Cancer researchers look to dogs to better understand intricacies of bone cancer

Posted by Biomechanism 

CANCER RESEARCH: A team led by Dr. Jaime Modiano, a College of Veterinary Medicine and Masonic Cancer center expert in comparative medicine, discovered a gene pattern that distinguishes the more severe form of bone cancer from a less aggressive form in dogs. Dogs are the only other species besides humans that develops this disease spontaneously with any frequency.

Dogs are much more likely to develop bone cancer than humans, but according to Modiano – who specializes in the relationship between animal and human disease – human and canine forms of bone cancer are very similar and the gene pattern is an exact match.

“Our findings pave the way to develop laboratory tests that can predict the behavior of this tumor in dogs and children at the time of diagnosis,” said Dr. Jaime Modiano, College of Veterinary Medicine and Masonic Cancer Center expert in comparative medicine. “This allows us to tailor individualized therapy to meet the patient’s needs.”

“Patients with less aggressive disease could be treated conservatively, reducing the side effects and the risks associated with treatment, while patients with more aggressive disease could be treated with more intense therapy,” said Modiano.

This new University of Minnesota discovery may help bone cancer patients fight their disease more effectively, according to new research published in the September issue of Bone.

Bone cancer typically affects children; the course and aggressiveness of the disease can vary from patient to patient and is very difficult to predict. Some patients respond remarkably well to conventional therapies. Their disease shows less aggressive behavior and they can survive for decades without recurrence. Others respond poorly to treatment or their disease comes back rapidly. Often, these patients survive less than five years.

Recently, a team led by Dr. Jaime Modiano, a College of Veterinary Medicine and Masonic Cancer Center expert in comparative medicine, discovered a gene pattern that distinguishes the more severe form of bone cancer from a less aggressive form in dogs. Dogs are the only other species besides humans that develops this disease spontaneously with any frequency.

In fact, dogs are much more likely to develop bone cancer than humans, but according to Modiano – who specializes in the relationship between animal and human disease – human and canine forms of bone cancer are very similar and the gene pattern is an exact match. The discovery of this key differentiating signature may be beneficial in the treatment planning of human bone cancer patients.

“Our findings pave the way to develop laboratory tests that can predict the behavior of this tumor in dogs and children at the time of diagnosis,” said Modiano. “This allows us to tailor individualized therapy to meet the patient’s needs.”

The downstream impact of the findings

University of Minnesota researchers hope to use their findings to develop practical and useful lab tests for humans and for companion animals that will help clinical care providers determine the type of cancer a patient faces, and how aggressive that cancer may be.

Then, depending on which type of cancer a patient has, clinicians could adjust interventions and treatment plans accordingly.

“Patients with less aggressive disease could be treated conservatively, reducing the side effects and the risks associated with treatment, while patients with more aggressive disease could be treated with more intense therapy,” said Modiano.

The study was funded by the National Cancer Institute, the AKC Canine Health Foundation and the Kate Koogler Canine Cancer Fund.

Scientists map attack tactics of plant pathogens

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(“Biomechanism.com“) — Every year, plant diseases wipe out millions of tons of crops, lead to the waste of valuable water resources and cause farmers to spend tens of billions of dollars battling them.

Now a new discovery from a University of North Carolina at Chapel Hill-led research team may help tip the war between plants and pathogens in favor of flora.

A leaf infected by a pathogen called an oomycete. The oomycete gains entry into the leaf's intracellular spaces through natural openings and then grows by extending hyphae (filaments) between cells. When the hyphae fill up the leaf, the oomycete releases the next generation of infectious spores (the white tree-like structures emerging from the leaf surface. Oomycetes cause downy mildew diseases of many plants; one was responsible for the Irish Potato Famine and another for Sudden Oak Death Syndrome. Credit: Petra Epple, Dangl Lab, UNC-Chapel Hill.

The finding – published in the July 29, 2011, issue of the journal Science – suggests that while pathogens employ a diverse arsenal of weapons, they use these to attack plants by honing in on a surprisingly limited number of cellular targets.

“This is a major advance in understanding the biomechanisms involved in the ongoing evolutionary battle between plants and pathogens,” said Jeff Dangl, Ph.D., the study’s lead author and John N. Couch Professor of Biology in the College of Arts and Sciences.

The new finding is one of two studies published concurrently in Science related to the first comprehensive plant “interactomes” – maps of the tens of thousands of interactions that link a cell’s proteins. Those connections govern how proteins assemble into complex functional machines that dictate the tasks a cell can perform, such as growth, division and response to light, water and nutrients. And these same machines are often recruited into the battle against infectious agents.

One of the new studies mapped the interactome for about a third of the proteins encoded by the genome of the plant Arabidopsis thaliana, or thale cress. Arabidopsis is widely used for research purposes as a model organism – similar to the way mice are used in medical research – because of traits that make it useful for understanding the workings of many other plant species.

A leaf infected by an oomycete pathogen. Special feeding structures, called haustoria, bulge from the pathogen's hyphae (filaments) into the inside of the plant cells (the purple balloon-like structures inside the clear-colored individual cells). Credit: Petra Epple, Dangl Lab, UNC-Chapel Hill.

Dangl’s group led an additional study incorporating that interactome data with the construction of a second interactome. The second map focused on understanding how two very different pathogens (the bacteria Pseudomonas syringae and the oomycete parasite Hyaloperonospora arabidopsidis) infect plants and how plants fight back.

