Tagged: Cancer Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 10:09 am on September 16, 2016 Permalink | Reply
    Tags: , Cancer, ,   

    From MIT: “High-capacity nanoparticle” 

    MIT News
    MIT News
    MIT Widget

    September 14, 2016
    Anne Trafton | MIT News Office

    Human colorectal cancer cells. Image: NCI Center for Cancer Research

    Particles that carry three or more drugs hold potential for targeted cancer therapy.

    Nanoparticles offer a promising way to deliver cancer drugs in a targeted fashion, helping to kill tumors while sparing healthy tissue. However, most nanoparticles that have been developed so far are limited to carrying only one or two drugs.

    MIT chemists have now shown that they can package three or more drugs into a novel type of nanoparticle, allowing them to design custom combination therapies for cancer. In tests in mice, the researchers showed that the particles could successfully deliver three chemotherapy drugs and shrink tumors.

    In the same study, which appears in the Sept. 14 issue of the Journal of the American Chemical Society, the researchers also showed that when drugs are delivered by nanoparticles, they don’t necessarily work by the same DNA-damaging mechanism as when delivered in their traditional form.

    That is significant because most scientists usually assume that nanoparticle drugs are working the same way as the original drugs, says Jeremiah Johnson, the Firmenich Career Development Associate Professor of Chemistry and the senior author of the paper. Even if the nanoparticle version of the drug still kills cancer cells, it’s important to know the underlying mechanism of action when choosing combination therapies and seeking regulatory approval of new drugs, he says.

    “People tend to take it as a given that when you put a drug into a nanoparticle it’s the same drug, just in a nanoparticle,” Johnson says. “Here, in collaboration with Mike Hemann, we conducted detailed characterization using an RNA interference assay that Mike developed to make sure the drug is still hitting the same target in the cell and doing everything that it would if it weren’t in a nanoparticle.”

    The paper’s lead authors are Jonathan Barnes, a former MIT postdoc; and Peter Bruno, a former MIT graduate student. Other authors are grad students Hung Nguyen and Jenny Liu, former postdoc Longyan Liao, and Michael Hemann, an associate professor of biology and member of MIT’s Koch Institute for Integrative Cancer Research.

    Precise control

    The new nanoparticle production technique, which Johnson’s lab first reported in 2014, differs from other methods that encapsulate drugs or chemically attach them to a particle. Instead, the MIT team creates particles from building blocks that already contain drug molecules. They can join the building blocks together in a specific structure and precisely control how much of each drug is incorporated.

    “We can take any drug, as long as it has a functional group [a group of atoms that allows a molecule to participate in chemical reactions], and we can load it into our particles in exactly the ratio that we want, and have it release under exactly the conditions that we want it to,” Johnson says. “It’s very modular.”

    A key advantage is that this approach can be used to deliver drugs that normally can’t be encapsulated by traditional methods.

    Using the new particles, the researchers delivered doses of three chemotherapy drugs — cisplatin, doxorubicin, and camptothecin — at concentrations that would be toxic if delivered by injection throughout the body, as chemotherapy drugs usually are. In mice that received this treatment, ovarian tumors shrank and the mice survived much longer than untreated mice, with few side effects.

    “Performing combination chemotherapy using these new designer polymer nanoparticles is an exciting new approach to chemotherapeutics, and this polymer platform is particularly promising for its ability to carry a large load of drugs and deliver them in a triggered, controlled manner,” says Todd Emrick, a professor of polymer science and engineering at the University of Massachusetts at Amherst who was not involved in the study.

    Unexpected mechanism

    Using a method developed by Hemann’s lab, the researchers then investigated how their nanoparticle drugs affect cells. The technique measures cancer drugs’ effects on eight genes that are involved in the programmed cell death often triggered by cancer drugs. This allows scientists to classify the drugs based on which clusters of genes they affect.

    “Drugs that damage DNA get clustered into DNA damage-inducing agents, and drugs that inhibit topoisomerases cluster together in another region,” Johnson says. “If you have a drug that you don’t know the mechanism of, you can do this test and see if the drug clusters with other drugs whose actions are known. That lets you make a hypothesis about what the unknown drug is doing.”

    The researchers found that nanoparticle-delivered camptothecin and doxorubicin worked just as expected. However, cisplatin did not. Cisplatin normally acts by linking adjacent strands of DNA, causing damage that is nearly impossible for the cell to repair. When delivered in nanoparticle form, the researchers found that cisplatin acts more like a different platinum-based drug known as oxaliplatin. This drug also kills cells, but by a different mechanism: It binds to DNA but induces a different pattern of DNA damage.

    The researchers hypothesize that after cisplatin is released from the nanoparticle, via a reaction that kicks off a group known as a carboxylate, the carboxylate group then reattaches in a way that makes the drug act more like oxaliplatin. Many other researchers attach cisplatin to nanoparticles the same way, so Johnson suspects this could be a more widespread issue.

    His lab is now working on a new version of the cisplatin nanoparticle that operates according to the same mechanism as regular cisplatin. The team is also developing nanoparticles with different combinations of drugs to test against pancreatic and other types of cancers.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    MIT Seal

    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

    MIT Campus

  • richardmitnick 7:59 pm on September 12, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Rice: “New tools join breast cancer fight” 

    Rice U bloc

    Rice University

    Sept. 12, 2016
    Jeff Falk

    Mike Williams

    International team finds existing drug may halt tumor growth, points way toward more effective treatments

    An international team including Rice University researchers has discovered a way to fight the overexpression of a protein associated with the proliferation of breast cancer.

    Dialing down the level of the protein NAF-1 and the activity of the iron-sulfur clusters it transports may be key to halting tumor growth, they reported.

    In a study this week in the Proceedings of the National Academy of Sciences, the researchers suggest a drug that is typically used to treat type 2 diabetes, pioglitazone, has proven effective at controlling NAF-1 levels.

    They also discovered that a single mutation to NAF-1 almost completely blocked the ability of cancer cells to proliferate, a result they said supports the idea that lowering NAF-1 expression can help stop tumors.

    Fine-tuning the drug to specifically address tumors could bring a new weapon to the battle against breast cancer and other cancers, the researchers said. Overexpression of NAF-1 also has been associated with prostate, gastric, cervical, liver and laryngeal cancer, they said.

