HEALTH NEWS

Scientists at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia have shown that the activity of a gene that commandeers other cancer-causing genes, returning them to normal, can predict the prognosis of an individual with breast cancer.
The gene, Dachshund, normally regulates eye development and development of other tissues, in essence playing a role in determining the fate of some types of cells. Richard Pestell, M.D., Ph.D., director of the Kimmel Cancer Center at Jefferson and professor and chair of cancer biology at Jefferson Medical College, and co-workers looked at cancer cells from more than 2,000 breast cancer patients and found that this commandeering or "organizing" ability is increasingly lost in cancer cells and associated with the progression of disease. The more the gene is expressed in breast cancer, the researchers saw, the better the patient did. The scientists report their findings in October in the journal Molecular and Cellular Biology.
"This is a new type of gene in cancer that commandeers the cancerous genes and returns them to normal," says Dr. Pestell. "The standard cancer treatment strategy has been to block the proliferation of cancer cells or cause them to die. This is quite different. We've shown that the Dachshund gene reverts the cancerous phenotype and turns the cell back to a pre-malignant state. Cells don't die, but rather, they revert.
"It's a bad prognostic feature if you lose this organizer gene," he says, adding that it could be used as a prognostic marker for breast cancer.
In the work, the researchers showed that Dachshund could block breast cancer growth in mice and also could halt breast cancer from invading other tissues in cell culture. They also found that the gene inhibits the expression of the cyclin D1 gene, a cancer-causing gene that is overexpressed in about half of all breast cancers.
The group used microarray technology -- silicon chips containing ordered selections of genetic material upon which sample material can be tested -- to analyze Dachshund expression during the development of breast cancer. The scientists compared normal breast cells, pre-cancerous "in situ" cells and more than 2,100 breast cancer cell samples. Dachshund gene expression was "significantly reduced" in breast cancer.
The average survival was almost 40 months better in women in whom their breast cancer continued to express Dachshund.
Dr. Pestell notes that the expression of Dachshund correlates with tumor size, stage and metastasis, with its expression greatly reduced in metastatic breast cancer cells. Dr. Pestell's team is examining other cell fate-determining genes in an attempt to identify new therapeutics for breast cancer and metastasis.

Gliomas are among the most common and most malignant brain tumors. These tumors infiltrate normal brain tissue and grow very rapidly. As a result, surgery can never completely remove the tumor.
Now, the neurosurgeons Dr. Darko S. Markovic (Helios Klinikum Berlin-Buch) and Dr. Michael Synowitz (Charité) as well as Dr. Rainer Glass and Professor Helmut Kettenmann (both Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch), have been able to show that glioma cells exploit microglia, the immune cells of the brain, for their expansion.
Microglial cells are the immune cells of the brain/central nervous system. They constantly screen the brain environment. On their surface they use sensors to detect changes in their environment due to brain damage or infections. An important family of these sensors are Toll-like receptors (TLR).
However, microglia do not attack glioma cells. On the contrary: they support the growth of the tumor and, thus, make the disease worse. Together with researchers in Warsaw, Poland, Amsterdam, The Netherlands, and Bethesda, USA, the researchers in Berlin have been able to show how the immune cells promote the tumor growth.
Microglial cells are attracted toward the glioma cells and gather in and around the tumor in large numbers. Interestingly, gliomas consist of up to 30 per cent of microglia, especially at the tumor edge.
Gliomas release certain enzymes, metalloproteases, which digest the extracellular matrix, and also dissolve the ties between cells. However, the metalloproteases are produced and released as inactive precursor protein which need to be cleaved to be activated. This cleavage is accomplished by another enzyme, which is produced by the microglial cells.
This enzyme is anchored in the membrane and was therefore named membrane type 1 metalloprotease (MT1-MMP). MT1-MMP activates the metalloproteases which clear the way for the glioma cells and allows them to infiltrate normal brain tissue and expand very rapidly.
Normally, microglial cells do not produce MT1-MMP. However, the glioma cells manipulate the microglial cells by stimulating microglial TLR which trigger the expression of MT1-MMP.
The researchers could confirm their data from petri dish in mice. "Those mice, in which we had knocked out the MT1-MMP gene or a crucial gene for TLR signalling, did attract fewer microglial cells and the tumor grew much more slowly", explains Professor Kettenmann.
They could also demonstrate that MT1-MMP was present in tissue from glioma patients. Remarkably, the gliomas with high level of microglial MT1-MMP were also more aggressive. Moreover microglial cells were more abundant in tissue sample from the tumor edge as compared to the center of the tumor.
Glioma cells themselves do not produce MT1-MMP. However, when the researchers experimentally over expressed MT1-MMP in glioma cells, they died.
The researchers hope, that interfering with TLR receptors or their intracellular pathways might reduce the rapid expansion of glioma cells. Professor Kettenmann: "Microglia are a new target for glioma researchers."

