Breast cancer patients face many horrors, including those that arise when fighting the cancer itself. Medications given during chemotherapy can have wicked side effects, including vomiting, dizziness, anemia and hair loss. These side effects occur because medications released into the body target healthy cells as well as tumor cells.

The trick becomes how to deliver cancer-fighting drugs directly to the tumor cells. Brown University chemists think they have an answer: They have created a twin nanoparticle that specifically targets the Her-2-positive tumor cell, a type of malignant cell that affects up to 30 percent of breast cancer patients.

The combination nanoparticle binds to the Her-2 tumor cell and unloads the cancer-fighting drug cisplatin directly into the infected cell. The result: Greater success at killing the cancer while minimizing the anti-cancer drug’s side effects.

“Like a missile, you don’t want the anti-cancer drugs to explode everywhere,” explained Shouheng Sun, a chemistry professor at Brown University and an author on the paper published online in The Journal of the American Chemical Society. “You want it to target the tumor cells and not the healthy ones.”

The researchers created the twin nanoparticle by binding one gold (Au) nanoparticle with an iron-oxide (Fe3O4) nanoparticle. On one end, they attached a synthetic protein antibody to the iron-oxide nanoparticle. On the other end, they attached cisplatin to the gold nanoparticle. Visually, the whole contraption looks like an elongated dumbbell, but it may be better to think of it as a vehicle, equipped with a very good GPS system, that is ferrying a very important passenger.

In this case, the GPS comes from the iron-oxide nanoparticle, which homes in on a Her-2 breast-cancer cell like a guided missile. The attached antibody is critical, because it binds to the antigen, a protein located on the surface on the malignant cell. Put another way, the nanoparticle vehicle “docks” on the tumor cell when the antibody and the antigen become connected. Once docked, the vehicle unloads its “passenger,” the cisplatin, into the malignant cell.

“It’s like a magic bullet,” said Chenjie Xu, a Brown graduate student and the lead author on the paper. Baodui Wang, a visiting scientist at Brown and now an associate professor at Lanzhou University in China, contributed to the paper.

In a neat twist, the Brown-led team used a pH-sensitive covalent bond to connect the gold nanoparticle with the cisplatin to ensure that the drug was not released into the body but remained attached to the nanoparticle until it was time for it to be released into the malignant cell.

In laboratory tests, the gold-iron oxide nanoparticle combination successfully targeted the cancer cells and released the anti-cancer drugs into the malignant cells, killing the cells in up to 80 percent of cases. “We made a Mercedes Benz now,” Sun joked. “It’s not a Honda Civic anymore.”

The research builds on previous work in Sun’s lab where researchers created peptide-coated iron-oxide nanoparticles that, in tests with mice, successfully located a brain tumor cell called U87MG.

The researchers will test the breast-cancer nanoparticle system in laboratory tests with animals. They also plan to create twin nanoparticles that can release the drug via remote-controlled magnetic heating.

Researchers at the University of California, San Diego School of Medicine have identified a key protein that is required for immune cells called B lymphocytes to divide and replicate themselves. The rapid generation of large numbers of these immune cells is critical to the body’s antibody defense mechanism. However, when B cells grow unchecked, it can lead to immune cell cancers such as multiple myeloma or, when they grow to attack the wrong targets, to autoimmune disease. By discovering the role of the CD98hc protein, scientists may find new therapy targets for such diseases.

The study from the laboratory of Mark H. Ginsberg, MD., professor of medicine, will be published online March 8 in advance of print in Nature Immunology. It describes why CD98hc is essential in order for B lymphocytes to transition into antibody-secreting cells. It also describes how this relates to the protein’s role in the signaling ability of integrins – a large family of adhesion molecules that transfer information between the inside and outside of a cell.

According to first author Joseph Cantor, PhD, UC San Diego School of Medicine, scientists have known for nearly 25 years that CD98hc, common to all vertebrates, probably played a role in their adaptive immune system, but it wasn’t known how this protein functioned.

“This protein was used as a marker of activation because it was found in low levels on resting lymphocytes,” said Cantor. “But when B or T lymphocytes were stimulated by antigens – for instance, to protect the body against bacteria – levels of CD98hc went up 20 fold.”

The scientists generated a mouse model lacking the CD98hc protein in B lymphocytes. When vaccinated, these mice were unable to mount a normal antibody response to the pathogen. Cantor says this was the first clue to the researchers of the protein’s importance.

“In purifying B lymphocytes without the CD98hc protein, we discovered that the lymphocytes couldn’t divide rapidly,” Cantor said, adding that this proved the protein was essential to expanding the number of immune cells, a necessary step in the immune response. While deletion of the protein didn’t impair early B cell activation, it did inhibit later activation of elements along the signaling pathway that push the cell forward to divide.

“Since B cells can’t rapidly divide and replicate without CD98hc, perhaps by blocking this protein we could stop the unchecked growth of B lymphocyte cells that can result in cancer or block misdirected B cell attacks that can cause certain autoimmune diseases,” said Ginsberg.