    José Onuchic, Rice’s Harry C. and Olga K. Wiess Chair of Physics and professor of physics and astronomy and co-director of the Center for Theoretical Biological Physics (CTBP), worked with Rice research scientist Mingyang Lu, Rice postdoc Fang Bai and scientists from Israel, the University of California, San Diego (UCSD) and the University of North Texas on a multifaceted approach to define the role of NAF-1 in breast cancers.

    Understanding the mechanism will help the Rice researchers improve computer simulations to aid in the rapid design and testing of novel drugs, Onuchic said.

    NAF-1 is a member of the NEET family of proteins; these proteins transport clusters of iron and sulfur molecules inside cells. The clusters help regulate processes in cells by controlling reduction-oxidation (redox) and metabolic activity. They naturally adhere to the outer surface of the mitochondria, the “power plant” that supplies cells with chemical energy.

    Experiments demonstrated that the overexpression of NAF-1 in breast cancer tumors enhanced cancer cells’ ability to tolerate oxidative stress. That enhancement allowed the tumors to become much larger and more aggressive, said Ron Mittler, a professor of biological sciences at the University of North Texas.

    “Now that we know tumors that overexpress this protein are more sensitive to this type of drug, we can design new drugs in a way that will attack the clusters,” Mittler said.

    NAF-1 “is kind of like a seesaw,” said Patricia Jennings, a CTBP affiliate and a professor of chemistry and biochemistry at UCSD. “It’s a sensor that tells your cells when they’re getting out of balance and works very hard to bring them back. But once they get a little too far out of balance, the cells can die.”

    Treating the tumors with pioglitazone stabilized the iron-sulfur clusters in NAF-1, reducing the tumors’ tolerance to oxidation. “We now have examples of five or six different types of tumors that need this protein to proliferate,” Mittler said. “If they don’t have it, they die.”

    The team also discovered through experiments that expression of an NAF-1 protein that carried a single-point mutation had a similarly toxic effect on cancer cells and prevented tumor proliferation.

    Study co-author Rachel Nechushtai, a professor at the Hebrew University of Jerusalem, said tumors depend on the lability, or the transient nature, of the clusters. “The more NAF-1 you make, and the more its clusters can be transferred, the bigger the tumor develops.

    “We knew from previous studies that pioglitazone stabilizes the cluster. With the mutant, we hardly got any tumors and didn’t see angiogenesis (the process through which new blood vessels form). When we did see tumors, they were white, not red, because they had no blood vessels.

    “We thought, ‘How do we connect this to the clinics?’ The only connection was to try a drug that, like the mutation, also stabilizes the cluster,” she said. “Fang showed in her simulations where the binding site is and why the drug stabilizes the cluster.”

    “This is where the initial results from Fang are very nice, because she can show exactly how to modify the drug,” said Onuchic, whose lab specializes in predicting protein folding pathways through computer modeling. “That way, one can computationally design the drug before trying to make the real drug. It’s a much less expensive way to come up with possibilities.”

    Bai said, “We can design selective drugs that only bind to NAF-1 and not to other proteins to reduce the side effects based on our new method.”

    Lu, Merav Darash-Yahana of Hebrew University of Jerusalem and Yair Pozniak of Tel Aviv University are lead authors of the paper. Co-authors are Yang-Sung Sohn, Ola Karmi and Sagi Tamir of Hebrew University of Jerusalem, Luhua Song of the University of North Texas, Eli Pikarsky of the Hebrew University-Hadassah Medical School and Tamar Geiger of Tel Aviv University.

    The research was supported by the Israel Science Foundation, the University of North Texas College of Arts and Sciences, the Israel Cancer Research Fund, the National Science Foundation, the Cancer Prevention and Research Institute of Texas, the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia, the Welch Foundation and the National Institutes of Health.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Rice U campus

    In his 1912 inaugural address, Rice University president Edgar Odell Lovett set forth an ambitious vision for a great research university in Houston, Texas; one dedicated to excellence across the range of human endeavor. With this bold beginning in mind, and with Rice’s centennial approaching, it is time to ask again what we aspire to in a dynamic and shrinking world in which education and the production of knowledge will play an even greater role. What shall our vision be for Rice as we prepare for its second century, and how ought we to advance over the next decade?

    This was the fundamental question posed in the Call to Conversation, a document released to the Rice community in summer 2005. The Call to Conversation asked us to reexamine many aspects of our enterprise, from our fundamental mission and aspirations to the manner in which we define and achieve excellence. It identified the pressures of a constantly changing and increasingly competitive landscape; it asked us to assess honestly Rice’s comparative strengths and weaknesses; and it called on us to define strategic priorities for the future, an effort that will be a focus of the next phase of this process.

  • richardmitnick 7:46 pm on September 12, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Princeton: “Stiff and oxygen-deprived tumors promote spread of cancer” 

    Princeton University
    Princeton University

    September 12, 2016
    Rachel Nuwer for the Office of Engineering Communications

    When Hippocrates first described cancer around 400 B.C., he referred to the disease’s telltale tumors as “karkinos” — the Greek word for crab. The “Father of Western Medicine” likely noted that cancer’s creeping projections mirrored certain crustaceans, and the tumors’ characteristic hardness resembled a crab’s armored shell.

    Later, scientists added another attribute: Tumors are hypoxic. That is, they grow so large and dense that they exclude blood vessels, causing a lack of oxygen in their cores. But what role these characteristics play in the development of cancer has remained a mystery.

    Moving possibly one step closer to an answer, scientists from Princeton University and the Mayo Clinic Cancer Center have found that, in breast cancer, tumor hardness and hypoxia trigger a biological switch that causes certain cells to embark on a cancer-promoting program. Reported Aug. 8 in an article in the journal Cancer Research, this biological switch is critical to a tumors’ ability to invade other tissue, a process called metastasis — and could offer a promising treatment target.

    “Our study suggests that to combat cancer, we should be developing treatments that target the stiff, hypoxic regions of tumors,” said lead author Celeste Nelson, a professor of chemical and biological engineering. “We were surprised to see just how important these two properties in the tumor microenvironment — stiffness and hypoxia — were for regulating cancer stem cells.”

    Researchers from Princeton University and the Mayo Clinic Cancer Center have found specific conditions — tumor hardness and a lack of oxygen at the tumor’s core — that lead to breast-cancer progression in laboratory cultures. The illustration above shows non-spreading cancer cells without these conditions (left), while those that are stiff and hypoxic (right) are beginning to spread. (Image courtesy of Celeste Nelson, Department of Chemical and Biological Engineering)

    The specific cells triggered by stiffness and hypoxia are called cancer stem cells. These cells represent only a small proportion of the total cells in a tumor, but researchers believe they play a key role in spreading the disease. As normal stem cells help form an embryo, or aid in repairing muscles, cancer stem cells specialize in generating new malignant cells. In addition to spreading cancer, just 10 to 100 leftover cancer stem cells are needed to regenerate a tumor after it has been removed.

