Genetic Signature Predicts Outcome Of Pediatric Liver Cancer

identified a genetic signature that is remarkably effective at predicting the prognosis of an aggressive liver cancer in children. The research, published by Cell Press in the December issue of the journal Cancer Cell, may lead to better treatments for pediatric liver cancers.

Hepatoblastoma (HB), the most common liver cancer in children, is associated with abnormal activation of the Wnt/beta-catenin signaling pathway. Although the specific details are not clear, Wnt signaling is essential for normal liver development. HB tumors can be comprised of cells that resemble fetal cells or immature progenitor cells but the cellular make-up of the tumor is frequently heterogeneous, precluding its systematic use for guiding treatment or predicting outcome.

"At present, few studies have addressed whether intrinsic biological differences between tumors impact HB prognosis. Moreover, new treatments are urgently needed for advanced stage tumors, and better understanding of HB pathobiology is a prerequisite for developing targeted therapies," explains senior study author Dr. Marie-Annick Buendia from the Oncogenesis and Molecular Virology Unit at the Pasteur Institute and Inserm Unit in Paris, France.

Dr. Buendia and colleagues used a sophisticated genetic screening technique to investigate the pathogenesis of HB. They found that beta-catenin was linked with two distinct tumor subclasses that reflect early and late phases of prenatal liver development. Further, they discovered a specific genetic signature that was useful for identifying the two tumor subclasses and predicting disease outcome.

The researchers also demonstrated that the highly proliferating, early stage tumors had characteristics associated with stem cells. Activation of Myc, a stem cell marker that is commonly overexpressed in cancer, appeared to play a key role in this tumor subtype. Further, activation of Myc in mice induced tumors that were strikingly similar to the human immature subtype of HB and inhibition of Myc in HB cells impaired tumorigenesis.

"We demonstrate that hepatic differentiation stage and clinical behavior of HB are intimately linked, and we identify an expression signature with dual capacities in recognizing liver developmental stage and predicting disease outcome. These data can be applied to improve clinical management of pediatric liver cancer and develop therapeutic strategies," concludes Dr. Buendia.

Molecular Marker Identifies Normal Stem Cells As Intestinal Tumor Source

Jude Children's Research Hospital have answered a central question in cancer biology: whether normal stem cells can give rise to tumors. Stem cells are immature cells that can renew themselves and give rise to mature differentiated cells that compose the range of body tissues. In recent years, researchers have developed evidence that cancers may arise from mutant forms of stem cells.

Tumor Suppressor Gene: Gene Function 'Lost' In Melanoma And Glioblastoma

Georgetown University Medical Center have found a gene they say is inactivated in two aggressive cancers – malignant melanoma, a form of skin cancer, and glioblastoma multiforme, a lethal brain tumor. They add that because this gene, known as PTPRD, has recently been found to be inactivated in several other cancers as well, their discovery suggests that PTPRD may play a tumor suppressor role in a wide variety of different cancers.Over the past decade several dozen tumor suppressor genes have been identified, but only a minority of them is important in causing many different tumor types. PTPRD seems to be one of these broad spectrum tumor suppressor genes," says the study's lead investigator, Todd Waldman, MD, PhD, an associate professor of oncology at Georgetown's Lombardi Comprehensive Cancer Center.

If the hypothesis is true – and Waldman and his team are now investigating loss of PTPRD in a number of additional cancers – then it may be possible to design a therapy that has wide applicability in oncology, he says.

"Most targeted cancer drugs today work by inhibiting gene products that are overactive in cancer cells. In this case, it is loss of the PTPRD gene that leads to cancer," Waldman says. "Therefore, we are trying to discover the molecules that PTPRD's protein controls, and then we plan to target these downstream molecules with a novel agent."

Waldman found that when the researchers restored production of the gene's protein in cancer cells that harbored PTPRD deletions or mutations, these tumors stopped growing and initiated a program of cell suicide.

The researchers also discovered PTPRD mutations in both the blood and in tumors of a patient with multiple different kinds of cancers. "This suggests that the gene could be responsible for an inherited predisposition to cancer," Waldman says

PTPRD produces a receptor protein tyrosine phosphatase that bisects the outer membrane of a cell. The part that protrudes outside the cell body is thought to be involved in helping cells stick to each other to form a tissue as well as in cell-to-cell communication. The part that juts into the cell is an enzyme that removes phosphates from other proteins – in other words, it changes the activity of proteins either by activating or deactivating them, Waldman says.

"In the absence of PTPRD, there are as yet unknown proteins floating around inside the cell with more phosphate residues than they should have, and it is a well known fact that the presence of these residues activates cellular growth pathways," he says. But it is not yet known which specific proteins PTPRD regulates, Waldman says.

