Protein that turns normal cells into cancer stem cells offers target to fight colon cancer

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Colon cancer: Photo courtesy WebMD

Colon cancer is a global killer. Each year more than one million people worldwide are diagnosed with it; more than half a million die from it. If diagnosed early enough the standard treatment involves surgery, chemotherapy, radiation or targeted drug therapy to destroy the tumors. In many cases this may work. But in some cases, while this approach helps put people in remission, eventually the cancer returns, spreads throughout the body, and ultimately proves fatal.

Now researchers may have identified a protein that causes normal cells to become cancerous, and turn into cancer stem cells (CSCs). This discovery could help provide a new target for anti-cancer therapies.

Cancer stem cells are devilishly tricky. While most cancer cells are killed by chemotherapy or other therapies, cancer stem cells are able to lie dormant and hide, then emerge later to grow and spread, causing the person to relapse and the cancer to return.

In a study published in Nature Research’s Scientific Reports, researchers at SU Health New Orleans School of Medicine and Stanley S. Scott Cancer Center identified a protein, called SATB2, that appears to act as an “on/off” switch for specific genes inside a cancer cell.

In normal, healthy colorectal tissue SATB2 is not active, but in colorectal cancer it is highly active, found in around 85 percent of tumors. So, working with mice, the researchers inserted extra copies of the SATB2 gene, which produced more SATB2 protein in normal colorectal tissue. They found that this produced profound changes in the cell, leading to uncontrolled cell growth. In effect it turned a normal cell into a cancer stem cell.

As the researchers state in their paper:

“These data suggest that SATB2 can transform normal colon epithelial cells to CSCs/progenitor-like cells which play significant roles in cancer initiation, promotion and metastasis.”

When the researchers took colorectal cancer cells and inhibited SATB2 they found that this not only suppressed the growth of the cancer and it’s ability to spread, it also prevented those cancer cells from becoming cancer stem cells.

In a news release about the study Dr. Rakesh Srivastava,  the senior author on the paper, said the findings are important:

“Since the SATB2 protein is highly expressed in the colorectal cell lines and tissues, it can be an attractive target for therapy, diagnosis and prognosis.”

Because SATB2 is found in other cancers too, such as breast cancer, these findings may hold significance for more than just colorectal cancer.

The next step is to repeat the study in mice that have been genetically modified to better reflect the way colon cancer shows up in people. The team hope this will not only confirm their findings, but also give them a deeper understanding of the role that SATB2 plays in cancer formation and spread.

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Taming the Zika virus to kill cancer stem cells that drive lethal brain tumor

An out of control flame can be very dangerous, even life-threatening. But when harnessed, that same flame sustains life in the form of warm air, a source of light, and a means to cook.

A similar duality holds true for viruses. Once it infects the body, a virus can replicate like wildfire and cause serious illness and sometimes death. But in the lab, researchers can manipulate viruses to provide an efficient, harmless method to deliver genetic material into cells, as well as to prime the immune system to protect against future infections.

In a Journal of Experimental Medicine study published this week, researchers from the University of Washington, St. Louis and UC San Diego also show evidence that a virus, in this case the Zika virus, could even be a possible therapy for a hard-to-treat brain cancer called glioblastoma.

Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). Image: Zhe Zhu, Washington U., St. Louis.

Recent outbreaks of the Zika virus have caused microcephaly during fetal development. Babies born with microcephaly have a much smaller than average head size due to a lack of proper brain development. Children born with this condition suffer a wide range of devastating symptoms like seizures, difficulty learning, and movement problems just to name a few. In the race to understand the outbreak, scientists have learned that the Zika virus induces microcephaly by infecting and killing brain stem cells, called neural progenitors, that are critical for the growth of the developing fetal brain.

Now, glioblastoma tumors contain a small population of cells called glioblastoma stem cells (GSCs) that, like neural progenitors, can lay dormant but also make unlimited copies of themselves.  It’s these properties of glioblastoma stem cells that are thought to allow the glioblastoma tumor to evade treatment and grow back. The research team in this study wondered if the Zika virus, which causes so much damage to neural progenitors in developing babies, could be used for good by infecting and killing cancer stem cells in glioblastoma tumors in adult patients.

To test this idea, the scientists infected glioblastoma brain tumor samples with Zika and showed that the virus spreads through the cells but primarily kills off the glioblastoma stem cells, leaving other cells in the tumor unscathed. Since radiation and chemotherapy are effective at killing most of the tumor but not the cancer stem cells, a combination of Zika and standard cancer therapies could provide a knockout punch to this aggressive brain cancer.