    Using cultures of human breast-cancer cells and mouse mammary-cancer cells, Nelson and colleagues from Princeton and the Mayo Clinic in Jacksonville, Florida, discovered an association between a protein called integrin-linked kinase and the creation of cancer stem cells. Normally, integrin-linked kinase assists cells with a variety of important cellular tasks. But in dense, oxygen-poor tumors, the protein’s function goes awry.

    In the lab, the researchers created a range of human and mouse breast-cancer cultures reflecting different tissue conditions. They showed that stiff hypoxic cultures did indeed promote cancer stem cells. But when they eliminated the integrin-linked kinase from those samples, they found that the cancer stem cells stopped forming. Conversely, when they forced abnormal levels of integrin-linked kinase in samples containing softer or less hypoxic tissue, cancer stem cells formed. They also confirmed a significant association between tumor stiffness, integrin-linked kinase and cancer stem cell presence in samples from human breast-cancer patients.

    “We could see tumor cells expressing cancer stem-cell markers and integrin-linked kinase located at regions with high collagen, which is used to estimate stiffness in a tumor,” says Mei-Fong Pang, a postdoctoral fellow in Nelson’s Tissue Morphodynamics Laboratory.

    The findings suggest that stiffness and hypoxia cause integrin-linked kinase to behave abnormally, which in turn triggers cancer stem-cell formation.

    There are likely other features in tumors that cause cancer stem cells to form, but the findings indicate that stiff, hypoxic conditions — and their effects on integrin-linked kinase — are two of the most prominent ones. This means the findings could be applicable for better understanding some types of cancer and for developing treatments for those characterized by solid tumors — including for more than just breast cancer.

    “These findings may lead to the identification of a new therapeutic target to halt cancer progression and metastasis,” said Ren Xu, an associate professor at the University of Kentucky’s Markey Cancer Center who is familiar with the study but had no role in it.

    “Given the crucial function of integrin-linked kinase in hypoxia and stiff-induced cancer progression, it is now critical to define the molecular mechanisms by which integrin-linked kinase expression is regulated under these conditions,” Xu said.

    Nelson and her colleagues plan to investigate the specific molecular pathways that promote the formation of cancer stem cells in the presence of rigidity, hypoxia and integrin-linked kinase. Building on that knowledge, treatments could eventually be created that specifically kill cancer stem cells. Finding a way to change conditions in the tumor itself could provide another solution.

    “If we can make the tumor softer or reduce hypoxia,” Nelson said, “we could potentially have a way to treat breast cancer and maybe other cancers as well.”

    The paper, “Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast cancer stem-like cells,” was published Aug. 8 in Cancer Research.

    This work was supported by grants from the National Institutes of Health (grant nos. GM083997, HL110335, HL118532, HL120142, CA187692); the National Science Foundation (grant no. CMMI-1435853); the NSF Graduate Research Fellowship program; the David and Lucile Packard Foundation; the Alfred P. Sloan Foundation; the Camille and Henry Dreyfus Foundation; and the Burroughs Wellcome Fund; postdoctoral fellowships from the Swedish Society for Medical Research and the New Jersey Commission on Cancer Research.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition
    Princeton University Campus

    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

    Princeton Shield

  • richardmitnick 5:52 am on September 10, 2016 Permalink | Reply
    Tags: , Cancer, ,   

    From Vanderbilt: “In search of new cancer targets” 

    Vanderbilt U Bloc

    Vanderbilt University

    Sep. 9, 2016
    Leigh MacMillan

    Molecularly heterogeneous cancers such as triple-negative breast cancer are challenging to treat, because they often lack the “driver” mutations that are targeted by the newest cancer therapies. These cancers exhibit genomic instability, resulting in chromosomal rearrangements and gene fusions, and identifying these alterations is technically difficult.

    Timothy Shaver and Brian Lehmann, Ph.D., working with Jennifer Pietenpol, Ph.D., developed a new algorithm, Segmental Transcript Analysis (STA), to predict gene rearrangements.

    Using STA, they identified multiple known and novel gene rearrangements in triple-negative breast cancer and then expanded their analysis to other malignancies using a cohort from The Cancer Genome Atlas.

    Two of the gene rearrangements that the team characterized in triple-negative breast cancer involve molecular targets for therapies already in clinical investigation or development.

    The findings, reported Aug. 15 in Cancer Research, provide evidence that STA is an effective prediction tool for gene rearrangements and highlight the need to advance gene fusion detection for molecularly heterogeneous cancers.

    This research was supported by grants from the National Institutes of Health (CA183531, GM008554, CA098131, CA105436, CA068485) and from the Susan G. Komen Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Vanderbilt Campus

  • richardmitnick 5:12 am on September 8, 2016 Permalink | Reply
    Tags: , Cancer, , , Venetoclax immunotherapy   

    From Science Alert: “The US has given fast-track approval to a surprising new cancer drug” 


    Science Alert

    7 SEP 2016

    Jarhe Photography/Shutterstock.com

    “Even when it’s killing cells, you feel great.”

    A new cancer drug called Venetoclax is causing quite a stir in the medical community, with the announcement that the US FDA has given it fast-track approval for the treatment of patients with chronic lymphocytic leukemia (CLL).

    CLL is one of the most common types of leukemia in adults, and during a recent clinical trial, 80 percent of patients treated with Venetoclax experienced complete or partial remission of their cancer.

    Developed in Australia over several decades, Venetoclax is taken in pill-form, and of the small sample of patients who have been treated with it so far, some reported no adverse side-effects at all.

    “It causes no side-effects. Nothing, absolutely nothing,” Robert Oblak, who had recurring CLL when he was selected to participate in the trial in 2013, told the ABC. “Quite amazing. So even when it’s killing cells, you feel great.”

    Oblak estimates that he was just the 11th person in the world to be treated with Venetoclax, and within a year of treatment, he went into remission.

    The phase II trial involved 107 patients aged 18 or older with CLL, who had undergone at least one type of treatment already.

    The patients also had to have a particular chromosome abnormality in their leukemia cells called 17p deletion, which means they’re lacking a portion of the chromosome that acts to suppress cancer growth.