Deletions of PTPRD in human cancer cells were first discovered in 2005, and since then, deletions or mutations of the gene have been discovered in several cancer types, including those of the colon and lung.

In this study, Waldman and his research team, which includes investigators from the National Cancer Institute, the University of Iowa and Duke University, used a laboratory technique known as copy number analysis to look for PTPRD in melanoma cell lines and in samples of human glioblastoma multiforme, the deadliest of brain cancers.

This technique uses a gene microarray that contains millions of probes that can stick to different regions of the human genome. The researchers purified DNA from tumors and then used the microarray chip to quantify genomic copy number. They found that PTPRD was deleted or mutated in 12 percent of melanoma tumors and in 14 percent of glioblastoma tumors examined. "That makes PTPRD one of the most commonly mutated genes discovered yet in melanoma," Waldman says.

"Before this study, no single tyrosine phosphatase was thought to play a generally important role as a tumor suppressor gene n multiple tumor types," Waldman says. "Now we have provided the first functional evidence that PTPRD is a tumor suppressor gene, and potentially an important one at that."

The findings are published in the December 15 issue of Cancer Research.

Molecule That Targets Brain Tumors Identified

Center researchers report today the discovery of a molecule that targets glioblastoma, a highly deadly form of cancer. The finding, which is published in the January 2009 issue of the European Journal of Nuclear Medicine and Molecular Imaging, provides hope for effectively treating an incurable cancer.

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. It is marked by tumors with irregular shapes and poorly defined borders that rapidly invade neighboring tissues, making them difficult to remove surgically.

"These brain tumors are currently treated with surgery to remove as much of the tumor as possible followed by radiation to kill cancer cells left behind and systemic chemotherapy to prevent spread to nearby tissues," said Kit Lam, senior author of the study and UC Davis chief of hematology and oncology. "It is unfortunate that this approach does not extend survival significantly. Most patients survive less than one year."

To find new options for treating the disease, Lam and his colleagues began searching for a molecule that could be injected into a patient's bloodstream and deliver high concentrations of medication or radionuclides directly to brain tumor cells while sparing normal tissues. Through their study, they identified a molecule — called LXY1 — that binds with high specificity to a particular cell-surface protein called alpha-3 integrin, which is overexpressed on cancer cells.

They also tested the molecule's ability to target brain cancer by implanting human glioblastoma cells both beneath the skin and in the brains of mice. The researchers injected the mice with a radiolabeled version of LXY1 and, using near-infrared fluorescence imaging, showed that the molecule did preferentially bind to human glioblastoma cells in both locations.

"This outcome gives us great hope that we will be able to deliver targeted therapies to treat glioblastoma," said Lam.

Lam is planning to continue this work by repeating the experiments with powerful cancer treatments linked to the LXY1 molecule. They will begin with iodine-131, a form of radionuclide currently used to treat some cancers, as well as a nanoparticle, or "smart bomb," that would carry cancer-fighting drugs to diseased cells.

Additional UC Davis study authors were Wenwu Xiao, Nianhuan Yao, Li Peng and Ruiwu Liu. Their research was funded by a grant from the National Institutes of Health.

Gene Therapy Eliminates Brain Tumors Through Selective Recruitment Of Immune Cells

to harness the power of the immune system to eradicate brain tumors face two major hurdles: recruiting key immune cells called dendritic cells into areas of the brain where they are not naturally found and helping them recognize tumor cells as targets for attack.

Researchers at Cedars-Sinai Medical Center, however, have identified a sequence of molecular events that accomplish both objectives. Their findings, based on laboratory and animal studies, appear in the Jan. 13 issue of PLoS Medicine, an open-access online journal of the Public Library of Science.

The Cedars-Sinai team discovered that a protein – HMGB1 – released from dying tumor cells activates dendritic cells and stimulates a strong and effective anti-tumor immune response. HMGB1 does so by binding to an inflammatory receptor called toll-like receptor 2, or TLR2, found on the surface of dendritic cells.

"Toll receptors play a major role in the immune system's recognition of bacterial and viral components, but now we have shown that they also trigger an immune response against tumors," said Maria G. Castro, Ph.D., co-director of Cedars-Sinai's Board of Governors Gene Therapeutics Research Institute and one of the article's senior authors. "Activation of Toll receptors was essential for two key stages in initiating immune responses against the tumor – the migration of peripheral dendritic cells into the brain tumor and the subsequent activation of dendritic cells and stimulation of a specific anti-tumor cytotoxic T-cell mediated response."

