'Glue' holding together skin cells, other epithelial tissue more active than realized

The strong mechanical attachments -- the "glue" -- that hold together the cells of the skin and the other epithelial tissues of the body are the adherens junctions.

These junctions are responsible for maintaining the shape and integrity of the sheets of epithelial cells that line such body cavities as the digestive tract, as well as the surfaces of structures such as the heart. Defects in the proteins of these attachments have been implicated as potential contributors to the development and spread of cancer.

Recent research on Drosophila flies, combined with previous studies in cell cultures, are challenging the traditional view that adherens junctions maintain tissue integrity by passively resisting disruptive forces.

In studies with Drosophila embryos, the Princeton University lab of Nobel laureate Eric Wieschaus, Ph.D., has uncovered the first evidence in living organisms that adherens junctions actively respond to mechanical cues by remodeling their own position and intensity, which in turn restructures the cells.

Mo Weng, Ph.D., postdoctoral fellow in the lab, used live imaging and quantitative image analysis of fixed and live embryos to determine that these changes depend on mechanical force mediated by the motor protein myosin and precede the changes in the distribution of cell polarity proteins, such as Bazooka, that are responsible for spatial organization of the cells.

Understanding the regulation and functioning of adherens junctions sheds light on the organization of multi-cellularity -- from cell-cell contacts to the remodeling of tissues and organs during life.

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Plasma tool for destroying cancer cells

Plasma medicine is a new and rapidly developing area of medical technology. Specifically, understanding the interaction of so-called atmospheric pressure plasma jets with biological tissues could help to use them in medical practice.

Under the supervision of Sylwia Ptasinska from the University of Notre Dame, in Indiana, USA, Xu Han and colleagues conducted a quantitative and qualitative study of the different types of DNA damage induced by atmospheric pressure plasma exposure, the paper is published inThe European Physical Journal D, as part of a special issue on nanoscale insights into Ion Beam Cancer Therapy. This approach, they hope, could ultimately lead to devising alternative tools for cancer therapy as well as applications in hospital hygiene, dental care, skin diseases, antifungal care, chronic wounds and cosmetics treatments.

To investigate the DNA damage from the so-called non-thermal Atmospheric Pressure Plasma Jet (APPJ), the team adopted a common technique used in biochemistry, called agarose gel electrophoresis. They studied the nature and level of DNA damage by plasma species, so-called reactive radicals, under two different conditions of the helium plasma source with different parameters of electric pulses.

They also identified the effect of water on DNA damage. To do so, they examined the role of reactive radicals involved in DNA damage processes occurring in an aqueous environment. They then compared them to previous results obtained in dry DNA samples.

The next step would involve investigating plasma made from helium mixtures with different molecular ratios of other gases, such as oxygen, nitrous oxide, carbon dioxide and steam, under different plasma source conditions. The addition of another gas is expected to increase the level of radical species, such as reactive oxygen species and reactive nitrogen species, known to produce severe DNA damage. These could, ultimately, help to destroy cancerous tumour cells.

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New technique targets specific areas of cancer cells with different drugs

Jan. 6, 2014 — Researchers have developed a technique for creating nanoparticles that carry two different cancer-killing drugs into the body and deliver those drugs to separate parts of the cancer cell where they will be most effective. The technique was developed by researchers at North Carolina State University and the University of North Carolina at Chapel Hill.

"In testing on laboratory mice, our technique resulted in significant improvement in breast cancer tumor reduction as compared to conventional treatment techniques," says Dr. Zhen Gu, senior author of a paper on the research and an assistant professor in the joint biomedical engineering program at NC State and UNC-Chapel Hill.

"Cancer cells can develop resistance to chemotherapy drugs, but are less likely to develop resistance when multiple drugs are delivered simultaneously," Gu says. "However, different drugs target different parts of the cancer cell. For example, the protein drug TRAIL is most effective against the cell membrane, while doxorubicin (Dox) is most effective when delivered to the nucleus. We've come up with a sequential and site-specific delivery technique that first delivers TRAIL to cancer cell membranes and then penetrates the membrane to deliver Dox to the nucleus."

Gu's research team developed nanoparticles with an outer shell made of hyaluronic acid (HA) woven together with TRAIL. The HA interacts with receptors on cancer cell membranes, which "grab" the nanoparticle. Enzymes in the cancer cell environment break down the HA, releasing TRAIL onto the cell membrane and ultimately triggering cell death.

When the HA shell breaks down, it also reveals the core of the nanoparticle, which is made of Dox that is embedded with peptides that allow the core to penetrate into the cancer cell. The cancer cell encases the core in a protective bubble called an endosome, but the peptides on the core cause the endosome to begin breaking apart. This spills the Dox into the cell where it can penetrate the nucleus and trigger cell death.

"We designed this drug delivery vehicle using a 'programmed' strategy," says Tianyue Jiang, a lead author in Dr. Gu's lab. "Different drugs can be released at the right time in their right places," adds Dr. Ran Mo, a postdoctoral researcher in Gu's lab and the other lead author.

"This research is our first proof of concept, and we will continue to optimize the technique to make it even more efficient," Gu says. "The early results are very promising, and we think this could be scaled up for large-scale manufacturing."

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University of Colorado researchers found that arise from stem cells of muscle invasion and another muscle-invasive bladder cancer

Published today in the journal stem cells University of Colorado Cancer Center Research create a dangerous, invasive bladder cancer precursor cells shows that muscle with non-invasive bladder cancer to create progenitor cells.