The CD98hc protein functions in cells by helping to transmit integrin signals, as well as transporting amino acids – the building blocks of proteins – into the cell. But the scientists didn’t know which, if either, of these functions was related to the protein’s role in the rapid division of immune cells. By replacing normal CD98hc in B cells with a version that lacked one or the other of these two functions, they discovered that the integrin-binding domain of this protein is required, but the amino acid transport function is dispensable for B cell proliferation.

“CD98hc interacts with certain integrin subunits to prompt signaling events that control cell migration, survival and proliferation. Our study shows that the rapid proliferation of B cells, necessary for the body to fight infection, is aided by the CD98hc protein’s support of integrin signaling,” Cantor said.

Notes:

Additional contributors to this paper include Cecille D. Brown and Robert C. Rickert of the Burnham Institute; Raphael Ruppert and Reinhard Fässler of the Max Planck Institutte, Germany; and Chloé C. Féral, Nice-Sophia Antipolis University, France.

This work was supported by National Institutes of Health grants; Joseph Cantor is a post-doctoral fellow of the National Multiple Sclerosis Society.

When it comes to solving complex problems, Geoffrey von Maltzahn, MIT graduate student and biomedical engineer, looks to nature for solutions. Finding inspiration in systems that evolution has produced, von Maltzahn is currently helping to tackle one of society’s biggest challenges: improving tumor detection and therapeutic delivery in order to boost the survival rate of cancer patients.

The 28-year-old Ph.D. candidate in the Harvard-MIT Division of Health Sciences and Technology (HST) received the prestigious $30,000 Lemelson-MIT Student Prize for his promising innovations in the area of cancer therapy, specifically two inventions in nanomedicine: a new class of cancer therapeutics and a new paradigm for enhancing drug delivery to tumors.

Cancer currently kills more people worldwide than HIV/AIDS, tuberculosis and malaria combined. Despite billions of dollars invested into drug development and decades of research, selectively eradicating cancer cells has remained an elusive goal. Chemotherapies, a common class of cancer treatments, are intended to kill the fast-growing cells that form tumors. However, these drugs travel throughout the entire body, and often affect normal, healthy tissue along with cancer cells, causing side effects such as hair loss, nausea, anemia, and even nerve and muscle problems. Furthermore, resistance to these drugs can arise and can cause even initially successful treatment regimens to fail.

Working at the confluence of nanotechnology, engineering and medicine, von Maltzahn’s innovations have the potential to reduce side effects and overpower drug resistance mechanisms by more powerfully concentrating external energy and targeted therapeutics in tumors.

Using Gold Nano-Antennas to Target and Destroy Tumors

Since 2004, von Maltzahn has worked closely with his advisor, Dr. Sangeeta N. Bhatia, an electrical engineering and computer science professor in the Harvard-MIT Division of HST, to invent novel treatments that could precisely target and destroy tumor cells without affecting healthy tissue. Seeking to improve the specificity of cancer ablation – the destruction of tumors through the application of heat – von Maltzahn developed polymer-coated gold ‘nano-antennas’ that can target tumors and convert benign-infrared light into heat.

The nanoparticles are designed to be injected intravenously, where they circulate through the bloodstream and progressively concentrate at the tumor site by infiltrating pores in rapidly growing tumor blood vessels. Once in the tumor, the antennas can be precisely heated with a non-invasive, near-infrared light to specifically kill the cancerous cells. “The polymer coated gold nano-antennas are the longest-circulating and most efficiently heated to date,” states Dr. Bhatia. “Pre-clinical trials reveal that a single intravenous nanoparticle injection eradicated 100 percent of tumors in mice using a near-infrared light. The results of these trials are very promising, meaning that the impact of this technology is wide-reaching with many potential applications.”

Scout and Assassin: Communicating Nanoparticles

Von Maltzahn’s second invention aims to fundamentally improve the intravenous delivery of therapeutics to tumors by taking a ‘systems’ approach to their design. This work draws on insights from biological systems, like ants foraging and bees swarming, where relatively simple methods of communication can lead to very sophisticated system behaviors.

Inspired by the potential for inter-nanoparticle communication to improve therapeutics’ ability to find tumors, von Maltzahn invented a series of ways for nanoparticles to ‘talk’ to one another in the body. One method involves benign ‘scout’ particles initially locating the tumor and, once inside, sending powerful signals to recruit secondary, ‘assassin’ particles that contain the therapeutics. In pre-clinical trials, this system has been able to deliver over 40-times higher doses of therapeutics to tumors in mice, in comparison to non-communicating control nanoparticles.

“If such highly-targeted delivery can be achieved clinically, this method would enable doctors to increase the drug dose that is delivered to tumors, increasing its overall efficacy and reducing side-effects,” von Maltzahn explains. “This concept of engineering systems of nanoparticles that collectively outsmart disease barriers has many potential applications in medicine, from improving regenerative medicines to ultra-sensitive diagnostics.”