Building on more than 10 years of research in this area, the researchers used a combined gene therapeutic approach, using one protein (Flt3L) to draw dendritic cells from bone marrow into the brain tumors, and a second protein (Herpes Symplex type I Thymidine Kinase, or TK), combined with the antiviral gancyclovir to kill tumor cells and elicit long-term survival. In this paper, they uncovered a novel mechanism by which tumor cell death in response to the treatment leads to the release of an endogenous tumor protein, HMGB1, which is essential to trigger the anti-tumor immunological cascade. The study showed for the first time that HMGB1 released from dying brain cancer cells activates TLR2 signaling on tumor infiltrating dendritic cells, resulting in the activation and expansion of tumor-antigen specific T cells. This caused the regression of the brain tumors and increased survival time by six months in experimental brain tumor models.

Glioblastoma multiforme is the most aggressive type of brain tumor, with only five percent of patients surviving five years following diagnosis. While new drugs have had some impact on survival rates, the traditional approaches to cancer treatment – surgery, radiation and chemotherapy – have failed to provide major improvements in long-term survival.

Immunotherapy – eradicating brain cancer cells by harnessing the patient's immune system – has been an attractive treatment approach, in theory. An effective anti-tumor immune response initially depends on dendritic cells that constantly "sample" the environment and can recognize unusual proteins, such as those belonging to cancers or infectious pathogens. However, since there are few dendritic cells in the brain, the immune responses in this organ are dampened when compared to those elicited in other parts of the body.

According to Pedro Lowenstein, M.D., Ph.D., director of the Board of Governors Gene Therapeutics Research Institute and co-senior author, "The discovery of a central role for HMGB1 and TLR2 in overcoming immune ignorance to brain tumor antigens provides a new therapeutic approach in the fight against brain tumors. Our conclusions relating to anti-glioma immune responses have also been extended to enhancing immune responses against a number of other metastatic brain cancers, such as melanoma."

He stated that plans are underway to test this novel therapeutic approach in a human clinical trial for recurrent brain tumors in 2009.

The work was supported by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics, the Linda Tallen and David Paul Kane Foundation Annual Fellowship, the Joseph Drown Foundation and the Board of Governors at Cedars-Sinai Medical Center.

Nearly A Century Later, New Findings Support Warburg Theory Of Cancer

German scientist Otto H. Warburg's theory on the origin of cancer earned him the Nobel Prize in 1931, but the biochemical basis for his theory remained elusive.

His theory that cancer starts from irreversible injury to cellular respiration eventually fell out of favor amid research pointing to genomic mutations as the cause of uncontrolled cell growth.

Seventy-eight years after Warburg received science's highest honor, researchers from Boston College and Washington University School of Medicine report new evidence in support of the original Warburg Theory of Cancer.

A descendant of German aristocrats, World War I cavalry officer and pioneering biochemist, Warburg first proposed in 1924 that the prime cause of cancer was injury to a cell caused by impairment to a cell's power plant – or energy metabolism – found in its mitochondria.

In contrast to healthy cells, which generate energy by the oxidative breakdown of a simple acid within the mitochondria, tumors and cancer cells generate energy through the non-oxidative breakdown of glucose, a process called glycolysis. Indeed, glycolysis is the biochemical hallmark of most, if not all, types of cancers. Because of this difference between healthy cells and cancer cells, Warburg argued, cancer should be interpreted as a type of mitochondrial disease.

In the years that followed, Warburg's theory inspired controversy and debate as researchers instead found that genetic mutations within cells caused malignant transformation and uncontrolled cell growth. Many researchers argued Warburg's findings really identified the effects, and not the causes, of cancer since no mitochondrial defects could be found that were consistently associated with malignant transformation in cancers.

Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg's theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.

Abnormalities in cardiolipin can impair mitochondrial function and energy production. Boston College doctoral student Michael Kiebish and Professors Thomas N. Seyfried and Jeffrey Chuang compared the cardiolipin content in normal mouse brain mitochondria with CL content in several types of brain tumors taken from mice. Bioinformatic models were used to compare the lipid characteristics of the normal and the tumor mitochondria samples. Major abnormalities in cardiolipin content or composition were present in all types of tumors and closely associated with significant reductions in energy-generating activities.

The findings were consistent with the pivotal role of cardiolipin in maintaining the structural integrity of a cell's inner mitochondrial membrane, responsible for energy production. The results suggest that cardiolipin abnormalities "can underlie the irreversible respiratory injury in tumors and link mitochondrial lipid defects to the Warburg theory of cancer," according to the co-authors.