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B cells can provide a potential treatment of RNA has changed a bit.

California College San Diego medical Moores Comprehensive Cancer Center (home) of researchers successfully different kinds of white blood cells, and designed to provide a bit of a non-coding RNA or microRNA (miRNA)-it plays a central role in the immune response of the body – is targeting the T lymphocytes. Achieved in the mouse study published in this week National Science Academy Journal online early Edition are probably used for genetic recombination miRNA therapeutic purposes, the first step of the prominent vaccine and cancer treatment.

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Cancer cells are controlled by epigenetic processes, new research shows

First time USC Norris Comprehensive Cancer Center (home) of Keck new research from medicine, according to epigenetics in the description of the human body a natural killer (NK) cells, kill can contain viruses and cancerous tumors can be manipulated. Opens the way to develop a National Science Academy of advanced discovery more effective cancer drugs.

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Study of 'sister' stem cells uncovers new cancer clue

Sep. 26, 2013 — Scientists have used a brand new technique for examining individual stem cells to uncover dramatic differences in the gene expression levels -- which genes are turned 'up' or 'down'- between apparently identical 'sister' pairs.

The research, published today in Stem Cell Reports, was conducted and funded by The Institute of Cancer Research, London. It provides the latest evidence that despite having identical DNA, sister stem cells can display considerable differences in their molecular characteristics.

The study showed that DNA methylation, a process that controls which genes are expressed in cells, plays an important role in generating non-genetic (or 'epigenetic') differences between sister cells.

DNA methylation could therefore be one of the reasons for the major molecular variation between different cancer cells in the same tumour -- and drugs to reduce methylation might help control variation and make cancers easier to treat.

In the new research, scientists at The Institute of Cancer Research (ICR) developed a novel micro-dissection technique to separate pairs of sister embryonic stem cells for single cell RNA analysis [1].

Using their new high-tech method, researchers separated and isolated mouse stem cells from their sister pairs and measured the behaviour of key genes known to be expressed in those cells. By comparing which of these genes were up -- or down -- regulated, they determined the levels of similarity between sister cells at the molecular level for the first time.

They found that under normal conditions, pairs of sister stem cells displayed considerable differences to each other, showing nearly as much diversity as two cells from different sister pairs.

The researchers then looked at cells grown in the presence of a chemical cocktail called 2i, which reverts cells back to their most primitive stem cell state where they can make identical copies of themselves. They found that the cells had reduced levels of two enzymes critical for DNA methylation and they produced more similar sister cells.

The results suggest that DNA methylation is a major cause of the diversity between sister cells when they divide.

Dr Tomoyuki Sawado, leader of the Stem Cells and Chromatin Team at The Institute of Cancer Research, said: "Embryonic stem cell division is generally believed to be a symmetrical process, but what we found was that sister cells are actually often quite different from one another.

"We used a new technique to separate paired stem cells combined with assays that measure RNA in individual cells. Our research showed that sister stem cells display considerable differences in which genes are expressed. These differences are advantageous for normal stem cells in their constantly changing environment, and in cancer cells, the same characteristics can enable them to evade treatments. If we can control a process like DNA methylation that creates diversity in cell populations, we could create more efficient treatments for cancer."

Professor Mel Greaves, Professor of Cell Biology at The Institute of Cancer Research, said: "How stem cells regulate expression of their genes is crucial to many fundamental biological processes, such as embryonic development, regeneration and turnover of blood, skin and other tissues in the body, but especially to cancer.

"One of the biggest challenges in cancer treatment is overcoming drug resistance. Research from the ICR has revealed that the cells of individual tumours are remarkably diverse and this new research highlights one way this might be achieved. The inherent variability of cancer cell populations provides them with the flexibility to adapt and survive even when confronted with innovative new drugs. If we could harness these new insights to restrict the diversity of cancer cells it would substantially increase the prospects for effective control or eradication of cancer."

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Feast to famine: Oxygen starvation regulates fat cells in obesity

Sep. 25, 2013 — Researchers at Kanazawa University have identified the role of the protein TIS7 in processes that regulate adipogenesis, whereby non-specialised cells become adipose or fat cells.

Studies of the effects of oxygen deprivation in the body fat of obese animals have revealed links with the regulation of fat cell generation. Researchers at Kanazawa University have identified the role of the protein TIS7 in processes that regulate adipogenesis, whereby non-specialised cells become adipose or fat cells. They add, "TIS7 could be a target for the discovery and development of a drug useful for the treatment and therapy of obesity or a variety of obesity-related metabolic diseases including type-2 diabetes and atherosclerosis."

Adipose tissue is essential for whole body homeostasis, storing excess energy and potentially a number of other physiological processes. Deregulation of these functions is found in obesity, prompting further study of the mechanisms behind white adipose tissue development.

Adipose tissue is poorly oxygenated in obese humans and animals. Poor oxygenation or 'hypoxia' has been linked to a number of diseases including heart and lung disorders, anemia, and circulation problems. There have also been reports indicating that the protein TIS7 is expressed in tissues following injuries, such as ischemia, stroke or muscle trauma. Yukio Yoneda and colleagues at the University of Kanazawa monitored TIS7 expression in vitro and found that it was drastically increased by hypoxic stress.