Glioma is the most common and most serious form of brain tumors that affect adults. It has not yet been determined which specific type of cell in the brain is the source of the tumor, but now a research team at Uppsala University can show that glioma can start from immature support cells. The findings are published in the scientific journal Oncogene.
In recent years it has been discussed more and more often that it is neural stem cells in the brain that are transmuted into cancer cells and can then develop into glioma.
“But our results show that immature support cells can function as the source cells for the tumor. We can thus establish that it does not have to be stem cells that cause glioma,” says Nanna Lindberg, a doctoral candidate at the Department of Genetics and Pathology, who is carrying out the study.
She says that patients with malignant glioma often die within a year of being diagnosed, since the tumor cells rapidly infiltrate normal brain tissue and are difficult to treat. It is also common for the tumor to recur after treatment. With a better understanding of the genesis and growth of brain tumors, researchers will be able to identify new targets for treatment and ultimately will enhance the chances of survival.
To study tumors, various models are used, often animal models where the tumor both looks and behaves as it would in a human. In the present study a model is described that Nanna Lindberg created together with Associate Professor Lene Uhrbom and is used specifically for studying how glioma arises in a certain type of support cells. In this model tumors are formed that in many ways are similar to glioma in humans.
“Combining knowledge from other models where tumors arise from other cell types, with our model we can examine how the source cell affects the genesis and growth of the tumor. We can also compare how tumors of various origin differ from each other,” says Nanna Lindberg, adding that the model can later be used for preclinical treatment studies.

Rice University bioengineers and physician-scientists at Baylor College of Medicine and Texas Children's Hospital have successfully destroyed tumors of human brain cancer cells in the first animal tests of a minimally invasive treatment that zaps glioma tumors with heat. The tests involved nanoshells, light-activated nanoparticles that are designed to destroy tumors with heat and avoid the unwanted side effects of drug and radiation therapies.The results of the new study are available online in the Journal of Neuro-Oncology. The researchers reported that more than half of the animals that received the nanoshell treatment for glioma tumors had no signs of cancer more than three months after treatment.
"This first round of in vivo animal tests suggests that photothermal therapy with nanoshells may one day be a viable option for glioma patients," said study co-author Jennifer West, the Isabel C. Cameron Professor of Bioengineering at Rice and chair of Rice's Department of Bioengineering. West cautioned that follow-up work in the laboratory is needed before any human testing of the therapy can begin. She said human clinical trials of nanoshell phototherapy for glioma are likely at least a year away.
Glioma is among the most aggressive and difficult-to-treat of all brain cancers. Fewer than five percent of glioma patients survive beyond five years. The disease is particularly difficult to treat because glioma tumors are often highly invasive and inoperable.
Study co-authors include pediatric oncologist Susan Blaney, deputy director of Texas Children's Cancer Center and Baylor College of Medicine professor and vice chair for research in the department of pediatrics, and Rebekah Drezek, professor in bioengineering at Rice. West, Blaney, Drezek and colleagues tested mice with abdominal tumors of human glioma cells. The researchers injected the mice with nanoshells and waited 24 hours for the nanoparticles to accumulate in the tumors. A laser of near-infrared light -- which is harmless to healthy tissue -- was shined at the tumor for three minutes. The nanoshells converted the laser light into tumor-killing heat. All seven animals that received the nanoshell treatment responded, but cancer returned in three. The other four remained cancer-free 90 days after treatment.
"The results of this study are encouraging, and we are cautiously optimistic that this process may bring us closer to finding a cure for glioma," said Blaney, also associate director for clinical research at Baylor College of Medicine's Dan L. Duncan Cancer Center and co-director of The Institute for Clinical and Translational Research. "This is very exciting, especially given the poor prognosis of the disease and the importance of finding brain tumor treatment alternatives that have minimal side effects."
Gold nanoshells, which were invented by Rice researcher Naomi Halas in the mid-1990s, are smaller than red blood cells. Nanoshells are like tiny malted milk balls that are coated with gold rather than chocolate. Their core is nonconducting, and by varying the size of the core and thickness of the shell, researchers can tune them to respond to different wavelengths of light.
Houston-based biomedical firm Nanospectra Biosciences, which holds the license for medical use of Rice's nanoshell technology, began the first human clinical trial of nanoshell phototherapy in 2008.
West, a co-founder and director of Nanospectra Biosciences, said the new glioma study is part of a larger ongoing effort within the Texas Medical Center to adapt nanoshell phototherapy for use against a variety of cancers. Researchers at Rice, Texas Children's Hospital, M.D. Anderson Cancer Center, Baylor College of Medicine and other institutions are working to develop nanoshell-based treatments for prostate cancer and pancreatic cancer.
The glioma study was funded by the National Science Foundation, the National Institutes of Health and Hope Street Kids.