New instrument helps researchers see how diseases start and develop in minute detail

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ScienceDaily (Oct. 21, 2011) — Researchers at Lund University can now study molecules which are normally only found in very small concentrations, directly in organs and tissue. After several years of work, researchers in Lund have managed to construct an instrument that 'hyperpolarises' the molecules and thus makes it possible to track them using MRI. The technology opens up new possibilities to study what really happens on molecular level in organs such as the brain.

Magnetic resonance imaging (MRI) is an established technique which over the years has made it possible for researchers and healthcare professionals to study biological phenomena in the body without using ionising radiation, for example X-rays.

The images produced by normal MRI are, to put it simply, pictures of water in the body, since the body is largely made up of water. MRI produces images of the hydrogen nuclei in water molecules. It can also be used to study other types of nuclei in many other interesting molecules. The only problem is that the concentration of molecules that are interesting to track is so low that they are not visible on a normal MRI scan. It is this problem that the researchers have now solved by constructing a 'polariser'.

In the polariser, the researchers make these molecules visible to the MRI scanner by hyperpolarising them. The molecules are then injected into their natural body tissue.

"Then we can follow the specific molecule and see the reactions in which it is involved. This gives us a unique opportunity to see and measure enzymatic reactions directly in the living tissue," explains Professor Deniz Kirik.

The technology could be used to study molecules in many different types of tissue in the body. Deniz Kirik, who is a Professor of Neuroscience, will focus on developing this technology to study the brain -- something which has not been done before.

"The brain is not an easy target!" he observes. "When we look inside the brain today using MRI, we see the molecules that are most numerous. However, it is rarely these common molecules we want to study. We want to study how molecules that have a low concentration in the tissue behave, for example how signal substances are produced, used and broken down. It is when these processes don't work that we become ill.

"This technology has the potential to help us do just that. If we can make it work, it will be a breakthrough not only for neuroscience but also for other research fields such as diabetes, cancer and inflammation, where similar obstacles limit our understanding of the basic molecular processes which lead to disease."

Professor Hindrik Mulder is one of the co-applicants for the project and he will develop and use the technology in diabetes research. Dr Vladimir Denisov from the Lund University Bioimaging Centre is leading the technical development within the project.

At present there are only a few polarisers in the world and Lund's newly built device is the only one in Scandinavia to be fully available for academic research. "All the other equivalent instruments are purchased commercially and come with restrictions placed by the manufacturer. We therefore chose to take the longer and more complicated route of building the instrument ourselves," explains a pleased and proud Deniz Kirik.

Now that the instrument has become operational, the researchers have started on the first experiments.

"This is the first of two steps," says Deniz Kirik. "The next step in this frontline research is to develop the unique technology by constructing an even more sophisticated polariser which will enable advanced experiments on animal models for various diseases."

The project has been made possible through a grant from the Swedish Research Council and earlier grants from the Swedish Foundation for Strategic Research.

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Coupling of proteins promotes glioblastoma development, researchers find

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ScienceDaily (Oct. 21, 2011) — Two previously unassociated proteins known to be overly active in a variety of cancers bind together to ignite and sustain malignant brain tumors, a research team led by scientists at The University of Texas MD Anderson Cancer Center reports this week in the journal Cancer Cell.

This research is the first to connect FoxM1 to a molecular signaling cascade that regulates normal neural stem cells, said senior author, Suyun Huang, M.D., Ph.D., associate professor in MD Anderson's Department of Neurosurgery.

"When FoxM1 binds to beta-catenin, we found that it also supports the self-renewal and differentiation of glioma-initiating cells, cancer stem cells thought to drive glioblastoma multiforme," Huang said.

Glioblastoma multiforme is the most common and lethal form of brain tumor. Glioma-initiating cells are prime suspects in the disease's resistance to treatment and ability to reoccur.

Protein's connection could be drug target

The scientists established the relationship between FoxM1 and beta-catenin in a series of cell line experiments and then confirmed their findings in mouse models of human glioblastoma and in an analysis of human tumors.

FoxM1 and beta-catenin separately so far have largely evaded targeting by drugs. Huang and her team are focusing on the details of the connection between the two proteins in search of small molecules that might block their binding.