    They were asked to take one Venetoclax pill per day for five weeks straight, with doses starting at 20 mg and gradually increasing to 400 mg.

    At the end of the trial, which involved patients and researchers from 31 centres in the US, Canada, the UK, Germany, Poland, and Australia, four out of five patients experienced a positive result, with complete remission reported for one in five.

    “These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumour cells alive,” Richard Pazdur from the FDA’s Centre for Drug Evaluation and Research, announced back in April.

    “For certain patients with CLL who have not had favourable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

    The results of the trial, which were published in The Lancet in June, informed the FDA’s decision to fast-track approval of the drug and make it available to patients in the US.

    Despite being developed by researchers at Australia’s Walter and Eliza Hall Institute of Medical Research, it’s not yet been approved for use by Australian patients, but an application has been made.

    So, how does the drug work? Venetoclax is one of a new generation of immunotherapy cancer drugs that are designed to address certain failings of a person’s own immune system – such as missing portions of chromosomes that inhibit the cells’ ability to fight the spread of cancer.

    In CLL patients with 17p deletion, malignant cells don’t proliferate all that much, but they don’t die, because the body’s immune response has been hindered, and abundant levels of a protein called BCL2 helps keep them alive.

    “Cells, when they are born, are destined to die and cancer cells and particularly leukaemia cells delay that death by using a protein called BCL2 that stops the normal time of death,” John Seymour from the Peter MacCallum Cancer Centre in Melbourne, who helped oversee the trial, told the ABC.

    “Venetoclax works by specifically blocking the action of that BCL2, and allows the cells to die in the way that they were destined to.”


    So rather than killing off the cancer cells – and a bunch of healthy cells in the vicinity – like current treatments like chemo and radiotherapy do, the drug reestablishes the balance of the body’s immune system, and effectively allows the cancer cells to die on their own.

    This explains why some patients, like Oblak can undergo treatment with no discernible side-effects. But let’s be clear – Oblak was very lucky.

    The FDA reports that, depending on the patient, side-effects from Venetoclax include low white blood cell count, diarrhoea, nausea, anaemia, upper respiratory tract infection, low platelet count, and fatigue. Serious complications can include pneumonia, fever, and death.

    During the Venetoclax trial, of the 107 patients, 11 ended up dying, seven because of the progression of their cancer, and four from adverse side-effects.

    Similar results were seen in a separate trial of a similar immunotherapy cancer drug, Ipilimumab, which has recently been approved for the Australian market.

    While Australian patient Greg Lawson was declared free from melanomas 12 months after treatment, and reportedly suffered “virtually no side-effects”, his wife, who was treated with a different melanoma immunotherapy drug at the same time, died when her body could not tolerate the treatment.

    “She had two sets of the treatment, but was so ill from the side-effects that the decision was made to take her off it,” Lawson told the ABC.

    But with immunotherapy drugs seeing “extraordinary” results in other trials this year, and with the possibility of a ‘universal cancer vaccine’ hanging in the air, this is just the beginning for the next generation of cancer treatment.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

  • richardmitnick 11:55 am on September 4, 2016 Permalink | Reply
    Tags: , , Cancer, Mitosis   

    From Brown: “Mitosis study finds potential cancer target” 

    Brown University
    Brown University

    August 30, 2016
    David Orenstein

    An unusual relationship. A rendering depicts the specific and unique interaction between proteins PP1-gamma and either RepoMan or Ki-67, which presents a potential target for cancer. Senthil Kumar/Brown University.

    By drilling down to the atomic level of how specific proteins interact during cell division, or mitosis, a team of scientists has found a unique new target for attacking cancer.

    Structural biologists show in a new study [eLife] that an apparently key step in the process of cell division depends on a unique interaction among specific proteins, including one that is strongly linked to cancer. Their hope now is that the detailed new characterization of the interaction will make it a target for exploring a new cancer therapy.

    Cell division, or mitosis, is a staple of high school biology classwork, but scientists are still making new discoveries about its intricate workings. Now, researchers have discovered that as copied chromosomes begin to exit mitosis and pull away from their sisters to form a new cell, a stage called anaphase, a protein called Ki-67 brings a protein called PP1 to the chromosomes.

    Mitosis is essential to life, but it is also a process that occurs to a runaway degree in cancer. And that made Ki-67 of particular interest to the authors of the new study, which appears in the journal eLife, because Ki-67 is highly expressed throughout the various stages of mitosis, said lead author Senthil Kumar, assistant professor (research) of molecular pharmacology, physiology and biotechnology at Brown University.

    “Ki-67 is a protein that is widely used as a prognostic marker in cancer biology,” Kumar said. “People use this as a marker to study how far cancer has progressed.”

    Along with fellow Brown faculty members Wolfgang Peti and Rebecca Page and colleagues from other institutions, Kumar therefore wanted to understand exactly how Ki-67 interacts with PP1 in anaphase to bring it to the chromosomes. It turns out that Ki-67 binds to PP1 very tightly and — they also show this to exacting degrees in the new study — that another protein called RepoMan acts just like Ki-67.

    Understanding how the proteins and PP1 interact during anaphase, the researchers hoped, could reveal a way to perhaps reduce or slow down mitosis in tumors.

    It was particularly important to achieve a precise characterization of Ki-67 and RepoMan’s interaction with PP1, Page said, because PP1 interacts with hundreds of proteins in the body, which regulate many key processes that they wouldn’t want to hinder. Instead, they wanted to see if there was something specific in mitosis with these two regulator proteins that they could pinpoint.

    “PP1 has this interaction with 200 different regulators, but a number of those regulators use a couple of [binding] sites over and over again,” said Page, professor of molecular, cellular biology and biochemistry. “You obviously can’t develop an inhibitor for those two sites, because then you’d disrupt PP1 function in a whole array of biological processes. But the really neat thing that Senthil discovered is that this whole interaction is completely unique to these two regulators.”

    Kumar and Page led the effort by using nuclear magnetic resonance and x-ray crystallography that resolved the proteins and their interactions down to the scale of individual atoms — 1.3 tenths of billionths of a meter. What he and the team found was that RepoMan and Ki-67 were binding with PP1 in an unusual way, forming a “hairpin” shape on the surface of PP1 at specific locations. A bioinformatics database search later confirmed that the binding was unique.

    Moreover, they identified a novel binding region which is unique only to RepoMan and Ki-67. This novel region could be a potential target for cancer therapy, Kumar said.