The researchers then compared mice fed different diets and found significant up-regulation of TIS7 in the white adipose tissue of mice fed a high fat diet. Following further studies of various aspects of adipogenesis and the role of hypoxia and TIS7, the researchers conclude, "It thus appears that TIS7 is a novel pivotal transcriptional regulator of hypoxia-induced repression of adipogenesis." They add that further studies are needed to understand the exact mechanism underlying the up-regulation of TIS7 under hypoxia in cells prior to adipogenesis.

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Human brain tumor cells erased in mice

Sep. 23, 2013 — Working with mice, Johns Hopkins researchers have discovered that weeks of treatment with a repurposed FDA-approved drug halted the growth of -- and ultimately left no detectable trace of -- brain tumor cells taken from adult human patients.

The scientists targeted a mutation in the IDH1 gene first identified in human brain tumors called gliomas by a team of Johns Hopkins cancer researchers in 2008. This mutation was found in 70 to 80 percent of lower-grade and progressive forms of the brain cancer. The change occurs within a single spot along a string of thousands of genetic coding letters, and is disruptive enough to keep the seemingly innocuous protein from playing its role in converting glucose into energy. Instead, the mutation hijacks the protein to make a new molecule not normally found in the cell, which is apparently a linchpin in the process of forming and maintaining cancer cells.

Encouraged by the new findings, described online Sept. 16 in the open-access journal Oncotarget, the Johns Hopkins researchers say they want to work quickly to design a clinical trial to bring what they learned in mice to humans with gliomas. Despite the growing understanding of IDH1 mutant gliomas, the development of effective therapies has proven challenging, they say.

"Usually in the lab, we're happy to see a drug slow down tumor growth," says Alexandra Borodovsky, a graduate student in the Cellular and Molecular Medicine Program at the Johns Hopkins University School of Medicine who performed the experiments. "We never expect tumors to regress, but that is exactly what happened here."

"This therapy has worked amazingly well in these mice," says study leader Gregory J. Riggins, M.D., Ph.D., a professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine. "We have spoken with neurosurgeons here, and as soon as possible, we want to start discussing the parameters of a clinical trial to see if this will work in our patients as a follow-up to surgery."

The researchers caution that many treatments have cured cancers in mice, and then failed in humans.

The IDH1 gene, whose name stands for isocitrate dehydrogenase 1, produces an enzyme that regulates cell metabolism. Mutations, or changes in the DNA code, force the IDH1 gene to increase production of a flawed version of the enzyme. The flawed enzyme produces large amounts of an entirely new molecule, called 2-hydroxyglutarate. This molecule is believed to cause groups of atoms called methyl groups to latch onto the DNA strand.

Although methylation is a normal cellular process, when too many methyl groups glom onto the DNA, Riggins says, this can interfere with normal cell biology and eventually contribute to cancer formation and growth.

Borodovsky, Riggins and their colleagues -- including Timothy A. Chan, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center in New York -- thought that a drug that could strip those methyl groups might be able to reverse the cancer process in those cancers with IDH1 mutations. They chose 5-azacytidine, which is approved to treat a pre-leukemia condition called myelodysplastic syndrome and is being tested on lung and other cancers at Johns Hopkins and elsewhere.

Riggins notes that one of the difficulties in developing treatments for IDH1 mutant brain cancers is finding a model in which to study them. Cell lines containing the IDH1 mutation are difficult to grow in the laboratory, for example. Borodovsky worked with Johns Hopkins neurosurgeons to obtain tumor cells from glioma patients likely to have IDH1 mutations and injected them under the skins of mice. She did this for months, before finally getting the tumor cells to grow.

Once the tumors grew, the researchers injected the mice with 5-azacytidine for 14 weeks and saw a dramatic reduction in growth and what appeared to be complete regression. Then they withdrew therapy. Seven weeks later, the tumors had not regrown. The researchers, however, said they do expect the tumors to regrow at some point, and are still monitoring the mice.

The type of tumor targeted by the researchers eventually progresses to a subtype of glioblastoma multiform -- the deadliest form of brain cancer -- known as progressive or secondary glioblastoma. They arise as a lower-grade glioma and are initially treated with surgery alone, but eventually they progress to the more lethal form of tumor. Survival is longer than with glioblastoma, but it is found in younger patients, those under the age of 50. While both types of tumor look the same at the end, they look very different at the molecular level, Riggins says, leading researchers to believe they may have a better chance at targeting the progressive tumors, which are more likely to have the IDH1 mutation.

Chan's team at Sloan-Kettering simultaneously published a paper in Oncotarget, along with Borodovsky and Riggins, which describes similar results in a different animal model using a similar drug. This is further evidence that the strategy is a sound one, Riggins says.

Other Johns Hopkins researchers involved in the Borodovsky paper include Charles G. Eberhart, M.D., Ph.D.; Jon D. Weingart, M.D.; Gary L. Gallia, M.D., Ph.D.; and Stephen B. Baylin, M.D.

The work was supported by the Conrad N. Hilton Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Margaret H. Riggins, and the Irving J. Sherman Research Professorship in Neurosurgery. Funding also came from grants from the National Institutes of Health's National Cancer Institute (P30 CA006973) and the National Center for Research Resources (UL1 RR025005 and 1S10RR026824-01).

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Cancer-killing cells controlled by epigenetic process

Sep. 23, 2013 — Natural killer (NK) cells in the human body can kill and contain viruses and cancerous tumors, and a new study from the University of Southern California (USC) describes for the first time how those cells can be manipulated by epigenetics. The discovery, detailed in the Proceedings of the National Academy of Sciences, paves the way for developing more effective cancer drugs.

