cellular autophagy involves the degradation and synthesis of some internal cellular elements to ensure survival of the whole.

The scientists found that AMPK regulates different complexes of an enzyme class called Vps34 kinase in different ways. Some Vps34 enzymes are involved in normal cellular vesicle trafficking – the vital movement of molecules inside a cell. Other Vps34 complexes are involved in autophagy. Guan and colleagues say AMPK inhibits some non-autophagy enzymes, but activates autophagous ones.

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Bakersfield community to have expanded access to top cancer care


UC Davis Cancer Care Network partnership extends expertise to patients in rural areas.

San Joaquin Community Hospital

San Joaquin Community Hospital

Residents of Kern County, where cancer rates overall are higher than the state average, will now have access to the expertise and experience of UC Davis Comprehensive Cancer Center researchers and clinicians through a new hospital affiliation.

Officials from San Joaquin Community Hospital and UC Davis Comprehensive Cancer Center announced the new partnership at a media event this morning in Bakersfield. The hospital’s affiliation links San Joaquin Community Hospital’s new AIS Cancer Center with UC Davis through the university health system’s Cancer Care Network.

“For more than 100 years, San Joaquin Community Hospital has served our community through the formation of innovative health-care programs and facilities,” said SJCH President and CEO Robert J. Beehler. “Our goal is to continue this mission at The AIS Cancer Center by blending the latest technology with compassionate care, delivered by skilled doctors and clinicians.”

The UC Davis Cancer Care Network, which includes community cancer centers in Truckee, Merced and Marysville, extends the reach of UC Davis Comprehensive Cancer Center expertise to patients in rural areas of Central and Northern California.  The partnership with San Joaquin Community Hospital represents the network’s first affiliation with Adventist Health, a faith-based, not-for-profit health-care delivery system.

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Surgical technique spots cancer invasion with fluorescence


It could help avoid unnecessary removal of healthy lymph nodes.

Quyen Nguyen, UC San Diego

One of the greatest challenges faced by cancer surgeons is to know exactly which tissue to remove, or not, while the patient is under anesthesia. A team of surgeons and scientists at UC San Diego School of Medicine have developed a new technique that will allow surgeons to identify during surgery which lymph nodes are cancerous so that healthy tissue can be saved. The findings will be published in the Jan. 15 print edition of Cancer Research.

“This research is significant because it shows real-time intraoperative detection of cancer metastases in mice,” said Quyen T. Nguyen, M.D., PhD, associate professor of head and neck durgery at UC San Diego School of Medicine. “In the future, surgeons will be better able to detect and stage cancer that has spread to the patient’s lymph nodes using molecules that were designed and developed at UC San Diego.”

Lymph nodes, located throughout the body, serve as filters that contain immune cells to fight infection and clean the blood. When cancer cells break away from a tumor, the cells can travel through the lymph system and hide in these tiny organs. Surgeons remove the nodes to determine if a cancer has spread. However, human nodes, only half a centimeter in size, are difficult to discern among the surrounding tissue during surgery. Furthermore, even when surgeons are able to map the location of the nodes, there is no current technique that indicates whether or not the lymph nodes contain cancer, requiring removal of more lymph nodes than necessary.

“With molecular-targeted imaging, surgeons can avoid unnecessary removal of healthy lymph nodes which is better long-term for patients,” said Nguyen, director of the facial nerve clinic at UC San Diego Health System. “The range of the surgeon’s visual field is greatly enhanced by a molecular tool that can help achieve accurate surgical margins and detection of metastases so that no tumor is left behind.”

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‘Intermittent dosing’ strategy holds promise for late-stage melanoma


Drug-resistant melanoma tumors in lab mice shrink when therapy is interrupted.

Martin McMahon, UCSF

Martin McMahon, UCSF

Researchers in California and Switzerland have discovered that melanomas that develop resistance to the anti-cancer drug vemurafenib (marketed as Zelboraf), also develop addiction to the drug, an observation that may have important implications for the lives of patients with late-stage disease.

The team, based at UC San Francisco, the Novartis Institutes for Biomedical Research (NIBR) in Emeryville and University Hospital Zurich, found that one mechanism by which melanoma cells become resistant to vemurafenib also renders them “addicted” to the drug. As a result, the melanoma cells nefariously use vemurafenib to spur the growth of rapidly progressing, deadly and drug-resistant tumors.

As described this week in the journal Nature, the team built upon this basic discovery and showed that adjusting the dosing of the drug and introducing an on-again, off-again treatment schedule prolonged the life of mice with melanoma.

“Remarkably, intermittent dosing with vemurafenib prolonged the lives of mice with drug-resistant melanoma tumors,” said co-lead researcher Martin McMahon, Ph.D., the Efim Guzik Distinguished Professor of Cancer Biology in the UCSF Helen Diller Family Comprehensive Cancer Center.

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UCSF cancer center awarded $36M grant


Award will fund infrastructure for clinical trials, research and programmatic support.

Frank McCormick, UC San Francisco

The National Cancer Institute (NCI) has awarded the UC San Francisco Helen Diller Family Comprehensive Cancer Center a $36 million support grant that will fund infrastructure for clinical trials, cutting-edge research and programmatic support over five years.