    Crucial to the research was that in the anaphase of mitosis the binding is even more specific than just either protein linking up with just any form of PP1. Instead they showed that in anaphase, RepoMan and Ki-67 link to a particular form of PP1 called gamma. The proteins’ selectivity for PP1-gamma, they found, depended on just one amino acid on the PP1 protein at position 20.

    The team, including co-authors at Brunel University in London and the University of Leuven in Belgium, confirmed this in living cells in imaging studies. They also confirmed that preference for Ki-67 and RepoMan to the gamma form of PP1 happens in the live cells during mitosis. In addition, they showed that substituting the single amino acid at position 20 stopped the function.

    The exact role that PP1-gamma or the two regulator proteins may play in cancer is not yet known, Page said, but now they know exactly how they interact and that the interaction is unique. That pushes the door wide open to develop a way to hinder it so they can see what the consequences are for cancer when they do.

    “Now we have an approach for trying to dissect what’s really happening because we can target this interface in particular,” Page said.

    In addition to Kumar, Page and Peti at Brown, the study’s other authors are Ezgi Gokhan and Paola Vagnarelli at Brunel and Sofie De Munter and Matthieu Bollen at Leuven.

    The National Institutes of Health (U.S.), the Fund for Scientific Research (Belgium) and the Biotechnology and Biological Science Research Council (U.K.) funded the research.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition
    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

  • richardmitnick 8:05 am on September 1, 2016 Permalink | Reply
    Tags: , Cancer, , Neuroblastoma,   

    From Vanderbilt: “Proliferative capacity of neuroblastoma” 

    Vanderbilt U Bloc

    Vanderbilt University

    Aug. 31, 2016
    Sanjay Mishra

    Neuroblastoma is a neural crest cell-derived extracranial solid cancer that affects infants and young children. The most vigorous of these cancers spreads through self-renewing cancer stem cells. Knowing the nature of these cells is essential to understanding the progression of neuroblastoma and devising the right treatment strategy.

    Reporting in the journal Biochemical and Biophysical Research Communications, Dai Chung, M.D., and colleagues use a technique called “limiting dilution analysis” to show that the frequency with which neuroblastoma stem cells form spheres in suspension cultures accurately quantifies their stemness, or ability to “self-renew.”

    Cell lines formed spheres more frequently when the MYCN oncogene was overactive. Retinoic acid, used clinically to induce differentiation of residual disease after chemotherapy and radiation, almost blocked sphere formation entirely, while fibroblast growth factor (FGF) promoted sphere formation.

    Limiting dilution analysis is an accurate method of quantifying sphere-forming frequency, and should be adopted as an effective way to assess the stemness or proliferative capacity of neuroblastoma stem cells, they conclude.

    This research was supported by a grant from the National Institutes of Health (DK061470) and by a Rally Foundation for Cancer Research Pediatric Oncology Fellowship Award.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Vanderbilt Campus

  • richardmitnick 7:11 am on August 31, 2016 Permalink | Reply
    Tags: , Cancer, , , Study Finds Potential New Biomarker for Cancer Patient Prognosis   

    From LBNL: “Study Finds Potential New Biomarker for Cancer Patient Prognosis” 

    Berkeley Logo

    Berkeley Lab

    August 31, 2016
    Sarah Yang
    (510) 486-4575

    To treat or not to treat? That is the question researchers at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) hope to answer with a new advance that could help doctors and their cancer patients decide if a particular therapy would be worth pursuing.

    The centromeres and kinetochores of a chromosome play critical roles during cell division. In mitosis, microtubule spindle fibers attach to the kinetochores, pulling the chromatids apart. A breakdown in this process causes chromosome instability. Researchers have linked the overexpression of centromere and kinetochore genes to cancer patient outcome after adjuvant therapies. (Credit: Zosia Rostomian/Berkeley Lab)

    Berkeley Lab researchers identified 14 genes regulating genome integrity that were consistently overexpressed in a wide variety of cancers. They then created a scoring system based upon the degree of gene overexpression. For several major types of cancer, including breast and lung cancers, the higher the score, the worse the prognosis. Perhaps more importantly, scores could accurately predict patient response to specific cancer treatments.

    The researchers said the findings, published today in the journal Nature Communications, could lead to a new biomarker for the early stages of tumor development. The information obtained could help reduce the use of cancer treatments that have a low probability of helping.

    Overtreating Cancer

    “The history of cancer treatment is filled with overreaction,” said the study’s principal investigator, Gary Karpen, a senior scientist in Berkeley Lab’s Division of Biological Systems and Engineering with a joint appointment at UC Berkeley’s Department of Molecular and Cell Biology. “It is part of the ethics of cancer treatment to err on the side of overtreatment, but these treatments have serious side effects associated with them. For some people, it may be causing more trouble than if the growth was left untreated.”

    One of the challenges is that there has been no reliable way to determine at an early stage if patients will respond to chemotherapy and radiation therapy, said study lead author Weiguo Zhang, a project scientist at Berkeley Lab.

    “Even for early stage cancer patients, such as lung cancers, adjuvant chemotherapy and radiotherapy are routinely used in treatment, but overtreatment is a major challenge,” said Zhang. “For certain types of early stage lung cancer patients, there are estimates that adjuvant chemotherapy improves five-year survival only about 10 percent, on average, which is not great considering the collateral damage caused by this treatment.”

    The researchers noted that there are many factors a doctor and patient must consider in treatment decisions, but this biomarker could become a valuable tool when deciding whether to use a particular therapy or not.

    Study co-author Anshu Jain, an oncologist at the Ashland Bellefonte Cancer Center in Kentucky and a clinical instructor at the Yale School of Medicine, added that the real value of this work may be in helping doctors and patients consider alternatives to the typical course of treatment.

    “These findings are very exciting,” said Jain. “The biomarker score provides predictive and prognostic information separate from and independent of clinical and pathologic tumor characteristics that oncologists have available today and which often provide only limited clinical value.”

    Hunting for new biomarkers

    The study authors focused on genes regulating the function of centromeres and kinetochores – the essential sites on chromosomes that spindle fibers attach to during cell division – based upon results from earlier research by the Karpen group and other labs in the field. In normal cell division, microtubule spindles latch on to the kinetochores, pulling the chromosome’s two chromatids apart.

    What the Karpen team previously found in fruit flies is that the overexpression of a specific centromere protein resulted in extra spindle attachment sites on the chromosomes.