"Natural killer cells are very attractive targets for immunotherapy because they are able to kill tumor cells," said Si-Yi Chen, M.D., Ph.D., a faculty member of the USC Norris Comprehensive Cancer Center and senior author of the study. "While scientists all around the world are working on developing new drugs using NK cells, none of the drugs in development focuses on epigenetic regulation of the cells. Our study describes how an epigenetic process involving the enzyme MYSM1 plays a critical role in the development of natural killer cells."

Epigenetics involve biochemical changes in the body that directly affect DNA, turning some genes on and turning others off. MYSM1 is an enzyme in the body's immune system that turns genes on and off by modifying proteins called histones embedded in DNA.

Through a series of experiments in mice, Chen and his colleagues demonstrate that MYSM1 is required for natural killer cells to mature and function properly.

"We found that MYSM1 creates access to proteins that enhance gene transcription and, ultimately, the maturation of natural killer cells themselves," said Vijayalakshmi Nandakumar, a Ph.D. student at the Keck School of Medicine of USC and the study's first author. "To date, there are no elaborate reports linking an epigenetic phenomenon to natural killer cell development. More importantly, unlike conventional therapies, NK cell-based therapies have shown to be more effective against metastasis. We believe cancer drugs targeting this pathway could be a viable option for future immunotherapies."

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The above story is based on materials provided by University of Southern California - Health Sciences, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. V. Nandakumar, Y. Chou, L. Zang, X. F. Huang, S.-Y. Chen. Epigenetic control of natural killer cell maturation by histone H2A deubiquitinase, MYSM1. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1308888110

Note: If no author is given, the source is cited instead.

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Adjust the cells of the USC scientists ID protein anticancer therapy, human trafficking and potential.

Molecular microbiologist South California University （ USC Norris Comprehensive Cancer Center home ） but could lead to treatment for cancer and other disease treatment within a cell complex control mechanisms have been found. Have significance over the years on basic understanding of cell biology, their findings appear in the journal nature cell biology.

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Researchers discover a new way that influenza can infect cells

Sep. 23, 2013 — Scientists at Fred Hutchinson Cancer Research Center have uncovered a new mechanism by which influenza can infect cells -- a finding that ultimately may have implications for immunity against the flu.

Influenza viruses have two main proteins on their surface that allow them to do their dirty work: a protein called hemagglutinin allows viruses to infect cells, while a protein called neuraminidase allows viruses to escape from cells.

Now in a paper published online ahead of the December print issue of the Journal of Virology, Jesse Bloom, Ph.D., an evolutionary biologist and assistant member of the Fred Hutch Basic Sciences Division, and Kathryn Hooper, a graduate research assistant in the Bloom Lab, describe the discovery of an influenza virus that instead uses neuraminidase to attach to cells.

The researchers discovered the new mechanism of infection after mutating the hemagglutinin of a lab-adapted strain of influenza so that it could no longer attach to cells.

"We expected that viruses with the mutated hemagglutinin wouldn't be able to infect cells," said Bloom, who also is a computational biologist and an assistant member of the Fred Hutch Public Health Sciences Division. "So we were surprised when a virus with this hemagglutinin started to grow. We were even more surprised when we sequenced the virus and discovered that it had evolved a mutation in neuraminidase."

Hooper began characterizing the new virus in detail. She discovered that the mutation allowed neuraminidase to attach the virus to cells. Hemagglutinin's ability to bind to cells -- long considered one of the protein's most crucial and conserved properties -- was no longer necessary for infection.

What does this finding mean for influenza in humans? That remains an open question, but Bloom and Hooper have already shown that the neuraminidase mutation they discovered is present in some human isolates of influenza.

"This was not a mutation we expected to find in the lab, let alone in viruses that have infected humans over the past few years," Hooper said. "It suggests there is influenza circulating in nature that may be infecting cells by a mechanism that has been overlooked by others in the field."

The researchers are now carefully characterizing human influenza isolates that have the mutation. They are also looking for other mutations that allow neuraminidase to attach viruses to cells.

They say there is a possibility that these types of mutations may have implications for immunity against influenza, since they might enable the virus to escape from antibodies that block the binding of hemagglutinin to cells.

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Cancer cells supported by normal cells in and near tumors

Sep. 19, 2013 — Cold Spring Harbor Laboratory -- Investigators at Cold Spring Harbor Laboratory (CSHL) today report important progress in research aimed at finding ways to fight cancer by targeting the local environment in which tumors grow and from which they draw sustenance.

The targeting of interactions between cancer cells and their environment together with the traditional tactic of directly targeting cancer cells with drugs or radiation is an important new front in the fight against cancer.

The study was conducted by two CSHL scientists from different disciplines who joined forces in the Laboratory's tradition of collaborative research. Mikala Egeblad, Ph.D., is an expert in the analysis of interactions between cancer cells and normal cells, and Scott Powers, Ph.D., is an expert in applying genome-wide "big-picture" methods to the study of cancer.

Together, they decided to make the first systematic effort to catalog the repertoire of interactions between cancer cells and their environment and to determine how many of these interactions were involved in promoting cancer. In previous studies, different types of cancers and different types of normal cells were utilized; this work brought to light a bewildering array of potential targets. This made it difficult to know how best to proceed with the development of new therapies directed against the tumor environment.