Looking Forward

Von Maltzahn’s work has already made a significant impact scientifically and commercially, resulting in eight patent applications, 19 submitted or published papers, and his founding roles in two companies: Nanopartz Inc. and Resonance Therapeutics.

Nanopartz was founded more than one year ago to address the nanotechnology industry’s need for dependable and standardized nanoparticle sources. Von Maltzahn’s goal with Nanopartz is to aid in research endeavors worldwide by supplying a repertoire of gold nanoparticles for a broad spectrum of commercial applications, ranging from biomedicine to energy.

Resonance Therapeutics was founded to bring nano-rods towards clinical applications and to develop technologies that amplify the efficacy of existing cancer therapeutics.

“In addition to the long hours spent in the lab, finishing up his Ph.D., and founding two companies, Geoff mentored 14 undergraduate students, taking them out of the classroom setting and inspiring them to make the link from science to the real world,” states Joshua Schuler, the executive director of the Lemelson-MIT Program. “Geoff is not only a mentor for aspiring scientists, but also a shining example of bridging the gap between technological invention and entrepreneurship.”

Additional Inventions

During von Maltzahn’s time at MIT he has also developed inventions outside of the polymer nano-rods and ‘systems nanotechnology’ paradigm for improving drug delivery, including: a low-cost method for hemorrhage detection; a new class of ‘self-assembling’ lipid-like peptides with promising applications in gene therapy; sensors for detecting tumor protease hot-spots in MRI; a method for remotely-controlling drug release from nanoparticles; and a variety of new nanostructures for improved drug delivery and imaging.

Collegiate Student Prize Expansion

On March 4th, the winners of the third annual $30,000 Lemelson-Illinois Student Prize and $30,000 Lemelson-Rensselaer Student Prize will be announced at the University of Illinois at Urbana-Champaign and Rensselaer Polytechnic Institute, respectively. Following, on March 5th the first $30,000 Lemelson-Caltech Student Prize will be announced at the California Institute of Technology.

Notes:

ABOUT THE $30,000 LEMELSON-MIT STUDENT PRIZE

The $30,000 Lemelson-MIT Student Prize is awarded annually to an MIT senior or graduate student who has created or improved a product or process, applied a technology in a new way, redesigned a system, or demonstrated remarkable inventiveness in other ways. A distinguished panel of MIT alumni including scientists, technologists, engineers and entrepreneurs chooses the winner.

ABOUT THE LEMELSON-MIT PROGRAM

The Lemelson-MIT Program recognizes outstanding inventors, encourages sustainable new solutions to real-world problems, and enables and inspires young people to pursue creative lives and careers through invention.

Jerome H. Lemelson, one of U.S. history’s most prolific inventors, and his wife Dorothy founded the Lemelson-MIT Program at the Massachusetts Institute of Technology in 1994. It is funded by the Lemelson Foundation, a philanthropy that celebrates and supports inventors and entrepreneurs in order to strengthen social and economic life in the U.S. and developing countries. More information on the Lemelson-MIT Program is online at http://web.mit.edu/invent/.

Two researchers at UT Southwestern Medical Center have been named Alfred P. Sloan Research Fellows, an award intended to “support the work of exceptional young researchers early in their academic careers, and often at pivotal stages in their work.”

Dr. Jennifer Kohler and Dr. Joseph Ready were honored for their work in chemistry. The Alfred P. Sloan Foundation recognizes excellence in physics, chemistry, computational and evolutionary molecular biology, computer science, economics, mathematics and neuroscience.

Dr. Kohler, assistant professor of internal medicine, and Dr. Ready, associate professor of biochemistry, each will receive $50,000 over two years. Sloan Fellows may pursue whatever line of research they wish, and the funds may be used in a wide variety of ways.

“It was a bit of a surprise to me, because I thought they’d forgotten about me,” said Dr. Kohler, who was originally nominated last year.

Her research involves carbohydrates on cell surfaces, which interact with other cells and the environment in many tasks. These often-fleeting interactions, however, are difficult to study. She and her colleagues make “unnatural sugars” that, when exposed to light, permanently bind to whatever they’re contacting.

“It’s like a snapshot of what’s going on,” she said. Her group plans to focus on enzymes that remove cell-surface carbohydrates from various types of human cancer cells. This interaction appears to be involved in resistance to some chemotherapies and radiation treatments.

Dr. Ready, a synthetic chemist, works with naturally occurring molecules from algae and soil bacteria to search for antibiotics and anti-cancer agents.

“It’s been known for a long time that natural sources represent a wonderful supply of antibiotics and other drugs,” he said. “And bacteria generate a great variety of small, biologically active molecules.”

Once a potentially useful compound is identified, Dr. Ready and his colleagues find ways to synthesize it in large quantities. In addition, they may modify it chemically to make it more effective, or to make the synthesis easier.