These findings can provide insight into new cancer therapies that could exploit the bioenergetic defects of tumor cells without harming normal body cells.

Seyfried, Chuang and Kiebish were joined by co-authors Xianlin Han and Hua Cheng from the Washington University School of Medicine, Department of Internal Medicine, in St. Louis.

Inherited Factors Play Important Role In Breast Cancer Progression, According To New Study In Mice

mice and five independent collections of human breast tumors has enabled National Cancer Institute (NCI) scientists to confirm that genes for factors contributing to susceptibility for breast cancer metastasis can be inherited.

The new findings support earlier results from the same laboratory and appear in the Jan. 1, 2009, issue of Cancer Research.

The study results also show that gene activities in tumor cells and immune cells that infiltrate, or invade, tumors can contribute to the development of expression profiles, called gene signatures, that are predictive of cancer progression. The analysis of normal mouse tissue as well as tumors transplanted into mice suggests that predictive, or prognostic, gene signatures that point to a tumor’s potential for spreading throughout the body can be the result of both inherited and non-inherited factors, with inherited factors being more consistently predictive. The research team that reported these findings is from the Center for Cancer Research at NCI, which is part of the National Institutes of Health.

The researchers were able to perform their analyses by using advances in microarray technology, which allows scientists to scan vast amounts of genetic information and identify gene signatures that can be used to predict cancer outcomes. Many scientists had assumed that metastatic ability is primarily determined by somatic, or non-inherited, gene mutations in tumor tissue. "Our earlier studies clearly established that inherited factors also play an important role in metastatic progression and can help distinguish which tumors have a propensity to metastasize," said author Kent W. Hunter, Ph.D., head of NCI’s Metastasis Susceptibility Section in the Laboratory of Cancer Biology and Genetics. "Hopefully in the future we will be able to determine which women are more likely to have a tumor that would metastasize, and we could then tailor therapy specifically for them, avoiding the use of harsh treatments for those with a low probability of metastasis."

To determine whether mouse tumor gene expression profiles could be used to predict outcomes in human breast cancer, the investigators identified a gene expression signature that allowed them to distinguish between the tumors of mice that have a high or a low inherited susceptibility to tumor metastasis (a 20-fold difference). They then converted the mouse gene signature to the corresponding human gene signature and analyzed five pre-existing sets of human breast tumors. This signature successfully predicted outcomes (either relapse or disease-free survival) in four of the five sets of human breast tumors.

Because other studies have suggested that gene expression patterns in the nearby tissue, or stroma, are altered in tumors that are prone to metastasis, the investigators conducted transplant experiments by putting highly metastatic tumor cells into the mammary fat pads of mice that have either a high or a low susceptibility to tumor metastasis. These transplants resulted in tumors that had identical tumor cells but different stroma and immune cells that infiltrated the tumor. No significant differences were seen in tumor weight or metastasis to the lung in the two types of mice after 28 days, suggesting that metastatic differences between individual mice in this experiment were possibly due to genes in the outer layer of tissue that surrounds the tumor (the epithelium) rather than in the stroma.

However, differences in gene signatures were still seen in mice with either high or low potential to develop metastases, and the corresponding human gene signatures were predictive of relapse or survival in patients. The researchers concluded that both the tumor epithelium and the stroma probably contributed to the development of the prognostic gene profiles.

"Our study provides additional evidence of the role of inherited genes in human breast cancer progression. Therefore our next step is to improve our current understanding of the role of the epithelium and stroma in tumor progression and develop more effective therapeutic strategies based on our new knowledge," said Hunter.

Gene May Lead To Early Onset Of Brain Tumor

particular gene variant may be more likely to develop brain tumors, and at an earlier age, than people without the gene, according to a study published in the January 27, 2009, print issue of Neurology®, the medical journal of the American Academy of Neurology.

The study involved 254 people with brain tumors and 238 people with no cancers. All those with tumors had glioblastoma multiforme, the most common type of brain cancer. People with this type of tumor survive an average of 12 to 15 months.

Through blood samples, researchers looked at the tumor suppressor TP53 gene. This gene acts as a tumor suppressor and is involved in preventing cancer.

People younger than 45 with brain tumors were more likely to have the Pro/Pro variant of the gene than older people with brain tumors or the healthy participants. A total of 20.6 percent of the young people with brain tumors had the gene variant, compared to 6.4 percent of the older people with brain tumors and 5.9 percent of the healthy participants.