The first year’s award amounts to $7.2 million, including indirect costs. The balance of the support grant from the National Cancer Institute was recommended by the National Institutes of Health subject to the availability of funds and satisfactory progress in various initiatives.

The Helen Diller Family Comprehensive Cancer Center is one of the country’s leading cancer research and clinical care centers. It is the only comprehensive cancer center in the San Francisco Bay Area.

“We are pleased that the National Cancer Institute has recognized the work of our cancer center and has continued to make financing cancer research a high priority,’’ said Frank McCormick, Ph.D., who has served as director of the UCSF Helen Diller Family Comprehensive Cancer Center since 1997.

“Cancer is a devastating disease that takes the life of an American every minute of every day,’’ said McCormick, who is president of the American Association for Cancer Research, a member of the Institute of Medicine and a Fellow of the Royal Society as well as a scientist actively engaged in cancer research. “Federal support for cancer research is imperative as we move forward with research to save lives in our generation and for future generations.”

The Helen Diller Family Comprehensive Cancer Center received the fifth largest amount of funding for its cancer support grant last year among the 67 NCI-designated cancer centers in the United States, according to NCI statistics. All UC medical center campuses have comprehensive cancer centers.

UCSF received the comprehensive cancer center designation in 1999. The NCI awards the comprehensive designation after a rigorous evaluation process demonstrating breadth of research in laboratory, clinical and population-based research, as well as substantial interdisciplinary research that bridges these scientific areas.

“The NCI-designated cancer centers program recognizes centers around the country that meet rigorous criteria for world-class, state-of-the-art programs in multidisciplinary cancer research,” said Linda K. Weiss, Ph.D., director of the Office of Cancer Centers of the National Cancer Institute. “These centers – including the UCSF Helen Diller Family Comprehensive Cancer Center – have dedicated significant resources into developing research programs, faculty and facilities that will lead to better approaches to prevention, diagnosis and treatment of cancer. The NCI designation not only recognizes excellence but opens doors to greater federal funding, information sharing and resources.’’

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How prostate cancer therapies compare by cost, effectiveness


Surgery ranks as the most cost-effective type of treatment, according to UCSF-led study.

Matthew Cooperberg, UC San Francisco

The most comprehensive retrospective study ever conducted comparing how the major types of prostate cancer treatments stack up to each other in terms of saving lives and cost effectiveness is reported this week by a team of researchers at UC San Francisco.

Appearing in the British Journal of Urology International, the work analyzed 232 papers published in the last decade that report results from clinical studies following patients with low-, intermediate- and high-risk forms of prostate cancer who were treated with one or more of the standard treatments – radiation therapy, surgery, hormone therapies and brachytherapy.

The analysis shows that for people with low-risk prostate cancer, the various forms of treatment vary only slightly in terms of survival – the odds of which are quite good for men with this type of cancer, with a 5-year cancer-specific survival rate of nearly 100 percent. But the cost of radiation therapy is significantly more expensive than surgery for low-risk prostate cancer, they found.

For intermediate- and high-risk cancers, both survival and cost generally favored surgery over other forms of treatment – although combination external-beam radiation and brachytherapy together were comparable in terms of quality of life-adjusted survival for high-risk prostate cancer.

“Our findings support a greater role for surgery for high-risk disease than we have generally seen it used in most practice settings,” said urologist Matthew Cooperberg, M.D., M.P.H., who led the research. Cooperberg is an assistant professor of urology and epidemiology and biostatistics in the UCSF Helen Diller Family Comprehensive Cancer Center.

The UCSF Helen Diller Family Comprehensive Cancer Center is one of the country’s leading research and clinical care centers, and it is the only comprehensive cancer center in the San Francisco Bay Area. All UC medical center campuses have comprehensive cancer centers.

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Enzyme accelerates malignant stem cell cloning in chronic myeloid leukemia


Some cancer stem cells avoid destruction and eventually regenerate themselves.

Chronic myeloid leukemia blood cells

An international team, headed by researchers at the UC San Diego School of Medicine, has identified a key enzyme in the reprogramming process that promotes malignant stem cell cloning and the growth of chronic myeloid leukemia (CML), a cancer of the blood and marrow that experts say is increasing in prevalence.

The findings are published in the Dec. 24 online early edition of the Proceedings of the National Academy of Sciences (PNAS).

Despite the emergence of new therapies, such as tyrosine kinase inhibitors, CML and other leukemias remain problematic because some cancer stem cells avoid destruction and eventually regenerate themselves, a stem cell process known as self-renewal that can result in a return and spread (metastasis) of the disease.

In the PNAS paper, principal investigator Catriona H. M. Jamieson, M.D., Ph.D., associate professor of medicine at UC San Diego, with colleagues in the United States, Canada and Italy, report that inflammation – long associated with the development of cancer – boosts activity of  an enzyme called adenosine deaminase or ADAR1.

Expressed during embryogenesis to help blood cell development, ADAR1 subsequently turns off and is triggered by viral infections where it protects normal hematopoietic stem cells from attack. In leukemia stem cells, however, overexpression of ADAR1 enhances the missplicing of RNA, which leads to greater self-renewal and therapeutic resistance of malignant stem cells.

The findings build upon previous studies by Jamieson and others that elucidate the effects of RNA missplicing and instability. “People normally think about DNA instability in cancer, but in this case, it’s how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy.”

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