    “This essentially makes new centromeres functional at more than one place on the chromosome, and this is a huge problem because the spindle tries to connect to all the sites,” said Karpen. “If you have two or more of these sites on the chromosome, the spindles are pulling in too many directions, and you end up breaking the chromosome during cell division. So overexpression of these genes may be a major contributing factor to chromosomal instability, which is a hallmark of all cancers.”

    This chromosomal instability has long been recognized as a characteristic of cancer, but its cause has remained unclear.

    To determine if centromeres play a role in chromosome instability in human cancers, the researchers analyzed many public datasets from the National Center for Biotechnology Information, the Broad Institute and other organizations that together contained thousands of human clinical tumor samples from at least a dozen types of cancers. The researchers screened 31 genes involved in regulating centromere and kinetochore function to find the 14 that were consistently overexpressed in cancer tissue.

    The extensive records included information on DNA mutations and chromosome rearrangements, the presence and levels of specific proteins, the stage of tumor growth at the time the patient was diagnosed, treatments given, and patient status in the years following diagnosis and treatment. This allowed the researchers to correlate the centromere and kinetochore gene expression score (CES) with patient outcomes either with or without treatments.

    Genome Instability and Cancer Therapy

    “We were surprised to find such a strong correlation between CES and things like whether the patient survived five years later,” said Karpen. “Another finding – one that is counterintuitive – is that high expression of these centromere genes is also related to more effective chemotherapy and radiation therapy.”

    The researchers hypothesized that the degree of chromosomal instability may also make cancer cells more vulnerable to the effects of chemotherapy or radiation therapy.

    “In other words, there’s a threshold of genome instability,” said Zhang. “At low to medium-high levels, the cancer thrives. But at much higher levels, the cancer cells are more susceptible to the additional DNA damage caused by the treatment. This is a really key point.”

    The researchers pointed out that they found no link between very high levels of genome instability and improved patient survival without adjuvant treatments.

    Translating these findings into clinical advice and practice will take more research, the study authors caution. They are working to find that threshold of genome instability so that in the future, doctors and patients can make informed decisions about how to move forward.

    “Future steps will include investigating the CES in prospective clinical studies for validation in carefully selected patient cohorts,” said Jain. “By establishing the clinical significance of the CES, oncologists will have greater confidence in guiding cancer patients toward treatments with the greatest benefit.”

    Other co-authors of the study are Jian-Hua Mao at Berkeley Lab’s Division of Biological Systems and Engineering; Wei Zhu at the Cellular Biomedicine Group in Shanghai; and Ke Liu and James Brown at Berkeley Lab’s Division of Environmental Genomics and Systems Biology. Mao and Zhu provided critical expertise in bioinformatics for this research.

    The National Institutes of Health supported this work.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    A U.S. Department of Energy National Laboratory Operated by the University of California

    University of California Seal

    DOE Seal

  • richardmitnick 3:40 pm on August 29, 2016 Permalink | Reply
    Tags: , Cancer, Jammed Cells Expose the Physics of Cancer,   

    From Quanta: “Jammed Cells Expose the Physics of Cancer” 

    Quanta Magazine
    Quanta Magazine

    August 16, 2016
    Gabriel Popkin

    The subtle mechanics of densely packed cells may help explain why some cancerous tumors stay put while others break off and spread through the body.

    Ashley Mackenzie for Quanta Magazine

    In 1995, while he was a graduate student at McGill University in Montreal, the biomedical scientist Peter Friedl saw something so startling it kept him awake for several nights. Coordinated groups of cancer cells he was growing in his adviser’s lab started moving through a network of fibers meant to mimic the spaces between cells in the human body.

    For more than a century, scientists had known that individual cancer cells can metastasize, leaving a tumor and migrating through the bloodstream and lymph system to distant parts of the body. But no one had seen what Friedl had caught in his microscope: a phalanx of cancer cells moving as one. It was so new and strange that at first he had trouble getting it published. “It was rejected because the relevance [to metastasis] wasn’t clear,” he said. Friedl and his co-authors eventually published a short paper in the journal Cancer Research.

    Two decades later, biologists have become increasingly convinced that mobile clusters of tumor cells, though rarer than individual circulating cells, are seeding many — perhaps most — of the deadly metastatic invasions that cause 90 percent of all cancer deaths. But it wasn’t until 2013 that Friedl, now at Radboud University in the Netherlands, really felt that he understood what he and his colleagues were seeing. Things finally fell into place for him when he read a paper [Science Direct] by Jeffrey Fredberg, a professor of bioengineering and physiology at Harvard University, which proposed that cells could be “jammed” — packed together so tightly that they become a unit, like coffee beans stuck in a hopper.

    Fredberg’s research focused on lung cells, but Friedl thought his own migrating cancer cells might also be jammed. “I realized we had exactly the same thing, in 3-D and in motion,” he said. “That got me very excited, because it was an available concept that we could directly put onto our finding.” He soon published one of the first papers applying the concept of jamming to experimental measurements of cancer cells.

    Physicists have long provided doctors with tumor-fighting tools such as radiation and proton beams. But only recently has anyone seriously considered the notion that purely physical concepts might help us understand the basic biology of one of the world’s deadliest phenomena. In the past few years, physicists studying metastasis have generated surprisingly precise predictions of cell behavior. Though it’s early days, proponents are optimistic that phase transitions such as jamming will play an increasingly important role in the fight against cancer. “Certainly in the physics community there’s momentum,” Fredberg said. “If the physicists are on board with it, the biologists are going to have to. Cells obey the rules of physics — there’s no choice.”

    The Jam Index

    In the broadest sense, physical principles have been applied to cancer since long before physics existed as a discipline. The ancient Greek physician Hippocrates gave cancer its name when he referred to it as a “crab,” comparing the shape of a tumor and its surrounding veins to a carapace and legs.

    But those solid tumors do not kill more than 8 million people annually. Once tumor cells strike out on their own and metastasize to new sites in the body, drugs and other therapies rarely do more than prolong a patient’s life for a few years.

    Biologists often view cancer primarily as a genetic program gone wrong, with mutations and epigenetic changes producing cells that don’t behave the way they should: Genes associated with cell division and growth may be turned up, and genes for programmed cell death may be turned down. To a small but growing number of physicists, however, the shape-shifting and behavior changes in cancer cells evoke not an errant genetic program but a phase transition.

    The phase transition — a change in a material’s internal organization between ordered and disordered states — is a bedrock concept in physics. Anyone who has watched ice melt or water boil has witnessed a phase transition. Physicists have also identified such transitions in magnets, crystals, flocking birds and even cells (and cellular components) placed in artificial environments.

