Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find

STANFORD, Calif. – Killing cancerous tumors isn’t easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.

The surprising possibility that a cell’s own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of medicine (oncology) and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study to be published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.

“Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program,” said Felsher.

Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.

The gene Felsher’s team studied produces a protein called Myc (pronounced “mick”), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.

“What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all,” said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

The researchers worked with a series of mice engineered to have Myc-triggered cancers of either the liver, blood or bones, along with a specially constructed version of the Myc gene that they could switch off by feeding the mice antibiotics. When the mice dined on doses of the drugs, invariably, the tumors ceased growing and then diminished, with some disappearing over the course of just a few days.

Although Felsher’s lab had previously shown that mouse tumors diminished and disappeared when Myc was switched off, they hadn’t been sure how the process actually worked. Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors.

Felsher described senescence as acting like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell’s ability to proliferate, thus halting any cancer.

“In order to become tumor cells, those cells have to overcome senescence,” said Chi-Hwa Wu, PhD, postdoctoral researcher in Felsher’s lab and first author of the study. Wu had the inspiration to explore whether the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence.

Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied.

Consider it a cell version of the Jekyll-and-Hyde transformation. “It’s sort of like Mr. Hyde realizing that there’s something wrong with him and then being able to put himself back into his normal state as Dr. Jekyll,” Felsher said.

In addition to the deepened understanding of how the process of senescence works, Felsher and Wu see a lot of potential for new approaches to treating cancer, beyond the traditional tactic of trying to kill cancer cells directly. “This work implies that maybe part of the strategy should involve figuring out how to get the cancer cells to just be allowed to do what they originally wanted to do anyway, which is to not be proliferating endlessly and growing uncontrolled,” said Felsher.

The next step for the team is to see how well the approach works in human cancer cells. “And we’re also trying to figure out what the mechanism is,” Felsher said. “What are the molecular mechanisms of this, so that we can figure out how to better treat cancer””

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Other authors on the research paper are Jan van Riggelen, PhD, postdoctoral researcher; Alper Yetil, graduate student in cancer biology; Alice Fan, MD, instructor in medicine (oncology), and medical student Pavan Bachireddy.

The study was funded by the National Cancer Institute, the National Institutes of Health, the Leukemia and Lymphoma Society, the Burroughs Wellcome Fund, the Damon Runyon Lilly Clinical Investigator Award, the Lymphoma Research Foundation and the Howard Hughes Medical Institute.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.

Contact: Lou Bergeron
louisb3@stanford.edu
650-723-3900
Stanford University Medical Center

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New studies on goat milk show it is more beneficial to health than cow milk

-It helps to prevent diseases such as anaemia and bone demineralisation
-UGR researchers have carried out a comparative study on the properties of goat milk compared to those of cow milk. Rats with induced nutritional ferropenic anaemia have been used in the study
-Goat milk helps digestive and metabolic utilisation of minerals such as iron, calcium, phosphorus and magnesium
-Part of the results of this research have been published in the prestigious scientific journals International Dairy Journal and Journal Dairy Science

C@MPUS DIGITAL Research carried out at the Department of Physiology of the University of Granada has revealed that goat milk has more beneficial properties to health than cow milk. Among these properties it helps to prevent ferropenic anaemia (iron deficiency) and bone demineralisation (softening of the bones).

This project, conducted by Doctor Javier Díaz Castro and directed by professors Margarita Sánchez Campos, Mª Inmaculada López Aliaga and Mª José Muñoz Alférez, focuses on the comparison between the nutritional properties of goat milk and cow milk, both with normal calcium content and calcium enriched, against the bioavailability of iron, calcium, phosphorus and magnesium. To carry out this study, the metabolic balance technique has been used both in rats with experimentally induced nutritional ferropenic anaemia and in a control group of rats.

In order to know how the nutritive utilisation of these minerals may affect their metabolic distribution and destination, the UGR researcher has determined the concentration of these minerals in the different organs involved in their homeostatic regulation and different haematological parameters in relation to the metabolism of the minerals.

Better results with goat milk
Results obtained in the study reveal that ferropenic anaemia and bone demineralisation caused by this pathology have a better recovery with goat milk. Due to the higher bioavailability of iron, calcium, phosphorus and magnesium, the restoration of altered haematological parameters and the better levels of parathyroid hormone (PTH), a hormone that regulates the calcium balance in the organism was found in the rats that consumed this food.

