AUF1 Hat Trick: Suppresses Inflammation, Reduces Cancer Risk, and Inhibits Cellular Senescence

Researchers at NYU School of Medicine have, for the first time, identified a single gene that simultaneously controls inflammation, accelerated aging and cancer. _NYU SOM

AUF1 is a micro-RNA binding protein that has been found to perform multiple vital cell functions. Engineered mice that lack the AUF1 protein suffer rapid premature aging that worsens with each generation. By replacing AUF1 function in these mice, the harmful premature aging and accelerated cellular senescense can be reversed.

AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell-cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence. _Molecular Cell (ScienceDirect)

AUF1 also accelerates the degradation of inflammatory cytokine, reducing the inflammation load on cells and tissues. More from NYU School of Medicine, where much of the recent research on AUF1 was done:

For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery, Dr. Schneider said. What was known, due in part to past studies by Schneider and his team, was that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer.

When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. Now, more than a decade in the making, the mystery surrounding the connection between inflammation, advanced aging and cancer is finally being unraveled.

The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer, Dr. Schneider explained.

“AUF1 is a medical and scientific trinity,” Dr. Schneider said. “Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal.”

With this new information, Dr. Schneider and colleagues are examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically. _NYU

This is an exciting and potentially important finding. But it takes time for exciting research discoveries to be converted into potentially revolutionary therapies against cancer, aging, and crippling inflammatory diseases.

Early attempts to capitalise on this discovery are likely to be disappointing, particularly as expectations will tend to be raised prematurely. But as the ability to generate safe, effective, affordable treatments begins to catch up to the ability to discover the mechanisms of biological function at multiple levels, the pace of change may grow at a startling rate.

The important thing is to get the basic science findings into the hands of the research community for replication, clarification, and elaboration. After that, scientists can begin finding ways to make the research work in favour of an abundant human future.

Original 1997 identification of AUF1 at Rutgers and Wake Forest (PDF)

H/T Nextbigfuture

Intravenous Stem Cells: Where Do They Go? What Do They Do?

We usually think of stem cell therapy in terms of replacing damaged cells or tissues with stem cells, which can differentiate and become the type of cell or tissue which is being replaced. But there is more to it than that, particularly in the case of intravenous stem cell infusion.

Researchers have tracked the migration of stem cells administered intravenously following an injury. At first the majority of the cells lodge within the lung, where they appear to interact with pulmonary macrophages altering the type of cell signaling molecules those macrophages release into the blood. Next the stem cells migrate to the organs of the reticuloendothelial system which includes the spleen. Surprisingly, less than 3% of infused stem cells migrate into brain tissue. So the immunomodulatory effect does not require the majority of infused stem cells to interact directly with injured brain tissue. _SciAm

It turns out that much of the beneficial effect from the intravenous infusion of stem cells comes from their effect on the immune system. IV infused stem cells apparently shift the immune system's response to injury and rejuvenation, creating a more favourable environment for healing and regeneration.

This allows the few stems cells which make it all the way to the damaged tissue, to promote regeneration locally without a harmful immune response.

Immunomodulatory stem cell studies attempt to adjust the immune response in a way that minimizes the damage associated with the initial injury, and then allows the individual’s native repair machinery to function optimally.

With even mild injury, the immune system is activated. Macrophages are a type of immune cell which participate in the post-injury immune response. With “classic” macrophage activation, the immune response is aggressively induced. Classically activated macrophages are described as having an “M1” phenotype. In the nervous system, the M1 immune response can increase the severity of an injury. Alternatively activated or “M2” macrophages, are associated with a less destructive pattern of immune system activation. This alternate/M2 response results in less immune mediated post-injury damage, as well as the possible disinhibition of native nervous system repair.

Following traumatic brain injury (TBI) children experience a loss of 12-15% of their brain tissue in the 12 months following their injury (Levin). In a study where we treated TBI children with their own bone marrow stem cells, there was minimal post injury brain volume loss in the year after TBI (Cox). In animal models of TBI, animals that experienced injury were found to have M1 macrophages throughout their injured brain tissue.

Animals treated with stem cells after TBI were found to have M2 macrophages in their brain parenchyma. Interestingly, if an animal’s spleen was removed before stem cell infusion, the benefit of the stem cell treatment was eliminated. Somehow stem cell infusion causes a change in the pattern of macrophage activation from M1 to M2, which results in a less aggressive immune response and less post-injury brain tissue death. This effect requires an intact spleen. _SciAm

So you see that in an optimal response to stem cell infusion following an injury, the patient will experience both immunomodulatory effect and a regenerative effect from the IV stem cell infusion.

When the stem cells being infused are of a broad-spectrum nature -- such as cord blood, embryonic stem cells, or pluripotent adult stem cells -- the door is wide open for other effects beyond the immunomodulatory and the regenerative (replacement) effects. It should be clear that other rejuvenative effects are also possible from broad spectrum stem cell infusion. It will simply require a good deal of research and consideration before most of those effects can be discovered and decoded for optimal therapies in the future.