Powers and Egeblad determined that even when focusing only on the signals between breast cancer cells and just one single cell type in the local environment (called fibroblasts), the majority of these signals promoted cancer. Interestingly, each signal that was closely studied had a different impact on breast tumors: one contributed to cancer cell survival, another to proliferation, and a third to inflammation and the growth of local blood vessels (both of which support tumors). Further experiments showed that when several of these signals were blocked at once, the inhibiting effect on tumor growth was greater than when individual signals were blocked.

"This tells us that tumor and normal cells interact as a complex network and that the hope of finding a 'single most important interaction' for therapeutic targeting is misguided," Powers commented. "When dealing with something that is this biologically complex, it is really important to assess the entire set of signals involved, rather than just one."

Dr. Egeblad added: "The good news from our study is that we can probably make much better progress at fighting cancer by targeting multiple interactions between tumors and their local environment."

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Researchers identify switch that controls growth of most aggressive brain tumor cells

Sep. 20, 2013 — Researchers at UT Southwestern Medical Center have identified a cellular switch that potentially can be turned off and on to slow down, and eventually inhibit the growth of the most commonly diagnosed and aggressive malignant brain tumor.

Findings of their investigation show that the protein RIP1 acts as a mediator of brain tumor cell survival, either protecting or destroying cells. Researchers believe that the protein, found in most glioblastomas, can be targeted to develop a drug treatment for these highly malignant brain tumors. The study was published online Aug. 22 in Cell Reports.

"Our study identifies a new mechanism involving RIP1that regulates cell division and death in glioblastomas," said senior author Dr. Amyn Habib, associate professor of neurology and neurotherapeutics at UT Southwestern, and staff neurologist at VA North Texas Health Care System. "For individuals with glioblastomas, this finding identified a target for the development of a drug treatment option that currently does not exist."

In the study, researchers used animal models to examine the interactions of the cell receptor EGFRvIII and RIP1. Both are used to activate NFκB, a family of proteins that is important to the growth of cancerous tumor cells. When RIP1 is switched off in the experimental model, NFκB and the signaling that promotes tumor growth is also inhibited. Furthermore, the findings show that RIP1 can be activated to divert cancer cells into a death mode so that they self-destruct.

According to the American Cancer Society, about 30 percent of brain tumors are gliomas, a fast-growing, treatment-resistant type of tumor that includes glioblastomas, astrocytomas, oligodendrogliomas, and ependymomas. In many cases, survival is tied to novel clinical trial treatments and research that will lead to drug development.

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Cutting off all points of escape for melanoma cells

Sep. 19, 2013 — Despite the success of recent approved therapeutics to treat advanced melanoma, metastatic cancer cells inevitably evolve resistance to drugs. In the journal Cell Reports, a team of researchers based at The Wistar Institute, report on the mechanics by which melanoma can evolve resistance to a powerful combination of drugs -- BRAF and MEK inhibitors.

They found that resistant melanomas acquired a mutation in the MEK2 gene and multiple copies of the mutant BRAF oncogene, simultaneously decreasing the sensitivity to both drug targets. Their findings also uncovered a new potential target for melanoma therapy, a protein called S6K. Additionally, early studies in a laboratory model for melanoma show that a triple combination of drug inhibitors halted the growth of resistant tumors.

"Melanoma tumors are particularly adept at rewiring themselves so that anticancer drugs lose their effectiveness, and we must continue to outthink the disease in order to block off all points at which it can evade therapy," said Jessie Villanueva, Ph.D., assistant professor in Wistar's NCI-designated Cancer Center and member of The Wistar Institute Melanoma Research Center. "There are currently therapeutics available that can block the pathway that leads to S6K, but we are also interested in developing inhibitors to S6K itself."

Melanoma is the deadliest, most aggressive form of skin cancer. While surgical treatment of early-stage melanoma leads to 90 percent cure rates, advanced melanoma is notoriously resistant to chemotherapy and has a tendency to metastasize, or spread, throughout the body. According to the World Health Organization, cases of the disease continue to rise internationally, which has helped spur research into therapies such as BRAF and MEK inhibitors.

BRAF inhibitors were developed in response to discoveries that a specific mutation in the BRAF gene was responsible for nearly 50 percent of melanoma cases. The BRAF protein is part of the MAP kinase pathway, a chain of enzymatic reactions -- including the enzyme MEK -- that is commonly over-activated in cancers.

"Combining BRAF and MEK inhibitors was conceived as a one-two punch against the MAP kinase pathway," Villanueva said, "and while it is considered successful in the clinic, some tumors do not respond and others develop resistance, underscoring the need for new therapeutic strategies."

As cancer clinicians began to see patients develop resistance to BRAF and MEK inhibitors, the Wistar team began to explore the mechanisms by which tumors develop resistance. They found that melanoma cells used different tactics for each enzyme. Mutations in MEK2, for example, would render anti-MEK therapies ineffective. To defeat BRAF inhibitors, surviving melanoma cells exhibited numerous copies of the mutant BRAF gene, enough to overpower anti-BRAF drugs.

"There were simply too many copies of BRAF to block, it became a numbers game and the mutation was winning," Villanueva said. "Increasing the dosage of BRAF inhibitors could be one solution, but that cannot be done in patients without causing serious toxic effects."