Even though Zika virus is much more destructive to the developing fetal brain than to adult brains, it’s hard to imagine the US Food and Drug Administration ever approving the injection of a dangerous virus into the site of a glioblastoma tumor. So, the scientists genetically modified the Zika virus to make it more sensitive to the immune system’s first line of defense called the innate immunity. With just the right balance of genetic alterations, it might be possible to retain the Zika virus’ ability to kill off cancer stem cells without causing a serious infection.

The results were encouraging though not a closed and shut case: when glioblastoma cancer stem cells were infected with these modified Zika virus strains, the virus’ cancer-killing abilities were weaker than the original Zika strains but still intact. Based on these results, co-senior author and WashU professor, Dr. Michael S. Diamond, plans to make more tweaks to the virus to harness it’s potential to treat the cancer without infecting the entire brain in the process.

“We’re going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading,” said Diamond in a press release. “Once we add a few more changes, I think it’s going to be impossible for the virus to overcome them and cause disease.”

 

CIRM weekly stem cell roundup: stomach bacteria & cancer; vitamin C may block leukemia; stem cells bring down a 6’2″ 246lb football player

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This is what your stomach glands looks like from the inside:  Credit: MPI for Infection Biology”

Stomach bacteria crank up stem cell renewal, may be link to gastric cancer (Todd Dubnicoff)

The Centers for Disease Control and Prevention estimate that two-thirds of the world’s population is infected with H. pylori, a type of bacteria that thrives in the harsh acidic conditions of the stomach. Data accumulated over the past few decades shows strong evidence that H. pylori infection increases the risk of stomach cancers. The underlying mechanisms of this link have remained unclear. But research published this week in Nature suggests that the bacteria cause stem cells located in the stomach lining to divide more frequently leading to an increased potential for cancerous growth.

Tumors need to make an initial foothold in a tissue in order to grow and spread. But the cells of our stomach lining are replaced every four days. So, how would H. pylori bacterial infection have time to induce a cancer? The research team – a collaboration between scientists at the Max Planck Institute in Berlin and Stanford University – asked that question and found that the bacteria are also able to penetrate down into the stomach glands and infect stem cells whose job it is to continually replenish the stomach lining.

Further analysis in mice revealed that two groups of stem cells exist in the stomach glands – one slowly dividing and one rapidly dividing population. Both stem cell populations respond similarly to an important signaling protein, called Wnt, that sustains stem cell renewal. But the team also discovered a second key stem cell signaling protein called R-spondin that is released by connective tissue underneath the stomach glands. H. pylori infection of these cells causes an increase in R-spondin which shuts down the slowly dividing stem cell population but cranks up the cell division of the rapidly dividing stem cells. First author, Dr. Michal Sigal, summed up in a press release how these results may point to stem cells as the link between bacterial infection and increased risk of stomach cancer:

“Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed.”

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Vitamin C may have anti-blood cancer properties

Vitamin C is known to have a number of health benefits, from preventing scurvy to limiting the buildup of fatty plaque in your arteries. Now a new study says we might soon be able to add another benefit: it may be able to block the progression of leukemia and other blood cancers.

Researchers at the NYU School of Medicine focused their work on an enzyme called TET2. This is found in hematopoietic stem cells (HSCs), the kind of stem cell typically found in bone marrow. The absence of TET2 is known to keep these HSCs in a pre-leukemic state; in effect priming the body to develop leukemia. The researchers showed that high doses of vitamin C can prevent, or even reverse that, by increasing the activity level of TET2.

In the study, in the journal Cell, they showed how they developed mice that could have their levels of TET2 increased or decreased. They then transplanted bone marrow with low levels of TET2 from those mice into healthy, normal mice. The healthy mice started to develop leukemia-like symptoms. However, when the researchers used high doses of vitamin C to restore the activity levels of TET2, they were able to halt the progression of the leukemia.

Now this doesn’t mean you should run out and get as much vitamin C as you can to help protect you against leukemia. In an article in The Scientist, Benjamin Neel, senior author of the study, says while vitamin C does have health benefits,  consuming large doses won’t do you much good:

“They’re unlikely to be a general anti-cancer therapy, and they really should be understood based on the molecular understanding of the many actions vitamin C has in cells.”