Previous fellowship winners from UT Southwestern are Dr. Jef DeBrabander, professor of biochemistry, 2001; and Dr. Patrick Harran, former professor of biochemistry, 2002. The Sloan Research Fellowships have been awarded since 1955.

Notes:

The Sloan Foundation is a philanthropic, not-for-profit grant making institution based in New York City. It named 118 fellows from 61 colleges and universities this year. Established in 1934 by Alfred Pritchard Sloan Jr., then-President and Chief Executive Officer of the General Motors Corporation, the Foundation makes grants in support of original research and education in science, technology, engineering, mathematics and economic performance.

In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process – known as autophagy – takes place in special organelles called autophagosomes. It is a strategy that simple yeast cells have developed as a means of survival when times get tough, and in the course of evolution, it has become a kind of self-cleaning process. In mammalian cells, autophagosomes are also responsible for getting rid of misfolded proteins, damaged organelles or disease-causing bacteria.

If this process malfunctions, it can result in infectious diseases, as well as cancer, Parkinson’s or Alzheimer’s disease. Biochemists at Frankfurt’s Goethe University, working together with scientists from the University of Tromsø in Norway, the Weizmann Institute in Israel and the Tokyo Metropolitan Institute in Japan have just come up with an explanation as to how autophagosomes know exactly which proteins and organelles they should degrade.

“Although autophagy has been known for more than 30 years, it is astonishing that no-one thought of looking for the receptors that make this process so selective” explains Prof. Ivan Dikic from the Institute of Biochemistry II and the Cluster of Excellence ‘Macromolecular Complexes’ in Frankfurt. He had a head start in this field, since over several years, he and his group have researched and now published their work on another self-cleaning process in the cell: the degradation of small proteins in the proteasome, which acts as a kind of molecular shredder.

“We know that the molecules which are destined to be discarded are marked with the small protein ubiquitin and this is recognised by a receptor located at the gateway to the proteasome. It was natural to suggest a similar recognition mechanism for protein degradation by autophagosomes”, says Dikic.

Unlike the proteasome, which is a complex molecular machine, autophagosomes simply consist of a double membrane that floats around in the cytoplasm. Not unlike white blood cells, they can engulf larger proteins or even whole cell organelles. But since they have no enzymes with which they can digest their own cargo, they fuse with lysosomes. When a Yoshinori Ohsumi’s group in Japan reported that they had discovered ubiquitin-like proteins (ATG8) on the outer surface of the autophagosome and gone on to prove that they were specific for autophagy, Dikic and his colleague Dr. Vladimir Kirkin immediately began their search for potential autophagy receptors that might bind to the family of ATG8 proteins.

The team of international scientists report in the current issue of the renowned journal “Molecular Cell”, that by employing methods from cell biology, biochemistry and mouse genetics, they have been able to identify a further protein, in addition to the known p62/SQSTM1 protein, that may act as a receptor. This is the protein NBR1, which has long been associated with cancer. Both proteins have a similar chain-like structure. At one end they bind to the ubiquitin that marks the protein aggregates and organelles that are to be degraded. Next to the ubiquitin-binding site is a domain that binds to the ATG8 proteins found at the autophagosomal membrane. Here, the protein waste can dock onto the autophagosome and can then be wrapped up in the membrane.

Vladimir Kirkin, who is now at Merck Serono in Darmstadt, is continuing these investigations with the long-term aim of developing new drugs. Dikic and his group are now concentrating on mitochondria – which are implicated in oxidative stress in cells – hoping to locate the receptors for autophagy on these important organelles.

Adult stem cells and their more committed kin, progenitor cells, are prized by medical researchers for their ability to produce different types of specialized cells. The potential of using these cells to repair or replace damaged tissue holds great promise for cancer therapies and regenerative medicine. However, the question that must first be answered is what determines the ultimate fate of a stem or progenitor cell? A team of researchers led by Berkeley Lab’s Mark LaBarge and Mina Bissell appear to be well on the road to finding out.

Working with unique microenvironment microarrays (MEArrays) of their own creation, LaBarge and Bissell and their collaborators have shown that the ultimate fate of a stem or progenitor cell in a woman’s breast – whether the cell develops normally or whether it turns cancerous – may depend upon signals from multiple microenvironments.

“We found that adult human mammary stem and progenitor cells exhibit impressive plasticity in response to hundreds of unique combinatorial microenvironments,” said LaBarge, a cell and molecular biologist in Berkeley Lab’s Life Sciences Division. “Our results further suggest that rational modulation of the microenvironmental milieu can impose specific differentiation phenotypes on normal stem or progenitor cells, and perhaps even impose phenotypically normal behavior on malignant cells during tissue genesis. All of this points to the rational manipulation of adult stem and progenitor cells as a promising pathway for beneficial therapies.”