A possible answer, they reasoned, was in the PI3K/mTOR pathway, a network of signaling enzymes often active within melanoma cells. However, they could find no sign that any of the "usual suspects" -- points along the pathway commonly known to be involved in cancers -- had any evident part in BRAF/MEK resistance. It was not until they examined farther "downstream" that they found persistent activation of S6K, an enzyme that appears to be at the point where P13K/mTOR and MAP kinase pathways merge.

So the researchers tried combinations of inhibitors against BRAF, MEK and PI3K/mTOR (as there are currently no effective S6K inhibitors) in a mouse model of melanoma. "With a triple combination of drugs, the tumors slow down and just stop growing," Villanueva explained.

Although a cocktail of two drugs (a combination of BRAF and PI3K/mTOR inhibitors, for example) might work, they postulated that using three drugs could be more potent and counter intuitively less toxic at the same time. "We followed these mice with melanoma for three weeks, tumors remain stable, and mice did not show any evident signs of toxicity, " Villanueva said

"For patients, it is not a simple matter of introducing triple combination therapies into use," Villanueva said, " but now we have a mechanism and a rational approach to develop both new drugs and more effective combinations aimed at solving drug resistance in melanoma. Our findings might also offer important lessons for other forms of metastatic cancer."

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A protein that can mean life or death for cells

Sep. 17, 2013 — Each cell in an organism has a sensor that measures the health of its "internal" environment. This "alarm" is found in the endoplasmic reticulum (ER), which is able to sense cellular stress and trigger either rescue responses or the death of the cell. A team from the Institute for Research in Biomedicine (IRB), in Barcelona, has discovered that the protein Mitofusin 2 (Mfn2) plays a crucial role in correctly measuring stress levels, and also makes sure the pathways of cell repair or cell death are effective.

The researchers reveal some of the molecular mechanisms that connect Mfn2 to endoplasmic reticulum stress in the latest edition of the scientific journal, EMBO Journal, from the Nature Group, published by the European Molecular Biology Organization.

When the scientists removed Mfn2 from the cell under conditions of cell stress, the endoplasmic reticulum responded by over-activating the repair pathways. By doing so, it contradictorily functioned worse, reducing the capacity of cells to overcome the stress insult and promoting to a lesser degree apoptotic cell death. "When Mfn2 is removed, the cellular stress response pathways are completely disrupted," says Antonio Zorzano, coordinator of IRB's Molecular Medicine Programme and leader of the group "Heterogenic and polygenic diseases."

Not only diabetes

Mfn2 is a mitochondrial protein whose deficiency is related to diabetes. In an earlier publication in Proceedings of the National Academy of Sciences (PNAS), Dr. Zorzano's research team demonstrated that without Mfn2, tissues become resistant to insulin, a characteristic of diabetes and the so-called metabolic syndrome. In this study, they also observed that the cells had higher endoplasmic reticulum stress.

The current study investigates the relationship between mitochondria and the endoplasmic reticulum, and indicates that changes in mitochondria, caused by the loss of the Mfn2 protein, directly affect the endoplasmic reticulum function. "We have shown that Mfn2 is important for cell viability and has implications for numerous diseases, such as neurodegeration, cancer, cardiovascular disease, in addition to diabetes," says postdoctoral researcher Juan Pablo Munoz, first author of the study.

Is Mitofusin 2 a good therapeutic target?

"The fact that we can modulate cell damage response with Mfn2 opens a wide window of possible therapeutic avenues for further study," says Munoz. The Chilean scientist at IRB explains that tumour cells don't activate cell death properly and proliferate uncontrolled. "Cancer cells have already been noted to have low Mfn2 levels, and if we could increase such levels, we would be able to promote apoptosis," he continues. According to this, other research teams have already published work indicating that the overexpression of Mfn2 induce apoptosis.

To demonstrate the utility of Mfn2 as a target, the researchers now need to find a small molecule, or drug, that modulates its expression in animals. "Our work published on Mfn2 is a proof of concept that highlights the importance of this mitochondrial protein for cell health," says Zorzano. One of the challenges of the group is to secure funding to perform a massive screening of molecules with the ability to modulate Mfn2 expression and confirm its effects in mice.

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Pancreatic stem cells isolated from mice

Sep. 17, 2013 — Scientists have succeeded in growing stem cells that have the ability to develop into two different types of cells that make up a healthy pancreas. The research team led by Dr. Hans Clevers of the Hubrecht Institute, The Netherlands, have isolated and grown stem cells from the pancreases of mice using a 3-D culture system previously developed by the scientists. The results, which are reported in The EMBO Journal, could eventually lead to ways to repair damaged insulin-producing beta cells or pancreatic duct cells.

Cell signalling molecules known as Wnts and a protein called Lgr5 are essential to produce adult stem cells that can be coaxed to grow and divide rapidly. However, these signaling pathways and molecules are inactive in the adult pancreas. "We have found a way to activate the Wnt pathway to produce an unlimited expansion of pancreatic stem cells isolated from mice," Clevers said. "By changing the growth conditions we can select two different fates for the stem cells and generate large numbers of either hormone-producing beta cells or pancreatic duct cells." He added: "This work is still at a very early stage and further experiments are needed before we can use such an approach for the culture of human cells but the results are a promising proof-of-concept."

In the study, the pancreases of mice were altered in a way that makes duct cells proliferate and differentiate. Some cells in this new population were stem cells that were capable of self-renewal. The scientists were able to culture these cells to give rise to large numbers of pancreatic cells or tiny clumps of tissue referred to as organoids.