However, Neel says these findings do give scientists a new tool to help them target cells before they become leukemic.

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Bad toe forces Jordan Reed to take a knee: Photo courtesy FanRag Sports

Toeing the line: how unapproved stem cell treatment made matters worse for an NFL player  

American football players are tough. They have to be to withstand pounding tackles by 300lb men wearing pads and a helmet. But it wasn’t a crunching hit that took Washington Redskins player Jordan Reed out of the game; all it took to put the 6’2” 246 lb player on the PUP (Physically Unable to Perform) list was a little stem cell injection.

Reed has had a lingering injury problem with the big toe on his left foot. So, during the off-season, he thought he would take care of the issue, and got a stem cell injection in the toe. It didn’t quite work the way he hoped.

In an interview with the Richmond Times Dispatch he said:

“That kind of flared it up a bit on me. Now I’m just letting it calm down before I get out there. I’ve just gotta take my time, let it heal and strengthen up, then get back out there.”

It’s not clear what kind of stem cells Reed got, if they were his own or from a donor. What is clear is that he is just the latest in a long line of athletes who have turned to stem cells to help repair or speed up recovery from an injury. These are treatments that have not been approved by the Food and Drug Administration (FDA) and that have not been tested in a clinical trial to make sure they are both safe and effective.

In Reed’s case the problem seems to be a relatively minor one; his toe is expected to heal and he should be back in action before too long.

Stem cell researcher and avid blogger Dr. Paul Knoepfler wrote he is lucky, others who take a similar approach may not be:

“Fortunately, it sounds like Reed will be fine, but some people have much worse reactions to unproven stem cells than a sore toe, including blindness and tumors. Be careful out there!”

New target for defeating breast cancer stem cells uncovered

Stashed away in most of your tissues and organs lie small populations of adult stem cells. They help keep our bodies functioning properly by replenishing dying or damaged cells. Their ability to make more copies of themselves, as needed, ensures that there’s always an adequate supply set aside. But this very same self-renewing, life-sustaining property of adult stem cells is deadly in the hands of cancer stem cells. Also called tumor-initiating cells, cancer stem cells sustain tumor growth even after chemotherapy and are thought to be a primary cause of cancer relapse.

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Microscopic image of normal mouse mammary ducts. Mammary stem cells are found among basal cells (green). Image courtesy of Toni Celià-Terrassa and Yibin Kang, Princeton University

By studying adult and cancer stem cells side-by-side, Princeton researchers report this week in Nature Cell Biology that they’ve uncovered a common function in both cells types that not only helps explain an adult stem cell’s self-renewing ability but also points to new therapeutic approaches to targeting breast cancer stem cells.

Both adult and cancer stem cells continually resist signals from their environment that encourage them to specialize, or differentiate, into a particular cell type. Once specialized, the cells lose their ability to self-renew and will eventually die off. Now, if all the adult stem cells in an organ followed that instruction, they would eventually become depleted and the organ would lose the ability to repair itself. The same holds true for cancer stem cells which actually would be a good thing since it would lead to the tumor’s death.

The Princeton team first identified a molecule called miR-199a that allows mammary (breast) stem cells to resist differentiation signals by directly blocking the production of a protein called LCOR. Artificially boosting the amount of miR-199a led to a decrease in LCOR levels and an increase in stem cell function. But when LCOR levels were increased, mammary stem cell function was restricted.

The researchers then turned their attention to breast cancer stem cells and found the same miR-199a/LCOR function at work. In a similar fashion, boosting miR-199a levels enhanced cancer stem cell function and increased tumor formation while increasing LCOR restricted the tumor-forming ability of the breast cancer stem cells.

These lab results also matched up with tissue samples taken from breast cancer patients. High miR-199a levels in the samples correlated with low patient survival rates. But those with high levels of LCOR showed a better prognosis.

It turns out that cells in our immune system are responsible for boosting LCOR in mammary and breast cancer stem cells by releasing a protein called interferon alpha. So the presence of interferon alpha nudges mammary stem cells to mature into mammary gland cells and inhibits breast cancer stems from forming tumors. But in the presence of elevated miR-199a levels, mammary and breast cancer stem cells are protected and maintain their numbers by deactivating the interferon alpha/LCOR signal.

If you’re still with me, these results point to miR-199a as a promising target for restoring interferon-alpha’s cancer interfering properties. Team leader Dr. Yibin Kang highlighted this possibility in a Princeton University press release:

“Interferons have been widely used for the treatment of multiple cancer types. These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway.”