Previous studies on how microenvironments affect the development of adult human stem or progenitor cells have been based on the behavior of these cells in culture (in vitro) where they are exposed to a single molecular agent. However, when these cells are in an actual human being (in vivo) they are surrounded by a multitude of other cells plus a supporting network of fibrous and globular proteins called the extracellular matrix (ECM), as well as many other nearby molecules, all of which may be simultaneously sending them instructional signals.

“With our MEArrays, we can use combinations of proteins from a select tissue to create multiple microenvironments on a single chip about two square centimeters in area,” said LaBarge. “We think this approach will give us a much more realistic picture as to how stem and progenitor cells actually behave in vivo.”

Said Bissell, a Distinguished Scientist with Berkeley Lab’s Life Sciences Division and one of the world’s leading researchers on breast cancer, “We have demonstrated that each discrete cell fate decision requires the integration of multiple pathways, and we have identified combinations of components in the human mammary microenvironment that impose distinct cell fates. These results are exciting because they indicate that we can test a large number of effectors and determine which ones to use to direct the fate of adult stem and progenitor cells. This give hope that one day – sooner rather than later – the information could be used for therapy.”

Collaborating with LaBarge and Bissell on this study were Jason Ruth, now at the University of Pennsylvania, Martha Stampfer of Berkeley Lab, Celeste Nelson, now with Princeton University, and Rene Villadsen, Agla Fridriksdottir and Ole Petersen, of the Panum Institute in Denmark.

Human breast tissue harbors two types of epithelial cells: luminal – the cells that are able to produce milk and generally the ones that become cancerous; and myoepithelial – the cells that surround the luminal cells and push milk down the ducts to the nipples, but which rarely become cancerous. Like cells in other types of tissue these breast epithelial cells are spawned from stem and progenitor cells that despite being primitive – essentially a cellular blank slate – possess the exact same genome as their differentiated daughters. Once it was widely held that adult stem and progenitor cells intrinsically “know” when to self-renew and when to differentiate into one specific tissue cell or another based on pre-determined genetic programs. However, pioneering research by Bissell, in which it has been demonstrated that interactions between an epithelial breast cell and its ECM play a major role in determining whether that cell becomes cancerous, pointed the way to the idea that the ultimate fate of a stem or progenitor cell is heavily influenced by interactions with its neighboring microenvironments.

“Adult stem cells are maintained inside a specialized microenvironment called a niche, whereas progenitor cells migrate to surrounding microenvironments that are distinct from the one around the niche,” said LaBarge. “The ability of adult stem cells to self-maintain, as well as to give rise to progenitor cells that are targeted to become a specific tissue cell, indicates an ability to respond to changing microenvironmental demands, which would mean that a stem or progenitor cell is receiving instructional information from its surroundings.”

The fact that normal cells often lose their tissue-specific functions when placed in culture is further evidence of cell fate being tied in to signals from the microenvironment. However, proving such a hypothesis has been difficult in the past because the composition of cell microenvironments is extremely complex and requires a method by which a combination of carefully choreographed interactions can be observed. Given that experiments with human adult stem cell niches cannot be done in vivo and that scientists can only learn so much from mouse models, this means that cell culture studies must be done under as close as possible to in vivo conditions.

“Our technology mimics actual in vivo conditions and enables us to perform highly parallel functional analysis of combinatorial microenvironments, and image analysis of 3-D organotypic cultures and micro patterned culture substrata,” said LaBarge. “The 3-D capability is crucial because our studies show that orientation of the stem or progenitor cells with respect to the signaling molecules can be critical to what happens next.”

The MEArrays were fabricated using micro patterning technology originally adapted by co-author Nelson that LaBarge “tweaked.” A robot imprinted arrays of 2,304 individual combinations of molecules onto a rubber-coated glass microscope slide (the rubber facilitates adsorption of the proteins onto the slide). An individual MEArray consisted of 192 unique combinatorial microenvironments replicated 12 times, with a plastic barrier running along the perimeter so that cell cultures could be placed on top.

In addition to possible contributors to the stem cell niche, the microenvironments also comprised many ECM and signaling molecules that are expressed in the breast but had not been directly linked to stem cell function before.

In all, adult mammary stem and progenitor cells were exposed to 8,000 different combinations of breast tissue protein and biological molecules. LaBarge, Bissell and their collaborators were able to distinguish between effects resulting from cell interactions with other cells and those resulting from cell interactions with the ECM or other signaling molecules. Both immortalized and primary human breast progenitors were analyzed with the MEArrays and the results were used in conjunction with physiologically relevant 3-D human breast cultures. This approach enabled the research team to identify conditions that induced cells to convert into normal breast cell types as well as conditions that kept the cells in their original, non-specialized state.

One of the most intriguing results in this study was the suggestion that modulation of stem and progenitor cell differentiation pathways might be used to “normalize” malignant breast cells.

“Normal and malignant mammary epithelial cells in 3-D cultures have distinct phenotypes,” LaBarge said. “By impairing a signaling pathway known as Notch, we are able to revert malignant breast cancer cells to a normal phenotype.”

In previous studies, Bissell and her group had identified signaling pathways that could cause “phenotypic reversion” of breast cancer cells but this had never been tried before with stem cells.

Said Bissell, “The MEArray approach may be able to teach us how to direct stem cell function in a therapeutic setting and possibly to re-program non-stem cells to acquire other stem cell fates.”

While the MEArrays in this study were used to study adult stem and progenitor cells in breast tissue, the technique should also be applicable to any of the other 200 different types of tissue cells within other organs, LaBarge said.

This research was supported in part by grants and a distinguished Fellow Award from the U.S. Department of Energy’s Office of Biological and Environmental Research and low dose program, by grants from the National Cancer Institute and from the U.S. Department of Defense’s breast cancer research program. LeBarge was a fellow of the American Cancer Society.

Molecular Oncology (MOLONC), published by Elsevier on behalf of the Federation of European Biochemical Societies (FEBS), has been accepted by Thomson Reuters™ (formerly ISI), for inclusion in the Science Citation Index Expanded (SciSearch), Biosis Previews and Biological Abstracts.

MOLONC (published 6 times a year from January 1, 2009) highlights new discoveries, approaches, as well as technical developments, in basic, clinical and discovery-driven translational research. The first issue of MOLONC was published in June 2007 and has been managed from its inception by Prof. Julio E. Celis, Director of the Institute of Cancer Biology at the Danish Cancer Society in Copenhagen and Editor-in-Chief of Molecular Oncology.

“This is an excellent development, and demonstrates the high calibre of the journal. The editors are dedicated to making this journal a key source of ground-breaking research in this very exciting and stimulating field”, said Julio Celis.

Eleftherios P. Diamandis, Division Head of Clinical Biochemistry in the Department of Laboratory Medicine and Pathobiology at the University of Toronto in Ontario, Canada and a member of the Editorial Board of MOLONC commented, “This is a major milestone. I have no doubt that MOLONC will become a key journal in the field”

Anne Kitson, Senior Vice-President Life Sciences, at Elsevier added, “This is an exceptional achievement for a journal that is just 18 months old in this fast-moving and highly competitive field. It is indeed recognition of the exemplary work of our highly prestigious editor-in-chief, Julio Celis and his dedicated editorial board members.”

FEBS having pioneered the creation of scientific publication forums for European life scientists by its two leading journals, the FEBS Journal and FEBS Letters, is happy to see the progress of its third journal Molecular Oncology.

The 2009 Impact Factor will be the first Impact Factor for MOLONC. Coverage starts from Volume 1, 2007.

Molecular Oncology

Covers reviews, original articles, technical notes, editorials, news & views (commentary, science policy issues, ethical and legal issues, patient organisations, industry needs and alliances, regulatory issues, news items), letters to the editor, conference announcements, advertisements. The journal also publishes thematic Issues. A main feature of the journal is to provide an international forum for debating cancer issues, and for integrating the input of all the stakeholders.

Topics include key biological processes such as cell cycle, emerging technologies, cancer genetics, Minimal residual disease, pre-malignant lesions, cancer micro-environment, molecular pathology, tumor immunology, translational research, cancer therapy, drug design, immunotherapy, combination therapies, resistance, and individualized treatment, chemotherapy, radiotherapy and surgery, clinical pharmacology, clinical trials, integration of basic science into cancer clinical trials, epidemiology and prevention, infrastructures (biobanks, databases, genomic resources).

Federation of European Biochemical Societies (FEBS)

FEBS is a federation of learned societies with over 40,000 members and a charity established for the public benefit to advance research and education in Biochemistry and Molecular Biology and related life sciences. The federation supports short- and long-term fellowships, advanced courses and workshops, and a variety of events to increase the public awareness of science. In addition, FEBS arranges for the publication of high quality peer-reviewed research journals in the life sciences.

For more information about FEBS: http://www.febs.org

About Elsevier

Elsevier is a world-leading publisher of scientific, technical and medical information products and services. Working in partnership with the global science and health communities, Elsevier’s 7,000 employees in over 70 offices worldwide publish more than 2,000 journals and 1,900 new books per year, in addition to offering a suite of innovative electronic products, such as ScienceDirect (http://www.sciencedirect.com/), MD Consult (http://www.mdconsult.com/), Scopus (http://www.info.scopus.com/), bibliographic databases, and online reference works.

Elsevier (http://www.elsevier.com/) is a global business headquartered in Amsterdam, The Netherlands and has offices worldwide. Elsevier is part of Reed Elsevier Group plc (http://www.reedelsevier.com/), a world-leading publisher and information provider. Operating in the science and medical, legal, education and business-to-business sectors, Reed Elsevier provides high-quality and flexible information solutions to users, with increasing emphasis on the Internet as a means of delivery. Reed Elsevier’s ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Researchers at Purdue University have precisely measured the impact of a high-fat diet on the spread of cancer, finding that excessive dietary fat caused a 300 percent increase in metastasizing tumor cells in laboratory animals.

The researchers used an imaging technique to document how increasing fat content causes cancer cells to undergo changes essential to metastasis. Then they used another technique to count the number of cancer cells in the bloodstream of mice fed a high-fat diet compared to animals fed a lean diet.

The findings suggest that the combined tools represent a possible new diagnostic technique to determine whether a patient’s cancer is spreading, said Ji-Xin Cheng, an assistant professor in Purdue’s Weldon School of Biomedical Engineering and Department of Chemistry.

“It is generally accepted that diet and obesity are accountable for 30 percent of preventable causes of cancer, but nobody really knows why,” Cheng said. “These findings demonstrate that an increase in lipids leads directly to a rise in cancer metastasis.”

Researchers have theorized that tumor cells need more lipids than ordinary tissues to provide energy and material for tumor growth and metastasis.

“Before this work, however, most of the evidence was anecdotal, but here we present a mechanistic study,” said Thuc T. Le, a National Institutes of Health postdoctoral fellow at Purdue who is working with Cheng.

Findings were detailed in a paper published on Jan. 30 in the journal BMC Cancer. The paper was written by Le; Terry B. Huff, a graduate research assistant in Purdue’s Department of Chemistry; and Cheng. The research is supported by the Purdue Cancer Center.

The researchers implanted a cancerous lung tumor under the skin in each of the mice studied, and the animals were separated into two groups: one fed a high-fat diet and the other a lean diet.

The researchers then used an imaging method called coherent anti-Stokes Raman scattering, or CARS, to document how increasing lipids from fat intake induces changes to cancer cell membranes. Those changes, including processes called membrane phase separation and membrane rounding, enhance cancer metastasis.

“If the cancer cells don’t have excess lipids they stick together and form very tight junctions in tumors, but increasing lipids causes them to take on a rounded shape and separate from each other,” Le said.

The change in shape is critical to the ability of cancer cells to separate and spread throughout the body via the bloodstream.

The researchers then used another technique, called intravital flow cytometry, to count the number of cancer cells in the bloodstream of the mice. The technique works by shining a laser though the skin and into blood vessels, where the dyed cancer cells are visible.

Results showed the increase in lipids had no impact on the original tumors implanted in the mice. However, the rate of metastasis rose a dramatic 300 percent in the mice fed a high-fat diet.

The researchers later also examined the animals’ lungs and counted the number of cancer cells that had migrated to the lungs as a result of metastasis. Those findings supported the other results showing increased metastasis in animals fed a high-fat diet.

The researches used the imaging and cell-counting tools to document that linoleic acid, which is predominant in polyunsaturated fats, caused increasing membrane phase separation, whereas oleic acid, found in monounsaturated fats, did not. Increased membrane phase separation could improve the opportunity of circulating tumor cells to adhere to blood vessel walls and escape to organs far from the original tumor site. The new findings support earlier evidence from other research that consuming high amounts of polyunsaturated fat may increase the risk of cancer spreading.

The findings suggest that combining CARS and intravital flow cytometry represents a possible new diagnostic tool to screen patients for cancer. The tool can be used to count lipid-rich tumor cells circulating in a patient’s blood by shining a laser through the skin and into blood vessels. Because lipids can be detected without the need for dyes, the technique might be developed into a convenient method to diagnose whether a patient’s cancer is spreading aggressively, Cheng said.

“These findings open the possibility of an entirely new, relatively simple method for diagnosing whether cancer is metastasizing,” he said.

Future work will focus on not only how obesity increases metastasis but also how it might play a direct role in initiating the development of cancers.

The research has been funded by the National Institutes of Health.

Writer: Emil Venere

ABSTRACT

Coherent Anti-Stokes Raman Scattering Imaging of Lipids in Cancer Metastasis

Thuc T Le1, Terry B Huff2 and Ji-Xin Cheng*1,2,3

1Weldon School of Biomedical Engineering, Purdue University; 2Department of Chemistry, Purdue University; 3Purdue Cancer Center

Background: Lipid-rich tumours have been associated with increased cancer metastasis and aggressive clinical behaviours. Nonetheless, pathologists cannot classify lipid-rich tumours as a clinically distinctive form of carcinoma due to a lack of mechanistic understanding on the roles of lipids in cancer development. Methods: Coherent anti-Stokes Raman scattering (CARS) microscopy is employed to study cancer cell behaviours in excess lipid environments in vivo and in vitro. The impacts of a high-fat diet on cancer development are evaluated in a Balb/c mice cancer model. Intravital flow cytometry and histology are employed to enumerate cancer cell escape to the bloodstream and metastasis to lung tissues, respectively. Cancer cell motility and tissue invasion capability are also evaluated in excess lipid environments. Results: CARS imaging reveals intracellular lipid accumulation is induced by excess free fatty acids (FFAs). Excess FFAs incorporation onto cancer cell membrane induces membrane phase separation, reduces cell-cell contact, increases surface adhesion, and promotes tissue invasion. Increased plasma FFAs level and visceral adiposity are associated with early rise in circulating tumour cells and increased lung metastasis. Furthermore, CARS imaging reveals FFAs-induced lipid accumulation in primary, circulating, and metastasized cancer cells. Conclusion: Lipid-rich tumours are linked to cancer metastasis through FFAs-induced physical perturbations on cancer cell membrane. Most importantly, the revelation of lipid-rich circulating tumour cells suggests possible development of CARS intravital flow cytometry for label-free detection of early-stage cancer metastasis.

The National Institutes of Health’s National Cancer Institute (NCI) has awarded The City College of New York (CCNY) and Memorial Sloan-Kettering Cancer Center (MSKCC) a $15.9 million grant to implement a unique partnership in cancer research, education, and outreach. The five-year, renewable award is funded by NCI’s U54 program, an initiative created to develop partnerships between minority-serving institutions and NCI-designated cancer centers.

The Partnership for Cancer Research, Training, and Community Outreach will build upon a previous collaboration between the institutions. The grant will help support key research activities that provide a multidisciplinary, but unified approach to several objectives set forth by MSKCC and CCNY.

“We are looking forward to partnering with CCNY to improve cancer research, training, education, and outreach for underserved communities in the New York area,” said Dr. Tim A. Ahles, Director of MSKCC’s Neurocognitive Research Laboratory, and U54 Co-Principal Investigator. “We also want to have these successful approaches to address cancer disparities serve as new models for other minority-serving institutions and NCI-designated cancer centers.”

“By combining our talents and some of our resources, CCNY and Memorial Sloan-Kettering will be well equipped to build and nurture programs in areas such as cancer research and community outreach that will help address cancer disparities in underserved minority and economically disadvantaged communities,” said Dr. Karen Hubbard, Professor of Biology at CCNY, and U54 Co-Principal Investigator.

The Partnership for Cancer Research, Training, and Community Outreach includes four primary objectives:

* Investigators will work to develop translational research programs in cell biology, immunology, and biomedical research. Translational research is a concept in which basic science discoveries are applied in clinical practice and clinical observations are studied in the laboratory.

* MSKCC and CCNY will collaborate with diverse communities to help define and address cancer disparities. The proposed Partnership for Community Outreach Program (PCOP) will provide an infrastructure to work with members of the community to identify and prioritize specific areas for action. Other elements of this effort include at least two large-scale annual outreach events and several smaller, topical activities featuring experts on issues such as healthy eating, smoking cessation, and cancer screening.

* A collaborative effort will be made to recruit and retain students from high school to the post-graduate level, in particular those of minority backgrounds, who are interested in pursuing careers in cancer research. Enhanced education and training opportunities, as well as increased mentorship and support, will be made available.

* The partnership will recruit new faculty members at both institutions. U54 resources will help support appointments in key CCNY divisions. At MSKCC, faculty lines will add to the capacity to conduct community-based intervention research and to the development of the PCOP.

About The City College of New York

For more than 160 years, The City College of New York has provided low-cost, high-quality education for New Yorkers in a wide variety of disciplines. Over 15,000 students pursue undergraduate and graduate degrees in the College of Liberal Arts and Sciences; The School of Architecture, Urban Design and Landscape Architecture (SAUDLA); The School of Education; The Grove School of Engineering; and The Sophie Davis School of Biomedical Education. For additional information, visit http://www.ccny.cuny.edu.

About Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to http://www.mskcc.org.

Researchers are trying to open a door for a killer that breast cancer cells shut out.

“If we can figure out how to do that, we could have a new therapeutic target for fighting breast cancer,” says Dr. Thangaraju Muthusamy, assistant professor of biochemistry and molecular biology in the Medical College of Georgia School of Medicine.

Pyruvate is a metabolite in the blood that is lethal to rapidly-multiplying cells, like cancer, and transporters bring substances like pyruvate inside cells. Since breast cancer cells won’t allow pyruvate in, MCG researchers looked to a healthy group of rapidly-dividing breast cells that do let in a similar killer.

For breastfeeding, breast tissue must increase in size to allow milk production, says Dr. Vadivel Ganapathy, chair of the Department of Biochemistry and Molecular Biology in the School of Medicine. When breast-feeding stops, milk accumulates, and butyrate, a short-chain fatty acid similar to pyruvate, starts getting inside the cells. Breast size is reduced and lactation is halted via this process known as involution.

“The normal expansion of breast tissue during lactation is similar to breast cancer when tumors grow and multiply,” Dr. Muthusamy says. “But the cell death that occurs in normal breast tissue during involution does not occur in breast cancer. Tumor cells are smart; they silence the transporter to avoid death. No transporter means no pyruvate is getting into the cells.”

With new grants from the Department of Defense and the National Cancer Institute totaling $2.3 million, researchers will try to force cancer cells to express the transporter and open the door for pyruvate.