Thursday, 24 January 2019

Energizing the immune system to eat cancer


Immune cells called macrophages are supposed to serve and protect, but cancer has found ways to put them to sleep. Now researchers at the Abramson Cancer Center of the University of Pennsylvania say they've identified how to fuel macrophages with the energy needed to attack and eat cancer cells. It is well established that macrophages can either support cancer cell growth and spread or hinder it. But most tumors also express a signal called CD47, which can lull macrophages into a deep sleep and prevent them from eating. Researchers have found that rewiring macrophage metabolism can overcome this signal and act like an alarm clock to rouse and prepare macrophages to go to work. Their findings were published in Nature Immunology today.

Macrophages are immune cells just like T and B cells, but differ in that they can eat cells that are not supposed to be in the body. In fact, they are the most prominent immune cell found in cancer, but unfortunately, most are often convinced to help cancer grow and spread. Cancer cells frequently stop macrophages from attacking them by expressing CD47, a "don't eat me" signal. Researchers now say that merely blocking inhibitory signals like CD47 is not always sufficient to convince macrophages to attack cancer. Instead, two signals are required. First, they need a signal to activate them -- such as a toll-like receptor agonist. After that, a second signal -- such as a CD47 inhibitor -- can lower the threshold needed to wage battle on the cancer.

"It turns out macrophages need to be primed before they can go to work, which explains why solid tumors may resist treatment with CD47 inhibitors alone," said the study's senior author Gregory L. Beatty, Assistant Professor of Hematology-Oncology at Penn's Perelman School of Medicine. 
The team used this approach by activating macrophages with CpG, a toll-like receptor agonist that sends the first signal, and found that it rapidly induced shrinkage of tumors and prolonged survival of mice even without the requirement of T cells. Unexpectedly, they also found that the activated macrophages were able to eat cancer cells even in the presence of high levels of CD47.

To understand the molecular basis of this phenomenon, the team traced the metabolic activity of macrophages and determined that activated macrophages began to utilize both glutamine and glucose as fuel to support the energy requirements needed for them to eat cancer cells. This rewiring of the macrophages metabolism was necessary for CpG to be effective, and the researchers say these findings point to the importance of macrophage metabolism in determining the outcome of an immune response.
"Cancer does not shrink without the help of macrophages and macrophages need the right fuel to eat cancer cells and shrink tumors," Liu said. "To do this, a shift in metabolism is needed to steer the energy in the right direction. It is the metabolism that ultimately allows macrophages to override signals telling them not to do their job."
Beatty points out that patients with diabetes, cardiovascular disease, and other conditions are routinely treated with drugs that could affect macrophage metabolism, but virtually nothing is known about how these drugs might impact immunotherapy responses in cancer, meaning the team's discovery has implications even for existing treatments.
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 08. Advancement in Cancer Treatments

Wednesday, 23 January 2019

New nanoparticle targets tumor-infiltrating immune cells, flips switch


Immunotherapy's promise in the fight against cancer drew international attention after two scientists won a Nobel Prize this year for unleashing the ability of the immune system to eliminate tumor cells.

But their approach, which keeps cancer cells from shutting off the immune system's powerful T-cells before they can fight tumors, is just one way to use the body's natural defenses against deadly disease. A team of Vanderbilt University bioengineers today announced a major breakthrough in another: penetrating tumor-infiltrating immune cells and flipping on a switch that tells them to start fighting. The team designed a nanoscale particle to do that and found early success using it on human melanoma tissue.
"Tumors are pretty conniving and have evolved many ways to evade detection from our immune system," said John T. Wilson, Assistant Professor of Chemical and Biomolecular Engineering and Biomedical Engineering. "Our goal is to rearm the immune system with the tools it needs to destroy cancer cells.Checkpoint blockade has been a major breakthrough, but despite the huge impact it continues to have, we also know that there are a lot of patients who don't respond to these therapies. We've developed a nanoparticle to find tumors and deliver a specific type of molecule that's produced naturally by our bodies to fight off cancer."
That molecule is called cGAMP, and it's the primary way to switch on what's known as the stimulator of interferon genes (STING) pathway: a natural mechanism the body uses to mount an immune response that can fight viruses or bacteria or clear out malignant cells. Wilson said his team's nanoparticle delivers cGAMP in a way that jump-starts the immune response inside the tumor, resulting in the generation of T-cells that can destroy the tumor from the inside and also improve responses to checkpoint blockade.