Staggered Drug Therapies Hit Some Cancer Cells Harder

This treatment worked not only in cancer cells grown in a lab dish, but also in mice with tumors. When treated with a one-two punch of erlotinib and doxorubicin, the tumors shrank and did not grow back for the duration of the experiment (two weeks). With chemotherapy alone, or when the two drugs were given at the same time, the tumors initially shrank but then grew back. _MIT

Differential cell responses to chemotherapy treatment. The photo shows a range of responses of similar cells to the chemotherapeutic drug doxorubicin. The most intensely responding drugs are shown in yellow, many of which will die. Green cells are alive but not dividing. Red cells are continuing to grow and divide. Yaffe and colleagues have figured out how to increase the proprotion of triple negative breast cancer cells that can be killed by a specific time-ordered regiment of growth factor inhibitors and chemotherapy, with direct application to clinical treatment. Image courtesy of Neil Ganem, Michael Yaffe and David Pellman

Staggering the administration of cancer chemotherapy drugs can effectively treat some types of cancer which are highly resistant to conventional modes of chemotherapy treatment. MIT cancer researchers are leading the research to discover why a staggered treatment seems more effective, and to determine which types of cancer are most susceptible to this method of drug administration.

In the new paper, published in Cell on May 11, the researchers showed that staggering the doses of two specific drugs dramatically boosts their ability to kill a particularly malignant type of breast cancer cells.

The researchers, led by Michael Yaffe, the David H. Koch Professor of Biology and Biological Engineering at MIT, are now working with researchers at Dana-Farber Cancer Institute to plan clinical trials of the staggered drug therapy. Both drugs — erlotinib and doxorubicin — are already approved for cancer treatment.

Yaffe and postdoc Michael Lee, lead author of the Cell paper, focused their study on a type of breast cancer cells known as triple negative, meaning that they don’t have overactive estrogen, progesterone or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

“For triple-negative breast cancer cells, there is no good treatment. The standard of care is combination chemotherapy, and although it has a good initial response rate, a significant number of patients develop recurrent cancer,” says Yaffe, who is a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

Uncontrolled growth

For the past eight years, Yaffe has been studying the complex cell-signaling pathways that control cells’ behavior: how much they grow, when they divide, when they die. In cancer cells, these pathways often go haywire, causing the cells to grow even in the absence of any stimulus and to ignore signals that they should undergo cell suicide.

Yaffe became intrigued by the idea that drug-induced changes in these signaling pathways, if staggered in time, could switch a cancerous cell into a less malignant state. “Our previous systems-biology work had primed us to the idea that you could potentially drive a cell from a state in which only a fraction of the tumor cells were responsive to chemotherapy into a state where many more of them were responsive by therapeutically rewiring their signaling networks in a very time-dependent way,” he says.

Specifically, he and Lee thought it might be possible to sensitize cancer cells to DNA-damaging drugs — the backbone of most chemotherapy — by first giving them another drug that shuts down one of the haywire pathways that promote uncontrollable growth. They tested different combinations of 10 DNA-damaging drugs and a dozen drugs that inhibit different cancerous pathways, using different timing schedules.

“We thought we would retest a series of drugs that everyone else had already tested, but we would put in wrinkles — like time delays — that, for biological reasons, we thought were important,” Lee says. “I think had it not worked, we would have gotten a lot of pushback, but we were pretty convinced that there was a lot of information being left on the table by everyone else.”

Of all combinations they tried, they saw the best results with pretreatment using erlotinib followed by doxorubicin, a common chemotherapy agent. Erlotinib, approved by the FDA to treat pancreatic cancer and some types of lung cancer, inhibits a protein found on cell surfaces called the epidermal growth factor (EGF) receptor. When constantly active, as it is in many cancer cells, the EGF receptor stimulates a signaling pathway that promotes uncontrolled growth and division.

The researchers found that giving erlotinib between four and 48 hours before doxorubicin dramatically increased cancer-cell death. Staggered doses killed up to 50 percent of triple-negative cells, while simultaneous administration killed about 20 percent. About 2,000 genes were affected by pretreatment with erlotinib, the researchers found, resulting in the shutdown of pathways involved in uncontrolled growth.

“Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill,” Lee says.

However, if the drugs were given in the reverse order, doxorubicin became less effective than if given alone.

...A combination of high-throughput measurements and computer modeling was used to reveal the mechanism for increased tumor killing, and to identify a biomarker for drug response. The researchers found that the treatment was most effective in a subset of triple-negative breast cancer cells with the highest levels of EGF receptor activity. This should allow doctors to screen patients’ tumors to determine which would be most likely to respond to this novel treatment.

The research is “groundbreaking in its demonstration that the principles of order and time are essential to the development of effective therapies against complex diseases,” Rune Linding, research group leader at the Technical University of Denmark, and Janine Erler, associate professor at the University of Copenhagen, wrote in a commentary accompanying the paper in Cell. “As disease researchers, we must consider network states, and this and other studies serve as a model for a new generation of cancer biologists.”