    But compared to a homogeneous material like water or a magnet — or even a collection of identical cells in a dish — cancer is a hot mess. Cancers vary widely depending on the individual and the organ they develop in. Even a single tumor comprises a mind-boggling jumble of cells with different shapes, sizes and protein compositions. Such complexities can make biologists wary of a general theoretical framework. But they don’t daunt physicists. “Biologists are more trained to look at complexity and differences,” said the physicist Krastan Blagoev, who directs a National Science Foundation program that funds work on theoretical physics in living systems. “Physicists try to look at what’s common and extract behaviors from the commonness.”

    In a demonstration of this approach, the physicists Andrea Liu, now of the University of Pennsylvania, and Sidney Nagel of the University of Chicago published a brief commentary in Nature in 1998 about the process of jamming. They described familiar examples: traffic jams, piles of sand, and coffee beans stuck together in a grocery-store hopper. These are all individual items held together by an external force so that they resemble a solid. Liu and Nagel put forward the provocative suggestion that jamming could be a previously unrecognized phase transition, a notion that physicists, after more than a decade of debate, have now accepted.

    Though not the first mention of jamming in the scientific literature, Liu and Nagel’s paper set off what Fredberg calls “a deluge” among physicists. (The paper has been cited more than 1,400 times.) Fredberg realized that cells in lung tissue, which he had spent much of his career studying, are closely packed in a similar way to coffee beans and sand. In 2009 he and colleagues published [Nature Physics] the first paper suggesting that jamming could hold cells in tissues in place, and that an unjamming transition could mobilize some of those cells, a possibility that could have implications for asthma and other diseases.

    Lucy Reading-Ikkanda for Quanta Magazine

    The paper appeared amid a growing recognition of the importance of mechanics, and not just genetics, in directing cell behavior, Fredberg said. “People had always thought that the mechanical implications were at the most downstream end of the causal cascade, and at the most upstream end are genetic and epigenetic factors,” he said. “Then people discovered that physical forces and mechanical events actually can be upstream of genetic events — that cells are very aware of their mechanical microenvironments.”

    Lisa Manning, a physicist at Syracuse University, read Fredberg’s paper and decided to put his idea into action. She and colleagues used a two-dimensional model of cells that are connected along edges and at vertices, filling all space. The model yielded an order parameter — a measurable number that quantifies a material’s internal order — that they called the “shape index.” The shape index relates the perimeter of a two-dimensional slice of the cell and its total surface area. “We made what I would consider a ridiculously strict prediction: When that number is equal to 3.81 or below, the tissue is a solid, and when that number is above 3.81, that tissue is a fluid,” Manning said. “I asked Jeff Fredberg to go look at this, and he did [Nature Materials], and it worked perfectly.”

    Fredberg saw that lung cells with a shape index above 3.81 started to mobilize and squeeze past each other. Manning’s prediction “came out of pure theory, pure thought,” he said. “It’s really an astounding validation of a physical theory.” A program officer with the Physical Sciences in Oncology program at the National Cancer Institute learned about the results and encouraged Fredberg to do a similar analysis using cancer cells. The program has given him funding to look for signatures of jamming in breast-cancer cells.

    Meanwhile, Josef Käs, a physicist at Leipzig University in Germany, wondered if jamming could help explain puzzling behavior in cancer cells. He knew from his own studies and those of others that breast and cervical tumors, while mostly stiff, also contain soft, mobile cells that stream into the surrounding environment. If an unjamming transition was fluidizing these cancer cells, Käs immediately envisioned a potential response: Perhaps an analysis of biopsies based on measurements of tumor cells’ state of jamming, rather than a nearly century-old visual inspection procedure, could determine whether a tumor is about to metastasize.

    Käs is now using a laser-based tool to look for signatures of jamming in tumors, and he hopes to have results later this year. In a separate study that is just beginning, he is working with Manning and her colleagues at Syracuse to look for phase transitions not just in cancer cells themselves, but also in the matrix of fibers that surrounds tumors.

    More speculatively, Käs thinks the idea could also yield new avenues for therapies that are gentler than the shock-and-awe approach clinicians typically use to subdue a tumor. “If you can jam a whole tumor, then you have a benign tumor — that I believe,” he said. “If you find something which basically jams cancer cells efficiently and buys you another 20 years, that might be better than very disruptive chemotherapies.” Yet Käs is quick to clarify that he is not sure how a clinician would induce jamming.

    Castaway Cooperators

    Beyond the clinic, jamming could help resolve a growing conceptual debate in cancer biology, proponents say. Oncologists have suspected for several decades that metastasis usually requires a transition between sticky epithelial cells, which make up the bulk of solid tumors, and thinner, more mobile mesenchymal cells that are often found circulating solo in cancer patients’ bloodstreams. As more and more studies deliver results showing activity similar to that of Friedl’s migrating cell clusters, however, researchers have begun to question [Science] whether go-it-alone mesenchymal cells, which Friedl calls “lonely riders,” could really be the main culprits behind the metastatic disease that kills millions.

    Some believe jamming could help get oncology out of this conceptual jam. A phase transition between jammed and unjammed states could fluidize and mobilize tumor cells as a group, without requiring them to transform from one cell type to a drastically different one, Friedl said. This could allow metastasizing cells to cooperate with one another, potentially giving them an advantage in colonizing a new site.

    The key to developing this idea is to allow for a range of intermediate cell states between two extremes. “In the past, theories for how cancer might behave mechanically have either been theories for solids or theories for fluids,” Manning said. “Now we need to take into account the fact that they’re right on the edge.”

    Hints of intermediate states between epithelial and mesenchymal are also emerging from physics research not motivated by phase-transition concepts. Herbert Levine, a biophysicist at Rice University, and his late colleague Eshel Ben-Jacob of Tel Aviv University recently created a model of metastasis based on concepts borrowed from nonlinear dynamics. It predicts the existence of clusters of circulating cells that have traits of both epithelial and mesenchymal cells. Cancer biologists have never seen such transitional cell states, but some are now seeking them in lab studies. “We wouldn’t have thought about it” on our own, said Kenneth Pienta, a prostate cancer specialist at Johns Hopkins University. “We have been directly affected by theoretical physics.”

    Biology’s Phase Transition

    Models of cell jamming, while useful, remain imperfect. For example, Manning’s models have been confined to two dimensions until now, even though tumors are three-dimensional. Manning is currently working on a 3-D version of her model of cellular motility. So far it seems to predict a fluid-to-solid transition similar to that of the 2-D model, she said.