While the Vanderbilt team's research focused on melanoma, their work also indicates that this could impact treatment of many cancers, Wilson said, including breast, kidney, head and neck, neuroblastoma, colorectal and lung cancer.

His findings appear today in a paper titled "Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy" in the journal Nature Nanotechnology.

Daniel Shae, a Ph.D. student on Wilson's team and first author of the manuscript, said the process began with developing the right nanoparticle, built using "smart" polymers that respond to changes in pH that he engineered to enhance the potency of cGAMP. After 20 or so iterations, the team found one that could deliver cGAMP and activate STING efficiently in mouse immune cells, then mouse tumors and eventually human tissue samples.
"That's really exciting because it demonstrates that, one day, this technology may have success in patients," Shae said.
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 08. Advancement in Cancer Treatments

Gene therapy promotes nerve regeneration


Researchers from the Netherlands Institute for Neuroscience (NIN) and the Leiden University Medical Center (LUMC) have shown that treatment using gene therapy leads to a faster recovery after nerve damage. By combining a surgical repair procedure with gene therapy, the survival of nerve cells and regeneration of nerve fibers over a long distance was stimulated for the first time. The discovery, published in the journal Brain, is an important step towards the development of a new treatment for people with nerve damage.

During birth or following a traffic accident, nerves in the neck can be torn out of the spinal cord. As a result, these patients lose their arm function, and are unable to perform daily activities such as drinking a cup of coffee. Currently, surgical repair is the only available treatment for patients suffering this kind of nerve damage.
"After surgery, nerve fibers have to bridge many centimeters before reaching the muscles and nerve cells from which new fibers need to regenerate are lost in large numbers. Most regenerating nerve fiber do not reach the muscles. The recovery of arm function is therefore disappointing and incomplete," explains researcher Ruben Eggers of the NIN.
Combination of treatments

By combining neurosurgical repair with gene therapy in rats, many of the dying nerve cells can be rescued and nerve fiber growth in the direction of the muscle can be stimulated.

In this study, the researchers used regulatable gene therapy with a growth factor that could be switched on and off by using a widely used antibiotic. "Because we were able to switch off the gene therapy when the growth factor was no longer needed, the regeneration of new nerve fibers towards the muscles was improved considerably," says Ruben Eggers.

A stealth gene switch

To overcome the problem of the immune system recognizing and removing the gene switch, the researchers developed a hidden version, a so-called 'stealth switch'. Professor Joost Verhaagen (NIN) explains: "The stealth gene switch is an important step forward towards the development of gene therapy for nerve damage. The use of a stealth switch improves the gene therapy rendering it even safer."

The gene therapy is not yet ready for use in patients. While the ability to switch off a therapeutic gene is a large step forward, the researchers still found small amounts of the active gene when the switch was turned off. Therefore, further research is needed to optimize this therapy.
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 02. Gene Therapy

Monday, 21 January 2019

Why haven't cancer cells undergone genetic meltdowns?


Cancer first develops as a single cell going rogue, with mutations that trigger aggressive growth at all costs to the health of the organism. But if cancer cells were accumulating harmful mutations faster than they could be purged, wouldn't the population eventually die out?

How do cancer cells avoid complete genetic meltdown?
Famously isolated from cervical cancer victim Henrietta Lacks in 1951, they became the first immortalized cell line, helped in the development of the polio vaccine, and have become a biotechnology foundational resource for any in vitro drug development or cancer studies.

And they are still providing ample opportunities to further our understanding of cancer.
"In this study, HeLa cells are not used to reveal the process of tumorigenesis but mainly a model for addressing the underlying evolutionary forces, which need to be powerful enough to measure in laboratory settings. We examined variation in growth rate among individual HeLa cells by monitoring clones from a common ancestral HeLa cell population," said corresponding author Xuemei Lu.
They first established a HeLa cell line (E6) derived from an ancestral cell line. When the population size of E6 reached approximately 5 × 104 cells (15~16 divisions), five single-cell clones were generated and established in culture. They team DNA sequenced these clones to catalog the mutations. They focused on copy number variation (CNV) rather than single DNA changes because single-nucleotide mutation rates are too slow to produce significant sequence variation during the short-duration culturing experiments.
"We then estimated the deleterious mutation rate and the average fitness decrease per mutation by performing computer simulations of cell growth," said author Hurng-Yi Wang.
Overall, they found that the main mutations affect the copy number of genes, with an average of 0.29 deleterious events for every cell division. Each of these events reduces fitness 18 percent.