Stem cell stories that caught our eye: better ovarian cancer drugs, creating inner ear tissue, small fish big splash

Two drugs are better than one for ovarian cancer (Karen Ring). Earlier this week, scientists from UCLA reported that a combination drug therapy could be an effective treatment for 50% of aggressive ovarian cancers. The study was published in the journal Precision Oncology and was led by Dr. Sanaz Memarzadeh.

Women with high-grade ovarian tumors have an 85% chance of tumor recurrence after treatment with a common chemotherapy drug called carboplatin. The UCLA team found in a previous study that ovarian cancer stem cells are to blame because they are resistant to carboplatin. It’s because these stem cells have an abundance of proteins called cIAPs, which prevent cell death from chemotherapy.

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Ovarian cancer cells (blue) expressing cIAP protein (red) on the left are more sensitive to a combination therapy than cancer cells that don’t express the protein on the right. (UCLA Broad Stem Cell Research Center/Precision Oncology)

Memarzadeh discovered that an experimental drug called birinapant made some ovarian cancer tumors more sensitive to chemotherapy treatment by breaking down cIAPs. This gave her the idea that combining the two drugs, birinapant and carboplatin, might be a more effective strategy for treating aggressive ovarian tumors.

By treating with the two drugs simultaneously, the scientists improved the survival rate of mice with ovarian cancer. They also tested this combo drug treatment on 23 ovarian cancer cell lines derived from women with highly aggressive tumors. The treatment killed off half of the cell lines indicating that some forms of this cancer are resistant to the combination treatment.

When they measured the levels of cIAPs in the human ovarian cancer cell lines, they found that high levels of the proteins were associated with ovarian tumor cells that responded well to the combination treatment. This is exciting because it means that clinicians can analyze tumor biopsies for cIAP levels to determine whether certain ovarian tumors would respond well to combination therapy.

Memarzadeh shared her plans for future research in a UCLA news release,

“I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy.”

In a first, researchers create inner ear tissue. From heart muscle to brain cells to insulin-producing cells, researchers have figured out how to make a long list of different human cell types using induced pluripotent stem cells (iPSCs) – cells taken from the body and reprogrammed into a stem cell-like state.

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Human inner ear organoid with sensory hair cells (cyan) and sensory neurons (yellow). An antibody for the protein CTBP2 reveals cell nuclei as well as synapses between hair cells and neurons (magenta). | Photo: Karl Koehler

This week, a research group at the Indiana University School of Medicine successfully added inner ear cells to that list. This feat, published in Nature Biotechnology, is especially important given the fact that the inner ear is one of the few parts of the body that cannot be biopsied for further examination. With these cells in hands, new insights into the causes of hearing loss and balance disorders may be on the horizon.

The inner ear contains 75,000 sensory hair cells that convert sound waves into electrical signals to the brain. Loud noises, drug toxicity, and genetic mutations can permanently damage the hair cells leading to hearing loss and dizziness. Over 15%  of the U.S. population have some form of hearing loss and that number swells to 67% for people over 75.

Due to the complex shape of the inner ear, the team grew the iPSCs into three dimensional balls of cells rather than growing them as a flat layer of cells on a petri dish. With educated guesses sprinkled in with some trial and error, the scientists, for the time, identified a recipe of proteins that stimulated the iPSCs to transform into inner ear tissue. And like any great recipe, it wasn’t so much the ingredient list but the timing that was key:

“If you apply these signals at the wrong time you can potentially generate a brain instead of an inner ear,” first author Dr. Karl Koehler said in an interview with Gizmodo. “The real breakthrough is that we figured out the exact timing to do each one of these [protein] treatments.”

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Senior author, Eri Hashino, Ph.D., and first author, Karl R. Koehler, Ph.D. Photo: Indiana University

Careful examination shows that the tissue, referred to as organoids, not only contained the sensory hair cells of the inner ear cell but also nerve cells, or neurons, that are responsible for relaying the sound waves to the brain. Koehler explained the importance of this result in a press release:

“We also found neurons, like those that transmit signals from the ear to the brain, forming connections with sensory cells. This is an exciting feature of these organoids because both cell types are critical for proper hearing and balance.”