"Our study might lead to the development of a new class of small-molecule anti-cancer drugs, including but not necessarily limited to glioblastoma multiforme," Huang said. Much preclinical work remains before such a drug can be identified and brought to clinical trial.

Blocking FoxM1 reduces glioblastoma in mice 100 percent

FoxM1 previously was known solely as a transcription factor -- a protein that binds to the DNA in a gene's promoter region to prompt the gene's expression of messenger RNA that is processed into a protein.

Structural analysis led Huang and her team to suspect FoxM1 might be a binding match for beta-catenin, a crucial protein in the Wnt signaling pathway, which regulates self-renewal and differentiation of neural stem cells. When a normal cell divides, it produces two copies of itself. A neural stem cell produces one copy of itself (self-renewal) and a copy of a functional brain cell, such as a neuron or an astrocyte (differentiation). Mutations occur in the Wnt pathway in other types of cancer, but are largely absent in glioblastoma.

Blocking either FoxM1 or beta-catenin function strongly influenced whether mice injected with glioblastoma cells developed brain tumors. Most dramatically, blocking FoxM1 with short hairpin RNA completely prevented development of brain tumors in 38 mice, while all 20 with unimpeded FoxM1 developed tumors.

In a series of cell line experiments leading to the mouse model research, the group found:

FoxM1 is expressed at high levels in glioma and in glioma-initiating cells.FoxM1 and beta-catenin bind to each other in tumor cells.Wnt promotes the movement of both FoxM1 and beta-catenin to the cell nucleus.FoxM1 is required for beta-catenin to move to the cell nucleus in both neural stem cells and in tumor cells.The FoxM1 and beta-catenin connection is required for transcription and expression of beta-catenin Wnt-targeted genes in the nucleus.Interaction between the two proteins is critical to both cell renewal and differentiation in glioma stem cells.

The team analyzed 40 glioblastoma samples and found FoxM1 moderately expressed in 14 and highly expressed in 18. Levels of FoxM1 in the cell nucleus correlated directly with levels of beta-catenin expression and the expression of two Wnt target genes.

Additional analysis of eight tumors found the two proteins present together in the cell nuclei and a direct correlation with the presence of one protein marker for glioma-initiating cells.

Co-authors with Huang are first authors Nu Zhang, Ph.D., and Ping Wei, Ph.D., Aihua Gong, Ph.D., Wen-Tai Chiu, Ph.D, Hsueh-Te Lee, Ph. D, Jianfei Xue, Ph.D., Mingguang Liu, M.D., Yong Wang, Ph.D., and Raymond Sawaya, M.D. ,of MD Anderson's Department of Neurosurgery; Howard Colman, M.D., and W.K. Alfred Yung, M.D., of MD Anderson's Department of Neuro-Oncology. Keping Xie, M.D., Ph.D .,of MD Anderson's Department of Gastrointestinal Medical Oncology and the program in cancer biology at The University of Texas Graduate School of Biomedical Science at Houston; Rene Medema, M.D., of the Department of Medical Oncology, UMC Utrecht, Utrecht, The Netherlands; and Xi He, Ph.D., and He Huang, Ph.D., of the F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School.

Artwork chosen by Cell Press for the cover of Cancer Cell was designed by Huang's daughter Victoria Xie, a sophomore at Michael DeBakey High School for Health Professions in Houston.

This research was funded by grants from the National Cancer Institute, the National Institute of General Medical Sciences, a multidisciplinary research grant by MD Anderson, and the Leukemia and Lymphoma Society.

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Journal Reference:

Nu Zhang, Ping Wei, Aihua Gong, Wen-Tai Chiu, Hsueh-Te Lee, Howard Colman, He Huang, Jianfei Xue, Mingguang Liu, Yong Wang, Raymond Sawaya, Keping Xie, W.K. Alfred Yung, René H. Medema, Xi He, Suyun Huang. FoxM1 Promotes ß-Catenin Nuclear Localization and Controls Wnt Target-Gene Expression and Glioma Tumorigenesis. Cancer Cell, 2011; 20 (4): 427 DOI: 10.1016/j.ccr.2011.08.016

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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