Javier Díaz Castro points out that the inclusion of goat milk with normal or double calcium content in the diet “favours digestive and metabolic utilisation of iron, calcium and phosphorus and their deposit in target organs – parts of the organism to which these minerals are preferably sent – involved in their homeostatic regulation”.

According to this researcher, all these conclusions reveal that regular consumption of goat milk – a natural food with highly beneficial nutritional characteristics – “has positive effects on mineral metabolism, recovery from ferropenic anaemia and bone mineralisation in rats. In addition, and unlike observations in cow milk, its calcium enrichment does not interfere in the bioavailability of the minerals studied”.

Although there is no doubt that these findings may be a base for further in depth study of the multiple health benefits of goat milk, the UGR researcher warns that “studies in humans are still required in order to confirm the findings obtained in rats and to promote goat milk consumption both in the general population and in the population affected by nutritional ferropenic anaemia and pathologies related to bone demineralisation”. Part of the results of this research has been published in the prestigious scientific journals International Dairy Journal and Journal Dairy Science.

Reference: Dr Javier Díaz Castro. Department of Physiology of the University of Granada.
Tel.: +34 958248319. Mobile: +34 654574434. Email: javierdc@ugr.es

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Revealed — Mosquito genes that could be controlling the spread of killer viruses

Contact: Danielle Reeves
danielle.reeves@imperial.ac.uk
44-020-759-42198
Imperial College London

The genes that make up the immune system of the Aedes aegypti mosquito which transmits deadly viral diseases to humans have been identified in new research out today in Science.

The immune system of this mosquito is of great importance as scientists believe it plays a key role in controlling the transmission of viruses that cause yellow and dengue fevers – diseases that infect over 50 million people worldwide every year.

This study is the first of its kind on the newly-sequenced genome of the Aedes aegypti mosquito, which is also published in this week’s Science. The researchers identified over 350 genes which are involved in the Aedes mosquito’s immune system, and discovered that they evolve much faster than the rest of the genes in the genome. Identifying which of these key genes are implicated in the transmission of viral diseases is an area of future research that could lead to new ways of combating these diseases. One possibility would be to affect the activity of the genes and therefore help the mosquitoes fight off the viruses more effectively, preventing transmission to humans.

Imperial College scientists participating in this study established previously that other mosquitoes do have a robust immune system that can either allow or block transmission of malaria parasites. Further research will be needed to ascertain whether some of the newly discovered genes in Aedes may provide a similar defence mechanism that can fight the disease viruses.

Dr George Christophides of Imperial’s Division of Cell and Molecular Biology, senior author on the paper explains: “Our study has revealed the genetic ‘landscape’ made by parts of this mosquito’s newly-sequenced genome which are involved with immunity. By working to understand as much as possible about these genes, and the way they interact with specific pathogens, we hope to gain a more complete understanding of the mechanisms by which a pathogen either survives inside the insect body, or is killed by the insect’s defences.”

The international research team, led by Imperial PhD student Robert Waterhouse, focused on comparing the immunity genes of the Aedes mosquito with similar groups of genes in the harmless fruit fly and the Anopheles mosquito that transmits malaria. When comparing the two different mosquitoes, the scientists found some similarities in the genes controlling their respective immune systems, but also numerous differences. The team aims to discover which of these genetic differences could explain why one type of mosquito transmits dengue and yellow fevers, while the other transmits malaria. Beyond the present descriptive work, functional studies will be needed to clarify exactly how this happens.

“This study made us realise that the immune systems of insects are not static but evolve and differentiate rapidly, most likely in response to the different pathogens which each insect species encounters”, says Dr Christophides.

Professor Fotis Kafatos, senior researcher of Imperial’s immunogenomics lab and co-author of the paper, explains the significance of their study, saying: “Understanding the genetics behind pathogen/immune system interactions in disease vector mosquitoes may help us understand why, for example, some types of mosquitoes can transmit a particular human pathogen while others cannot. If those that cannot have evolved an effective immune system that fights off the pathogen, we may be able to use this knowledge to enhance specific reactions of the immune systems in other mosquitoes to control the spread of the disease.”

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