Their results indicate that heterogeneity in cell growth can be generated in a very short period of time in cancer cells and is heritable and genetically determined.
"Our estimates indicate that the HeLa cells experience a 5 percent reduction (0.29 ×0.18 ? 5%) in fitness for every generation. Our observations suggest that human cells that have been cultured for a sufficiently long period still generate deleterious mutations in the form of CNVs at a high rate and with a high intensity. For such systems, a mutational meltdown might be plausible."
For example, when they isolated 39 cells from B8 (a fast-growing clone) and 40 cells from E3 (slow growing clone), and monitored their growth from a single cell for seven days, approximately 23 percent of B8 and 50 percent of E3 cells died out within seven days, due to either damage caused during cell isolation or genetic defects.

Most cell lines with growth rates < 0.6 died within 2 months. In total, only 60 percent of B8 and 27 percent of E3 cells survived for more than two months.

Next, they picked about 20 cells from each of the single cell originated clones from B8 and counted their chromosome numbers.

The chromosomes varied far from the normal human number of 46. They ranged from 38 to 113 chromosomes, with most (72 percent) cells harboring between 55 and 70 chromosomes, indicating that they are triploid. Therefore, despite single-cell origin, the progeny quickly generated aneuploidy within only 20-30 cell divisions, again illustrating frequent cytogenetic change in cancer cells.

Despite the level of mutations occurring, reduction in growth rates, and chromosome numbers no longer representing that of normal humans, cancer cells still find a way to survive.
So how do HeLa cells persist?
"High deleterious mutation rate would raise an impression that the HeLa cell lines may have gone extinct long ago," said Lu.
Their simulation results indicated that although most of the cells accumulated deleterious mutations and were worse than the ancestral cells, there were still 13.1 percent of cells which were mutation-free.

"These mutation-free cells can avoid the population from extinction."
It also explains why, even if chemotherapy treatment successfully killed 90 percent of a cancer cell population, it may still not be enough.

The new study not only advances the understanding of the evolution of HeLa cells, and of tumors in general, but of the cells of multicellular organisms in culture in general. In future work, the scientists want to exploit their cancer cell fitness and growth rate findings to understand how cancer cells can become even more vulnerable to recent breakthroughs with checkpoint inhibitor drugs.
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 08. Advancement in Cancer Treatments
 

Saturday, 19 January 2019

How stem cells self-organize in the developing embryo


Embryonic development is a process of profound physical transformation, one that has challenged researchers for centuries. How do genes and molecules control forces and tissue stiffness to orchestrate the emergence of form in the developing embryo? How are the precise mechanics underlying emergence of the complexity of our organs and tissues encoded in our DNA?

One particular aspect of embryonic development: how a group of stem cells -- the endoderm -- moves from the surface of the developing embryo to the center, and in doing so transforms from a flat sheet to a hollow tube. This structure, known as the gut tube, then forms the lining of the entire respiratory and gastrointestinal tracts.

In a study published today in Nature, Nerurkar worked with colleagues at Harvard to shed new light on this critical step in early embryonic development. The team discovered gut tube formation is driven by collective cell movements of the endoderm, a process by which cells travel large distances en masse, without rearranging relative to one another. They also found that this collective movement is triggered by cells that are converting a molecular gradient to a force gradient that drives cells from the surface into the embryo. This discovery is one of the few examples, especially among vertebrates, of how molecular cues are converted into the physical forces that shape our organs.
The study findings could have important implications for how stem cells are used to create functional organs in the lab, and lead to a better understanding of the underlying causes of gastrointestinal birth defects. "Our major goal is to understand how we, as complex organisms, are formed with such precision from a seemingly disorganized ball of cells -- the early embryo," says Nandan Nerurkar, assistant professor of biomedical engineering at Columbia Engineering.
Identifying genes that drive differentiation of stem cells into mature cell types -- the primary focus in Nerurkar's field -- is an important step toward growing replacement organs in the lab. However, Nerurkar suggests this is only part of the picture: "It is equally important to understand how to instruct those cells to organize into functional three-dimensional organs. The developing embryo holds the recipe for this, and many research groups, including ours, are now leveraging the language of physics and mechanics to dissect it."

The team used an innovative approach at the leading edge of the developmental biology field. They combined conventional approaches of developmental biology, including analysis and manipulation of gene expression and live time lapse microscopy of cell movements in the developing chick embryo, with engineering methods, such as mathematical modeling and force and strain measurements.