    In addition, cells are not as simple as coffee beans. Cells in a tumor or tissue can change their own mechanical properties in often complex ways, using genetic programs and other feedback loops, and if jamming is to provide a solid conceptual foundation for aspects of cancer, it will need to account for this ability. “Cells are not passive,” said Valerie Weaver, the director of the Center for Bioengineering and Tissue Regeneration at the University of California, San Francisco. “Cells are responding.”

    Weaver also said that the predictions made by jamming models resemble what biologists call extrusion, a process by which dead epithelial cells are squeezed out of crowded tissue — the disfunction of which has recently been implicated in certain types of cancer. Manning believes that cell jamming likely provides an overarching mechanical explanation for many of the cell behaviors involved in cancer, including extrusion.

    Space-filling tissue models like the one Manning uses, which produce the jamming behavior, also have trouble accounting for all the details of how cells interact with their neighbors and with their environment, Levine said. He has taken a different approach, modeling some of the differences in the ways cells can react when they’re being crowded by other cells. “Jamming will take you some distance,” he said, adding, “I think we will get stuck if we just limit ourselves to thinking of these physics transitions.”

    Manning acknowledges that jamming alone cannot describe everything going on in cancer, but at least in certain types of cancer, it may play an important role, she said. “The message we’re not trying to put out there is that mechanics is the only game in town,” she said. “In some instances we might do a better job than traditional biochemical markers [in determining whether a particular cancer is dangerous]; in some cases we might not. But for something like cancer we want to have all hands on deck.”

    With this in mind, physicists have suggested other novel approaches to understanding cancer. A number of physicists, including Ricard Solé of Pompeu Fabra University in Barcelona, Jack Tuszynski of the University of Alberta, and Salvatore Torquato of Princeton University, have published theory papers suggesting ways that phase transitions could help explain aspects of cancer, and how experimentalists could test such predictions.

    Others, however, feel that phase transitions may not be the right tool. Robert Austin, a biological physicist at Princeton University, cautions that phase transitions can be surprisingly complex. Even for a seemingly elementary case such as freezing water, physicists have yet to compute exactly when a transition will occur, he notes — and cancer is far more complicated than water.

    And from a practical point of view, all the theory papers in the world won’t make a difference if physicists cannot get biologists and clinicians interested in their ideas. Jamming is a hot topic in physics, but most biologists have not yet heard of it, Fredberg said. The two communities can talk to each other at physics-and-cancer workshops during meetings hosted by the American Physical Society, the American Association for Cancer Research or the National Cancer Institute. But language and culture gaps remain. “I can come up with some phase diagrams, but in the end you have to translate it into a language which is relevant to oncologists,” Käs said.

    Those gaps will narrow if jamming and phase transition theory continue to successfully explain what researchers see in cells and tissues, Fredberg said. “If there’s really increasing evidence that the way cells move collectively revolves around jamming, it’s just a matter of time until that works its way into the biological literature.”

    And that, Friedl said, will give biologists a powerful new conceptual tool. “The challenge, but also the fascination, comes from identifying how living biology hijacks the physical principle and brings it to life and reinvents it using molecular strategies of cells.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

  • richardmitnick 8:40 pm on August 25, 2016 Permalink | Reply
    Tags: , Cancer, , Scientists have finally figured out how cancer spreads through the bloodstream   

    From Science Alert: “Scientists have finally figured out how cancer spreads through the bloodstream…” 


    Science Alert

    24 AUG 2016

    K. Hodivala-Dilke, M. Stone/Wellcome Images

    …And that means we might be able to stop it.

    In what could be a major step forward in our understanding of how cancer moves around the body, researchers have observed the spread of cancer cells from the initial tumour to the bloodstream.

    The findings suggest that secondary growths called metastases ‘punch’ their way through the walls of small blood vessels by targeting a molecule known as Death Receptor 6 (no, really, that’s what it’s called). This then sets off a self-destruct process in the blood vessels, allowing the cancer to spread.

    According to the team from Goethe University Frankfurt and the Max Planck Institute in Germany, disabling Death Receptor 6 (DR6) may effectively block the spread of cancerous cells – so long as there aren’t alternative ways for the cancer to access the bloodstream.

    “This mechanism could be a promising starting point for treatments to prevent the formation of metastases,” said lead researcher Stefan Offermanns.

    Catching these secondary growths is incredibly important, because most cancer deaths are caused not by the original tumour, but by the cancer spreading.

    To break through the walls of blood vessels, cancer cells target the body’s endothelial cells, which line the interior surface of blood and lymphatic vessels. They do this via a process known as necroptosis – or ‘programmed cell death’ – which is prompted by cellular damage.

    According to the researchers, this programmed death is triggered by the DR6 receptor molecule. Once the molecule is targeted, cancer cells can either travel through the gap in the vascular wall, or take advantage of weakening cells in the surrounding area.

    MPI for Heart and Lung Research

    The team observed the same behaviour in both lab-grown cells and mice. In genetically modified mice where DR6 was disabled, less necroptosis and less metastasis was recorded.

    The scientists have reported their findings in Nature.

    The next step is to look for potential side effects caused by the disabling of DR6, and to figure out if the same benefits can be seen in humans. If so – and there’s no guarantee of that – this has the potential to be a seriously effective way of slowing down the spread of cancer.

    There are other hypotheses on how some metastases get around the body to cause secondary growths, though. Scientists at the University of California, Los Angeles (UCLA) are currently investigating the idea that tumour cells could also spread through the body outside blood vessels and the bloodstream.

    The researchers suggest that a mechanism known as angiotropism could be used by some melanoma cancers to cling to the outside of blood vessels, rather than penetrating them. If this is confirmed, they would escape the effects of disabled DR6 and chemotherapy alike.

    “If tumour cells can spread by continuous migration along the surfaces of blood vessels and other anatomical structures such as nerves, they now have an escape route outside the bloodstream,” explained researcher Laurent Bentolila from UCLA.

    The findings from that research, also conducted on mice, have been published in Nature Scientific Reports.

    As the two studies show, not all cancers behave in the same way, which makes figuring out how they operate doubly difficult. But the more we come to appreciate how complex and varied this disease can be, the better chance we have of fighting it.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

Compose new post
Next post/Next comment
Previous post/Previous comment
Show/Hide comments
Go to top
Go to login
Show/Hide help
shift + esc
%d bloggers like this: