What causes brain cancer?

Glioblastoma is the most common and most lethal form of brain tumor in people. Research published in the International Journal of Computational Biology and Drug Design offers a novel way to determine what biological functions go awry when the tumor first begins to form. Understanding the problems at the molecular level might one day reveal the underlying mechanism of carcinogenesis in glioblastoma and ultimately lead to treatments or even preventative measures.

This form of brain tumor account for more than half of all cases in which the tumor is within the tissues of the brain and a fifth of cases in which a tumor is present within the skull.

Zhongming Zhao and colleagues at Vanderbilt University, in Tennessee, explain how problems that occur during the transcription of the genetic code for making proteins may play a role in the formation of a glioblastoma. These might arise through changes in the genetic materials itself or alterations to the molecules involved in regulating the transcription process. In their latest research, the team has tested the possibility that microRNAs (miRNAs) and transcription factors (TFs) might somehow regulate the genes glioblastoma. With this in mind, the researchers carried out a computer search of appropriate databases to uncover any links between these components of the genetic machinery and glioblastoma.

Although cancer exists in many different forms and is not a single disease but a complex array of different diseases, there are certain characteristics that define the different forms: self-sufficiency in growth signals, insensitivity to antigrowth signals, evading programmed cell death, limitless replicative potential of cells, sustained blood-vessel growth, evasion of the immune system, tissue invasion and spreading through the body in metastasis. Insights into these processes at the molecular level is now possible thanks to the advent of vast databases of genomic and biochemical information related to different types of cancer.

The Vanderbilt team has now searched three databases miR2Disease, HMDD (human miRNA-associated disease database) and PhenomiR, to find regulatory networks specific to glioblastoma. To do so they integrated data on glioblastoma-related miRNAs, TFs and genes. They utilized a well-known target-prediction tool, TargetScan, to trawl the databases and identified 54 so-called feed-forward loops (FFLs), these are molecular control systems involved in transcription and the required signaling processes. Follow up work revealed these FFLs to have functions important to carcinogenesis as well as unique functions specific to each FFL.

“Our work provided data for future investigation of the mechanisms underlying glioblastoma and also potential regulatory subunits that might be useful for biomarker discovery and therapy targets for glioblastoma,” the team concludes.

Gong, X., Sun, J., & Zhao, Z. (2011). Gene regulation in glioblastoma: a combinatorial analysis of microRNAs and transcription factors International Journal of Computational Biology and Drug Design, 4 (2) DOI: 10.1504/IJCBDD.2011.041006

Water, water

Scientists in Canada have identified a toxic chlorination by-product of chlorination in tap water, dichloroquinone, using a newly developed procedure based on liquid chromatography (LC), electrospray ionization (ESI), and tandem mass spectrometry (tandem-MS). The levels of the compound may be present at a few nanograms per litre, which the researchers suggest may represent a bladder cancer risk as well as being associated with adverse reproductive effects.

Untreated water can carry several potentially lethal diseases, including typhoid, dysentery, cholera, and diarrhoea. Treatment and disinfection through chlorination usually renders water safe to drink and helps keep these illnesses at bay, at least in those parts of the world where chlorination facilities exist.

However, some scientists are concerned that the chlorination of water itself may be a risk factor for more insidious diseases. For instance, some studies have suggested that there may be a link between drinking chlorinated tap water and an increased risk of bladder cancer. Now, researchers at the University of Alberta, in Canada, have identified a chlorination by-product that may represent a risk factor, dichloroquinone.

Xing-Fang Li group
Xing-Fang Li group

Xing-Fang Li and colleagues explain that common reactions between chlorinating agents and natural organic molecules in water are known to produce tiny quantities of chloroform and chlorinated acetic acid derivatives. The presence of these compounds in drinking water are tightly regulated but the team suspected that there are other compounds formed in disinfected tap water that are not, among them chlorinated quinones. The researchers point out that concentrations of such compounds were below detection thresholds previously but are now under suspicion.

Quinones are organic molecules containing a six-membered carbon ring to which are attached two oxygen atoms bound by double bonds on opposite sides of the ring; microbial activity can lead to the presence of these compounds in water. Earlier, independent work suggests that halogenated quinones, those containing chlorine or bromine, can react with DNA and proteins even at very low concentrations and cause damage to these critical biomolecules. The Canadian team has now successfully identified a representative of this class of compounds, 2,6-dichloro-1,4-benzoquinone, in chlorinated drinking water.

Chlorination graph
The chemistry of clean water

“The scientific understanding of drinking-water quality has advanced substantially since trihalomethanes [e.g. chloroform] were first discovered [in water] in 1974,” the team says. “Effective management of disinfection by-products health risks requires better knowledge of disinfection chemistry combined with toxicology,” the researchers add.

LINKS

Angew Chem Int Edn, 2010, in press
http://dx.doi.org/10.1002/anie.200904934

Fang group

Pathological proteins produce polymers

Deposits of distorted or otherwise errant proteins are key to understanding various brain diseases including Alzheimer’s, Parkinson’s, and the prion disease variant-CJD, they are also implicated in the pathology of type II diabetes. However, while such amyloids are a medical nightmare, researchers in Israel suggest that outside the body, synthetic versions of these substances could help us design a whole new range of nanomaterials and biomimetic plastics.

“The potential applications of these supramolecular assemblies exceed those of synthetic polymers,” explains Ehud Gazit of Tel Aviv University, writing in the current issue of Angewandte Chemie with co-author Izhack Cherny. “The building blocks may introduce biological function in addition to mechanical properties, he adds.

Prof. Ehud Gazit

Prof. Ehud Gazit

While the focus on amyloids is usually on their pathology, even in nature they are not always abnormal, misfolded proteins, they do have physiological roles in some organisms. For example, amyloids are an important protective material in the egg envelopes of insects and fish, they help form bacterial biofilms to protect a colony from natural antimicrobial substances that the bacteria may encounter, and they also allow such blooms to attach themselves to surfaces more effectively.

Technically speaking, amyloid fibrils are usually bundles of highly ordered protein filaments composed of ladder-like strands that can stretch to several micrometres in length. In cross-section, amyloids look like ribbons or like hollow cylinders. But, it is their resemblance to synthetic polymers (plastics) rather than their proteinaceous properties that drew the attention of the researchers in Israel.

Building amyloid polymers as templates for nanowires (Credit: Adapted from Angewandte)

Building amyloid polymers as templates for nanowires (Credit: Adapted from Angewandte)

Amyloids, for instance, are almost as strong mechanically as spider silk and by turn spider silk, weight for weight, is stronger than steel. They can also be stretched to many times their original length without splitting. Both properties are inaccessible to scientists working with synthetic polymers, but both properties are highly desirable for a wide range of engineering and technologies.

“The self-assembly properties of amyloids, together with their observed plasticity, makes them attractive natural building blocks for the design of new nanostructures and nanomaterials,” Gazit explains, “These building blocks can be broadly varied by means of simple molecular biological techniques.” The products might be used in novel sensors, tailored, biocompatible coatings, as enzyme mimics for speeding up chemical reactions, and for constructing nanoscale wires filled with silver and coated with gold for molecular electronics applications.

Further reading

Angew. Chem. Int. Edn, 2008, 47, 4062-4069
http://dx.doi.org/10.1002/anie.200703133

Prof. Ehud Gazit homepage
http://www.tau.ac.il/lifesci/departments/biotech/members/gazit/gazit.html