They focused on one part of endoderm internalization: the hindgut, which gives rise to half of the small intestine, the large intestine, and colon. What was previously known of gut tube formation came from fate-mapping experiments, wherein cells are labeled early in development and then mapped to where the labeled cells end up later in development. This static analysis, which uses static images of the beginning and the end of the process to make an educated guess of what happens in the middle, has led to a view of gut tube formation that is present in most embryology textbooks. "Based on our recent findings, this view is at best incomplete, and at worst completely wrong," says Nerurkar.

Unlike earlier fate-mapping studies, Nerurkar and his colleagues used live imaging in the embryo to directly observe cell movements as the endoderm is internalized to form a tube. They next applied a combination of mechanical engineering and developmental biology approaches to understand just how those cell movements occur, and how the movements are coordinated to form this critical structure in the early embryo.

The team found that the movements are coordinated by the conversion of a molecular gradient into a force gradient from cells that are contracting in proportion to the amount of a molecular cue -- fibroblast growth factor (FGF) -- that they sense. This results in a tug of war among endoderm cells: as one "team" begins to win, the cells actually recruit players from the opposing team by pulling them from low to higher concentrations of FGF.
Irregularities in FGF function can lead to a number of developmental defects. "During human development, errors in gut tube formation would likely lead to miscarriage, something that is a relatively high risk during the first trimester, when this process is occurring," says Nerurkar.
While this study focused on just one part of endoderm internalization, the hindgut, it is still unknown how the foregut, which forms the trachea, lungs, esophagus, stomach, and liver, and the midgut, which forms the pancreas and small intestine, are formed. Nerurkar plans to use his new approach to study these other areas of embryonic development and investigate if and how FGF signaling acts more broadly to control mechanics in the development of other tissues and organs.
"I want to learn more about how mechanics and molecules are integrated to coordinate the formation of these very distinct tissues by disparate mechanisms, yet from the same initial pool of stem cells," he says. "By focusing on the tissue-level mechanics downstream of FGF signaling, we may now be able to understand what this important pathway does to shape other organs and tissues during development, including the heart, brain, and spinal column."
Nerurkar is continuing this research at Columbia Engineering, developing quantitative molecular-mechanical relationships that could be used to design and construct replacement tissues in the lab, using controlled delivery of these diffusible cues -- the instructional signals that are secreted by cells and then float away to neighboring cells -- to instruct the self organization of cells into functional tissues and organs. If he and others in this field can establish the design principles of embryonic tissue formation, it will be possible to repurpose those same principles for regenerative medicine and tissue engineering applications.
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell TherapyCancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 09. Stem Cells and its Applications

Friday, 18 January 2019

Mathematical model can improve our knowledge on cancer


Researchers have developed a new mathematical tool, which can improve our understanding of what happens when cells lose their polarity (direction) in diseases such as cancer. The result is advancing our understanding of how the fertilized egg cell develops into a complete organism. Biological shapes, like individual organs or an entire body, can be reproduced or maintained with great accuracy, just like in the embryonic development or during the adult stage.

It remains unknown how cells "know" which structures to form in order to repair tissue damage:

Multicellular organisms can develop highly complex structures that make up their tissue or organs and are capable of regenerating perfect reproductions of these structures after injury. This involves folding of sheets, formed by groups of dividing and interacting cells. Yet, although much is understood about some of the intermediate steps that occur during development and tissue repair, exactly how thousands of cells together work out what shapes they need to form remains unknown.
Building the mathematical model:
"In this study, we wanted to see how cells organize into folded sheets and tubes, and how this process can be so precisely reproduced as is seen during development," says lead author Silas Boye Nissen, PhD student at the Center for Stem Cell Decision Making, StemPhys, University of Copenhagen, Denmark. "To answer this question, we built a mathematical tool that can model two types of cell polarities and simulated how many cells organize themselves into folded sheets and organs."
The researchers found that by changing one of two polarities in the model, they were able to simulate a rich diversity of shapes. The differences in the shapes were dictated by two factors: The initial arrangement of the cells and external boundaries -- such as the shape of an egg influencing the development of the embryo inside.