"Eventually we may be able to use this knowledge to help identify people who have a higher risk of developing brain tumors at an early age. However the risk of this population remains low, even multiplied by three or four as shown here, because these brain tumors (glioblastomas) are infrequent in young people," said study author Marc Sanson, MD, PhD, of the French National Institute of Health and Medical Research (INSERM) in Paris, France.

The study was supported by the Public Assistance Hospitals of Paris.

Individualized Approach To Breast Cancer Treatment

cancers are the same, and not all will have fatal consequences. But because clinicians find it difficult to accurately determine which tumors will metastasize, many patients do not receive the therapy fits their disease.

Tel Aviv University has now refined breast cancer identification so that each course of treatment is as individual as the woman being treated.

The new approach -- based on a combination of MRI and ultrasound -- is able to measure the metabolism rates of cancer cells. The approach helps determine at an earlier stage than ever before which cells are metastasizing, and how they should be treated.

The method, expected to start clinical trials in 2010, is currently being researched in Israel hospitals.

New Field of Medicine

“We have developed a non-intrusive way of studying the metabolism of breast cancer in real time,” says Dr. Ilan Tsarfaty, a lead researcher from TAU’s Sackler Faculty of Medicine. “It’s an invaluable tool. By the time results are in from a traditional biopsy, the cancer can already be radically different. But using our technique, we can map the tumor and its borders and determine with high levels of certainty — right away — which patients should be treated aggressively.”

The research falls in a new field called "translational and personalized medicine", and Dr. Tsarfaty says it has the potential to save thousands of lives. Papers describing his methodologies were published recently in the journals Cancer Research and Neoplasia.

“Current breast cancer treatments are not tailored to individual patients,” Dr. Tsarfaty says. “Our approach to profiling individual tumors will not only help save lives today, it will provide the basic research for developing cancer drugs of the future,” he says.

Application to Other Cancers

The new research can be applied to all solid tumors, including those resulting from lung and brain cancer, and could be used to respond to a wide spectrum of neurodegenerative diseases, such as Alzheimer’s, Dr. Tsarfaty reports.

Dr. Tsarfaty’s MRI-and-ultrasound-imaging application monitors the metabolic changes that occur during cancer metastasis. Increased blood flow (which can be sensed by ultrasound) and an increase of oxygen consumption (measured with an MRI) can indicate cancer metastasis with unprecedented levels of sensitivity.

Normally scientists look for structural changes in the body, such as the presence of a tumor. But with their new methods, Dr. Tsasfaty and his team which includes his wife, a radiologist are actually able to “see” cancer metastasis within a small group of cells long before the cancer spreads to other organs in the body.

Earlier Detection, Earlier Treatment

“Today, clinicians only diagnose cancer when they see a tumor several millimeters in size. But our diagnosis can be derived from observing only a few cells, and looks specifically at the activation levels of a protein called Met. Activated Met is an oncogen,” he says. “If the tumor cells show activation of Met, we can design personalized medicine to treat a specific kind of breast cancer.”

New Laser For Neurosurgery Allows Greater Precision And Efficiency For Removal Of Complex Tumors

Northwestern Memorial Hospital are among the first in the country to use a new micro-laser, which uses light energy in place of a cutting tool to remove complicated brain and spine tumors. The technique offers greater precision and efficiency during surgery, reducing the incision size, surgery time and patient recovery period following surgery.

Surgeons first used the laser in October when Stephen Abbott, a 70-year-old retired United States Army officer, presented with a brain tumor the size of a plum attached to one of the major veins draining blood from the brain. The tumor was discovered during a routine physical earlier in the year when a test indicated Mr. Abbott was experiencing some hearing loss.

Bernard Bendok, MD, a vascular and skull base neurosurgeon and Andrew Fishman, MD, a neurootologist and skull base surgeon, collaborated on the case and determined that Mr. Abbott was a prime candidate for surgery. The two then merged their specialties to operate on the complex tumor, using the laser, to help them remove the tumor quickly and safely. The removal of the tumor took less than one hour and after just five days Mr. Abbott was home, healthy and back to his daily routine.

The laser, called the BeamPath NEURO™, allows surgeons to direct CO₂ laser energy into deep holes and around blood vessels and other specific nerve structures and the brainstem. It is designed for operating near critical structures in the brain and spine and is used in place of a scalpel to cut tissue and remove tumors.

“When lasers were first used in neurosurgery some 30 years ago, surgeons were very excited, but it faded quickly because the devices were too cumbersome,” commented Dr. Bendok. “This new tool provides far greater control and precision in tight surgical corridors”

“The laser enables us to be much more efficient during surgery, we are able to remove tumors much more quickly which shortens overall surgery time,” commented Dr. Fishman. “That translates into a quicker recovery for patients.”