Therapeutic strategies for pancreatic disease have been hampered by a lack of cell culture systems that allow scientists to grow replacement tissue in a test tube or on a dish. Alternative approaches such as tissue transplantation are limited by the scarcity of donors and the possibility of tissue rejection. The new work offers access to an unlimited supply of pancreatic stem cells that would be beneficial for the development of new therapeutic interventions for pancreatic diseases like diabetes.

The next steps for the scientists will include further refinement of the cell culture methods developed in this study and investigation of ways to extend the approach to human pancreatic cells.

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The above story is based on materials provided by EMBO - excellence in life sciences.

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Journal Reference:

1. Meritxell Huch, Paola Bonfanti, Sylvia F Boj, Toshiro Sato, Cindy J M Loomans, Marc van de Wetering, Mozhdeh Sojoodi, Vivian S W Li, Jurian Schuijers, Ana Gracanin, Femke Ringnalda, Harry Begthel, Karien Hamer, Joyce Mulder, Johan H van Es, Eelco de Koning, Robert G J Vries, Harry Heimberg, Hans Clevers. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. The EMBO Journal, 2013; DOI: 10.1038/emboj.2013.204

Note: If no author is given, the source is cited instead.

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'Vicious cycle' shields, spreads cancer cells

Sep. 16, 2013 — A "vicious cycle" produces mucus that protects uterine and pancreatic cancer cells and promotes their proliferation, according to researchers at Rice University. The researchers offer hope for a therapeutic solution.

They found that protein receptors on the surface of cancer cells go into overdrive to stimulate the production of MUC1, a glycoprotein that forms mucin, aka mucus. It covers the exposed tips of the elongated epithelial cells that coat internal organs like lungs, stomachs and intestines to protect them from infection.

But when associated with cancer cells, these slippery agents do their jobs too well. They cover the cells completely, help them metastasize and protect them from attack by chemotherapy and the immune system.

Details of the new work led by biochemist Daniel Carson, dean of Rice's Wiess School of Natural Sciences, appear in the Journal of Cellular Biochemistry.

In the paper, Carson, lead author Neeraja Dharmaraj, a postdoctoral researcher, and graduate student Brian Engel described MUC1 overexpression as particularly insidious not only for the way it protects tumor cells and promotes metastasis, but also because the cells create a feedback loop in which epidermal growth factor receptors (EGFR) and MUC1 interact to promote each other.

Carson described EGFR as a powerful transmembrane protein that stimulates normal cell growth, proliferation and differentiation. "What hadn't been considered is whether this activated receptor might actually promote the expression of MUC1, which would then further elevate the levels of EGFR and create this vicious cycle.

"That's the question we asked, and the answer is 'yes,'" he said.

Carson compared mucus to Teflon. "Things don't stick to it easily, which is normally what you want. It's a primary barrier that keeps nasty stuff like pathogenic bacteria and viruses from getting into your cells," he said.

But cancer cells "subvert systems and find ways to get out of control," he said. "They auto-activate EGFR by making their own growth factor ligands, for example, or mutating the receptor so it doesn't require the ligand anymore. It's always on."

Mucin proteins can then cover entire surface of a cell. "That lets (the cell) detach and move away from the site of a primary tumor," while still preventing contact with immune system cells and cytotoxins that could otherwise kill cancer cells, Carson said.

Hope comes in the form of a controversial drug, rosiglitazone, in the thiazolidinedione class of medications used in diabetes treatment, he said. The drug is suspected of causing heart problems over long-term use by diabetes patients. But tests on cancer cell lines at Rice found that it effectively attenuates the activation of EGFR and reduces MUC1 expression. That could provide a way to weaken the mucus shield.

"Chronic use of rosiglitazone can produce heart problems in a subset of patients, but if you're dying of pancreatic cancer, you're not worried about the long term," Carson said. "If you can reduce mucin levels in just a few days by using these drugs, they might make cancer cells easier to kill by established methods."

He said more work is required to see if rosiglitazone or some variant is suitable for trials. "We think it's best to understand all the effects," he said. "That might give us a rational way to modify these compounds, to avoid unwanted side effects and focus on what we want them to do."

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Molecular structure reveals how HIV infects cells

Sep. 12, 2013 — In a long-awaited finding, a team of Chinese and US scientists has determined the high-resolution atomic structure of a cell-surface receptor that most strains of HIV use to get into human immune cells. The researchers also showed where maraviroc, an HIV drug, attaches to cells and blocks HIV's entry.

"These structural details should help us understand more precisely how HIV infects cells, and how we can do better at blocking that process with next-generation drugs," said Beili Wu, PhD, professor at the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences. Wu was the senior investigator for the study, which was published in Science Express on September 12, 2013.

The study, which focused on the CCR5 receptor, was supported by both US and Chinese research funding agencies. "International collaborations like this one are increasingly needed to solve big problems in science," said study co-author Raymond C. Stevens, PhD, a professor at The Scripps Research Institute (TSRI) in California. "Now that we have both human CXCR4 and CCR5 HIV co-receptor three-dimensional structures, it is likely we will see the next generation of HIV therapeutics."

A Major Target

The CCR5 receptor is one of the most sought-after targets for new anti-HIV drugs. Although the AIDS-causing virus was initially discovered to infect cells via another receptor, CD4, researchers found in 1996 that HIV infection also requires a co-receptor -- usually CCR5, which sits alongside CD4 on a variety of immune cells.