By exploring a multitude of theoretical scenarios in which the polarities were altered, the model was able to narrow down the focus to a few theories to be tested experimentally. In miniaturized versions of organs grown in the lab (called organoids), the model predicted that rapid, off-balance growth of cells will cause the growing organoid to develop lots of shallow folds, while external pressure caused by the medium on the organoids will cause fewer, deeper and longer folds. This means the model can improve our understanding of how folded organs like the brain or the pancreas are formed.
Few, simple rules apply for the formation of biological shapes:
"Our findings advance our understanding of how properties of individual cells lead to differences in shapes formed by thousands of cells," says senior author Professor Kim Sneppen, Director of the Center for Models of Life, CMOL, University of Copenhagen, and senior coauthor Ala Trusina concludes: "Our work suggests that body parts may not need detailed instructions to form, but instead can emerge as cells follow a few simple rules. We can now explore what happens if cells gain or lose their polarities at the wrong time or place, as often happens in cancer."
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 08. Advancement in Cancer Treatments

Thursday, 17 January 2019

Study of mutation order may change understanding of how tumors develop


Cancers most commonly arise because of a series of two to five mutations in different genes that combine to cause a tumor. Evidence from a growing number of experiments focused on truncal mutations the first mutations in a given suggests a new direction in understanding the origins of cancer.

This study was published in Cancer Cell by authors from Institute for Advanced Study and The University of Texas MD Anderson Cancer Center, present a new perspective of these data, highlighting two important variables: 1) the sequence of mutations that leads to the formation of a cancer, and 2) the cell type in which this occurs, providing a new meaningful insight into the growth, properties, and outcomes of these tumors.

The concepts developed in this paper suggest new avenues for future experimentation, help to explain previously unclear observations, and recommend new methods to impede cancer development, including blocking the defined sequence that is required to produce a tumor.
Arnold J. Levine of the Institute for Advanced Study explains, "This paper does not publish any new experiments. Rather, it outlines a new way to understand and interpret existing results, and in so doing helps to explain previously confusing facts, outlining the differences in developing cancers at young or older ages, and emphasizing the important role of inherited predispositions to developing cancers. The publication suggests entirely new paths to studying the origins of cancers over a lifetime."
The study collects numerous examples of how the order of mutations affects the outcome of the tumor and its response to therapy. This highlights of this paper is an opportunity for researchers to look at hundreds of these evolutionary trees with different orders of mutations that will perhaps provide a fingerprinting method that could reveal information about a cancer's type, growth, and potential to invade surrounding tissues at the time of diagnosis so that treatments can be planned. With an understanding of these complex mutational chains, pharmaceutical and biotechnology firms could begin to consider interventions to inhibit particular links within a mutational sequence that could block the further development of a cancer. Drugs directed against the first and second mutational outcomes may completely prevent the third and fourth mutations from ever being selected for in a clone of cells. The focus in this paper is thus on cancer prevention, not treatment.

Many different kinds of cancers arise by the random accumulation of mutations (mistakes in the information in a gene) over a lifetime. For instance, past research has shown that colorectal cancer is associated with mutations in the following four distinct genes: APC, RAS, TGF-beta, and p53, each of which contributes an error in different functions being carried out by the cells in one's colon.

Copeland and Jenkins have demonstrated that colon cancer develops most rapidly when the APC gene is mutated first, the RAS gene second, the TGF-beta gene third, and the p53 gene last. Mutations in the first three genes produce benign tumors. Only when all four genes are mutated is there a malignant tumor. But mutations occur randomly over a lifetime. The order is imposed by Darwinian selection. An APC mutation permits a clone of cells to grow (forming a benign polyp). When an RAS mutation occurs in this clone of cells the polyp enlarges, increasing the number of cells with these two mutations and, therefore, the probability that a cancer may arise. Thus, the ordering of these random mutations is selected for by the viability and replication of cells with this order of mutations. The Levine laboratory showed the same need for an order of mutations in five different genes to produce a different cancer: T-cell lymphomas. It was these two papers, published approximately three years ago, that started Copeland, Jenkins, and Levine exploring whether this was the pathway in the development of all cancers; "Order of Mutations and Cell Type Matters."

The trio's new Cancer Cell paper provides scientists and innovators with a new set of questions to ask about tumor development that could move the field of cancer research in a new and exciting direction.
Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem CellRegenerative MedicineStem Cell TherapyCancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019
You can submit your abstract on Session or Track : 07. Cancer Cell Biology

Energizing the immune system to eat cancer

Immune cells called macrophages are supposed to serve and protect, but cancer has found ways to put them to sleep. Now researchers a...