The concept of staggering drug treatments to maximize impact could be very broadly applicable, Yaffe says. The researchers found similar boosts in tumor killing by pretreating HER2-positive breast cancer cells with a HER2 inhibitor, followed by a DNA-damaging drug. They also saw good results with erlotinib and doxorubicin in some types of lung cancer.

“The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It’s just a matter of finding the right combinations,” Lee says.

The findings also highlight the importance of systems biology in studying cancer, Yaffe says. “Our findings illustrate how systems engineering approaches to cell signaling can have large potential impact on disease treatment,” he says. _MITNews

The scientists have barely begun to discover the mechanisms behind the effectiveness of staggered treatments.

What is not mentioned is that we are likely to discover methods of treating ageing, once we more fully understand the reasons for the success of staggered cancer chemotherapy. Because of the time sensitive nature of DNA repair and epigenetic shifting, certain combinations of interventions which affect the genetic and epigenetic apparatus need to be given at certain times in relation to each other. In other words, some interventions facilitate other interventions, but only for specific periods of time, until the system reverts to its original status.

There is a rich gold mine of discovery associated with this phenomenon. Stem cell research has already confronted this discovery, and is exploring it to good effect. Cancer research is likewise beginning to see the light. Soon, anti-ageing research will wield this powerful tool. Time-sensitive paired (and more) interventions are likely to revolutionise the field of genetic intervention across multiple fields.

Mastering Cell Signaling: A Worthy Goal

Cells make decisions in fluctuating environments using inherently noisy biochemical mechanisms. Such effects create considerable, unpredictable variation – known as ‘stochasticity’– both over time and between genetically identical cells. To understand how cells exploit and control these biochemical fluctuations, scientists must identify the sources of stochasticity, quantify their effects, and distinguish variation that carries information about the biological environment from confounding noise.

In their PNAS paper, Dr Bowsher and Professor Swain show how to decompose the fluctuations of biochemical networks into multiple components and how to design experimental ‘reporters’ to measure these components in living cells.

The paper, which describes the application of this approach to yeast cells, shows that the majority of cellular variation may be informational in origin and due to fluctuations in the cellular environment. The results pave the way to a better understanding of the dynamics of signal processing and decision-making by cells. _SD

Cell Signaling Network, Preliminary Sketch
We begin to comprehend the potential power of cell signaling mastery, when we observe research breakthroughs such as the following:

In laboratory experiments with mouse cells, the researchers found that a specific protein that regulates cell aging also controls a process that causes blood-making stem cells to age. Using drugs to inhibit the action of this protein (called Cdc42) reversed aging of the hematopoietic stem cells and restored their function to a level similar to that of younger stem cells.

It had been [previously] believed that the aging of hematopoietic stem cells was locked in by nature and could not be reversed by using drugs, according to a hospital news release.

...The study by scientists at Cincinnati Children's Hospital Medical Center and Ulm University Medicine in Germany appeared online May 3 in the journal Cell Stem Cell. _USN

Turning old hematopoietic stem cells into young hematopoietic stem cells is nothing to sneeze at. And it is only a slight foretaste of what is becoming possible, as we better understand cell signaling networks and the signaling involved in gene expression.

One of the more exciting near-to-intermediate term possibility arising from the coming mastery of cell signaling, is the ability to reverse neurodegenerative diseases which involve abnormal protein folding. Diseases such as Alzheimer's, Huntington's, Parkinson's, and "mad cow disease," for example, involve abnormal proteins leading to cell destruction and loss of neural function.

Researchers at the University of Leicester uncovered how the build-up of proteins in mice with prion disease resulted in brain cells dying.

They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins.

...The team at the Medical Research Council laboratory in Leicester then tried to manipulate the switch which turned the protein factory off. When they prevented cells from shutting down, they prevented the brain dying. The mice then lived significantly longer.

Each neuro-degenerative disease results in a unique set of misfolded proteins being produced, which are then thought to lead to brain cells dying.

Prof Giovanna Mallucci told the BBC: "The novelty here is we're just targeting the protein shut-down, we're ignoring the prion protein and that's what makes it potentially relevant across the board."

The idea, which has not yet been tested, is that if preventing the shut down protects the brain in prion disease - it might work in all diseases that have misfolded proteins.

Prof Mallucci added: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders. _BBC

Nature article

Complex cell signaling is also involved in the control of gene expression, including critically important DNA repair, and control of telomere length in cells -- which controls the number of cell doublings allowed.

If you click on the image above, you can view an enlarged version of a portion of a cell signaling network. Such complexity explains the need for high powered computational backup in the attempt to decode these networks, as a prelude to their mastery.

Cellular processes take place very quickly, and in a closely controlled and balanced chemical milieu. If we are to learn to intervene on the level of the cell in a beneficial way, we must proceed with care. But we definitely aim to proceed.