CCR5's importance to HIV infection is underscored by the fact that certain genetic variants of it can dramatically raise or lower HIV infection risk, as well as the speed of the disease process after infection. One shortened CCR5 variant, found in about 10 percent of Europeans, is not expressed at all on immune cell surfaces -- and people who produce only this variant are almost invulnerable to HIV infection.

Scientists therefore have sought to develop anti-HIV drugs that block the virus from binding to CCR5 or otherwise render the receptor inactive. Yet only a handful of CCR5-inhibiting compounds have been developed so far -- and no one knows exactly how they work. "One thing that we've lacked is a high-resolution molecular 'picture' of the CCR5 receptor structure that we can use for precise drug design," Wu said.

A Six-Year Quest

Wu came to the Stevens laboratory at TSRI in 2007 to conduct postdoctoral research on the two HIV co-receptors, CCR5 and the alternate HIV co-receptor CXCR4. A minority of HIV strains use CXCR4 instead of CCR5 as a co-receptor with CD4 for their initial infiltration of cells.

"Her goal from the beginning was to determine the structures and understand the functions of these two HIV co-receptors and she was very determined which was inspiring," said Stevens.

Wu spent her postdoctoral years focusing on CXCR4, which posed fewer technical challenges than CCR5. Her landmark study of the CXCR4 structure was published in Science in 2010. After moving back to China to start her own laboratory at SIMM, she returned to the "unfinished business" of the CCR5 structure.

Both CCR5 and CXCR4 belong to a large family of cell receptors known as G protein-coupled receptors (GPCRs). GPCRs are notoriously hard to produce in useful amounts for structural analysis. With their floppy structures, they are also very hard to coax into the ordered, solid lineups of individual molecules -- "crystals" -- needed for structure determination by X-ray crystallography. Eventually, however, with help from insights gained during the CXCR4 project, Wu, as a new professor, and her young team of students used a novel "fusion partner" molecule that would hold CCR5 proteins together enough to form usable crystals, together with efforts of computational modeling, compound synthesis and cell signaling assays from Drs. Hualiang Jiang, Hong Liu and Xin Xie's groups at SIMM, which led to the structure determination of CCR5.

As in most receptor-structure projects, Wu and her colleagues further stabilized CCR5 with a compound that is known to bind to it, in this case the Pfizer drug maraviroc (sold under the brand name SelzentryR or CelsentriR outside the US). Marketed for HIV infection since 2007, maraviroc grabs hold of CCR5 in a way that prevents HIV from using the receptor to get into cells. "Maraviroc was thought to lock CCR5 into an inactive conformation, and so we wanted to 'see' that conformation at high resolution," said Wu.

The resulting crystallography data provided that fine-grained picture of CCR5's HIV-resistant conformation. The data also revealed maraviroc's precise binding site on CCR5 -- a site from which the drug molecule clearly influences how the receptor works, even though it is separate from the sites on the receptor that are thought to be used by HIV. The maraviroc binding site is also different from the site used by CCR5's natural binding-partners, a set of immune proteins called chemokines. Maraviroc thus appears to work against HIV indirectly -- not by physically blocking the virus, but by locking the receptor structure into an HIV-insensitive conformation.

"Structural details can offer tremendous insight into how proteins and drugs work, also aiding the development of therapeutic agents," said Peter Preusch, PhD, of the National Institute of General Medical Sciences, which helped fund the research along with another component of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases. "This study provides knowledge about the interactions between maraviroc and CCR5, a target for anti-HIV therapy, that helps us understand how the drug works at the molecular level and could enable further explorations of HIV biology and approaches to improve drugs targeting such interactions."

Useful Insights

Comparison of the CCR5 structure with the previously determined CXCR4 structure also provided hints about an important aspect of HIV evolution during infections. Most HIV infections start by using only CCR5 as a co-receptor for cell entry, but in time the virus often switches its co-receptor usage from CCR5 to CXCR4. That opens up more cell types to HIV infection, and the further spread of the virus inside the body is liable to speed up the disease progression towards full-blown AIDS and death.

The new data suggest that the distinction between CCR5 and CXCR4 as co-receptors for HIV infection boils down to relatively subtle differences in structural shapes and electric charge distributions in the HIV binding region -- differences that will be of interest to HIV drug developers.

"Knowing the CXCR4 structure and now the CCR5 structure at this level of detail should accelerate the development of drugs that can block HIV by using both of these co-receptors," said Wu.

She and her colleagues now plan to follow up with structural studies of CCR5 and CXCR4 in complex with the HIV envelope protein gp120 and CD4 to obtain even more informative pictures of the process of viral infection.

Soon after the structure determination of CCR5, SIMM performed structure-based drug design and has obtained several drug lead compounds with more potent antiviral efficacies than maraviroc, which further proves the importance of CCR5 structure on the development of HIV theraputics.

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University of Southern California researchers find molecular quiets cancer cells chatter

While braking tumor cancer cell growth of the University of Southern California researchers discovered new complex interrupt conversations.

Learn to read the full text of the press release.

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Among the research institutions in NCI funding, all over the United States that current cancer specifies 68 as a Center. Based at research universities, these facilities are cancer's origin and development of intense laboratory research wide range, the scientists from NCI support many home. Cancer Center program is also focused on cross-cutting research, population Sciences, and clinical research please. Center for research results are often at the forefront of cancer research.

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