One method that these pathogens, which live in between cells, use for successful infection is to deploy virulence proteins (known as effectors) into the plant cell. The effectors muzzle the host’s defenses and allow the pathogen to hijack the plant’s cellular machinery.

In the new study, Dangl and his collaborators at institutions including Harvard University, the Salk Institute in La Jolla, Calif., and the University of Warwick, U.K., found that these two pathogens have evolved to focus their effectors onto a limited set of roughly 165 interconnected proteins that act in cellular machines in Arabidopsis cells – despite the fact that they last shared a common ancestor over 2 billion years ago, and use vastly different biomechanisms to colonize plants.

“This likely means that to suppress host plants’ defenses, all plant pathogens have evolved weapons that focus on a relatively small group of cellular machines,” Dangl said. “Knowing this should facilitate faster breeding for disease resistance and development of environmentally sustainable treatments for many devastating plant diseases.”

He said that neither interactome is a complete map, and more work needs to be done fully identify which protein networks are targeted by pathogens.

“We’ve found the needles in the haystack, but we still have to comb through another two-thirds of the hay,” said Dangl. “Our data suggest that there will be only a few hundred targets for effectors from all pathogens, out of the roughly 27,000 proteins encoded in the whole Arabidopsis genome.”

Academic scientists, seed breeders and biotech companies interested in these proteins will benefit from freely available data from both interactomes. The findings also could have implications for human health research.

“Professor Dangl and colleagues have used a powerful combination of network theory and laboratory experimentation to develop an approach to understanding the evolutionary logic by which pathogens and their hosts interact,” said James Anderson, Ph.D., who oversees regulatory biology grants at the National Institutes of Health. “While this study focused on plants, the results illustrate the value of model organisms in revealing fundamental principles that help us understand human responses to infectious diseases and provide the basis for devising new therapeutic strategies.”

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The study, “Independently Evolved Virulence Effectors Converge onto Hubs in a Plant Immune System Network,” was co-written by researchers from more than a dozen institutions.

The research in Dangl’s lab was funded by the National Institute of General Medical Sciences, part of the National Institutes of Health; the National Science Foundation’s Arabidopsis 2010 Program; and the Department of Energy.

Plant immunity discovery boosts chances of disease-resistant crops

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(“Biomechanism.com“) — Researchers funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have opened up the black box of plant immune system genetics, boosting our ability to produce disease- and pest-resistant crops in the future. The research is published in the journal Science.

Caption: Broccoli Head rot caused by Downy Mildew. Photo: UMASS

An international consortium of researchers, including Professor Jim Beynon at the University of Warwick, has used a systems biology approach to uncover a huge network of genes that all play a part in defending plants against attacks from pests and diseases – a discovery that will make it possible to explore new avenues for crop improvement and in doing so ensure future food security.

Professor Beynon said “Plants have a basic defence system to keep out potentially dangerous organisms. Unfortunately some of these organisms have, over time, evolved the ability to overcome plant defences and so plant breeders are always looking for new ways to catch them out. Understanding exactly how plant immunity works is key to making developments in this area.”

Professor Beynon’s team looked at downy mildew as an example of a plant disease. This is caused by mould-like organism called Hyaloperonospora parasitica, which, like many organisms that infect plants, produces proteins that it introduces into the plant to undermine its natural defences.

The team studied almost 100 different so-called effector proteins from Hyaloperonospora parasitica that are known to be involved in overcoming a plant’s immune system. They were looking to see how each of these proteins has an effect through interaction with other proteins that are already present in a plant. They found a total of 122 plant proteins from the commonly-studied plant Arabidopsis thaliana that are directly targeted by the proteins from Hyaloperonospora parasitica.

Caption: Broccoli Leaf symptoms caused by Broccoli Downy Mildew. Downy Mildew occurs wherever brassica crops are grown and infects cabbage, Brussels sprout, cauliflower, broccoli, kale, kohlrabi, Chinese cabbage, turnip, radish, and mustard as well as cruciferous weed species. The disease caused by Hyaloperonospora parasitica is particularly important on seedlings but can also cause poor growth and reduced yield and quality of produce at later plant stages. Photo: UMASS Extension

Professor Beynon continued “This shows that there are many more plant proteins involved in immunity than we first thought. By studying the genes that give rise to these proteins we can start to identify key genetic targets for crop improvement.”

The study has also identified many complex connections between the plant proteins suggesting that the network of activity is crucial in plant defences.

Professor Beynon concluded “Our discovery suggests that looking for single genes that confer resistance to pests and diseases is not going to be sufficient. Instead, researchers and breeders will have to work together to produce plants with robust networks of genes that can withstand attack.”

Professor Douglas Kell, Chief Executive, BBSRC said “Understanding the fundamental bioscience of plants is critical if we are to develop new ways of producing sustainable, safe, and nutritious food for a growing population. This discovery opens up a whole realm of possibilities in research about plant-pathogen interactions. It also points the way to new ways of working in this area; with a complex network operating behind the scenes in plant immunity, there is a clear need to take a systems approach to future research.”

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The work was a collaboration between Pascal Braun and Marc Vidal of the Dana Faber Institute, Boston, and Jeff Dangl, University of North Carolina, USA. It also involved a European consortium including Jonathan Jones, The Sainsbury Laboratory, Norwich; Guido van den Ackerveken, Utrecht University; and Jane Parker, Max Planck Institute, Cologne.