Though it’s still early days, these iPSC-derived inner ear organoids are a key step toward the ultimate goal of repairing hearing loss. Senior author, Dr. Eri Hashino, talked about the team’s approach to reach that goal:

“Up until now, potential drugs or therapies have been tested on animal cells, which often behave differently from human cells. We hope to discover new drugs capable of helping regenerate the sound-sending hair cells in the inner ear of those who have severe hearing problems.”

This man’s research is no fish tale
And finally, we leave you this week with a cool article and video by STAT. It features Dr. Leonard Zon of Harvard University and his many, many tanks full of zebrafish. This little fish has made a huge splash in understanding human development and disease. But don’t take my word for it, watch the video!

Stem Cell Stories That Caught Our Eye: Three new ways to target cancer stem cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Targeting cancer stem cells. This week, three studies came out with novel ways for targeting cancer stem cells in different types of cancers. Here’s a brief run-down of this trifecta of cancer stem cell-crushing stories:

Take your vitamins! Scientists in the UK were experimenting on cancer stem cells and comparing natural substances to on-the-market cancer drugs to determine whether any of the natural substances were effective at disrupting the metabolism (the chemical reactions that keep cells alive and functioning) of cancer stem cells. Interestingly, they found that ascorbic acid, which you’ll know as Vitamin C, was ten times better at curbing cancer stem cell growth compared to a cancer drug called 2-DG.

Vitamin C has popped up as an anti-cancer treatment in the past when Nobel Laureate Linus Pauling found that it dramatically reduced the death rate in breast cancer patients. However this current study is the first to show that Vitamin C has a direct effect on cancer stem cells.

In coverage by ScienceDaily, the UK team hinted at plans to test Vitamin C in clinical trials:

“Vitamin C is cheap, natural, non-toxic and readily available so to have it as a potential weapon in the fight against cancer would be a significant step. Our results indicate it is a promising agent for clinical trials, and a as an add-on to more conventional therapies, to prevent tumour recurrence, further disease progression and metastasis.”

 

A gene called ZEB1 determines how aggressive brain tumors are. A team from Cedars-Sinai Medical Center was interested to know how cancer stem cells in aggressive brain tumors called gliomas survive, reproduce and affect patient survival. In a study published in Scientific Reports, they studied the genetic information of over 4000 brain tumor samples and found ZEB1, a gene that regulates tumor growth and is associated with patient survival.

They found that patients with a healthy copy of the ZEB1 gene had a higher survival rate and less aggressive tumors compared to patients that didn’t have ZEB1 or had a mutated version of the gene.

In coverage by ScienceDaily, the senior author on the study explained how their study’s findings will allow for more personalized treatments for patients with glioma based on whether they have ZEB1 or not:

“Patients without the gene in their tumors have more aggressive cancers that act like stem cells by developing into an uncontrollable number of cell types. This new information could help us to measure the mutation in these patients so that we are able to provide a more accurate prognosis and treatment plan.”

 

Beating resistant tumors by squashing cancer stem cells. Our final cancer stem cell story today comes from the UCLA School of Dentistry. This team is studying another type of aggressive cancer called a squamous cell carcinoma that causes tumors in the head and neck. Often these tumors resist treatment and spread to a patient’s lymph nodes, which quickly reduces their survival rate.

The UCLA team thought that maybe pesky cancer stem cells were to blame for the aggressive and resistant nature of these head and neck tumors. In a study published in Cell Stem Cell, they developed a mouse model of head and neck carcinoma and isolated cancer stem cells from the tumors of these mice. When they studied these stem cells, they found that they expressed unique proteins compared to non-cancer cells. These included Bmi1, a well-known stem cell protein, and AP-1, a transcription factor protein that regulates other cancer genes.

At left, head and neck squamous cell carcinoma invasive growth, and at right, cancer stem cells (shown in red) in head and neck squamous cell carcinoma. (Image Demeng Chen and Cun-Yu Wang/UCLA)

After identifying the culprits, the team developed a new combination strategy that targeted the cancer stem cells while also killing off the tumors using chemotherapy drugs.

In a UCLA Newsroom press release, the lead scientist on the study Dr. Cun-Yu Wang explained the importance of their study for the future treatment of cancer and solid tumors:

“This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.”

Stem cell stories that caught our eye: drug safety for heart cells, worms hijack plant stem cells & battling esophageal cancer

Devising a drug safety measuring stick in stem cell-derived heart muscle cells
One of the mantras in the drug development business is “fail early”. That’s because most of the costs of getting a therapy to market occur at the later stages when an experimental treatment is tested in clinical trials in people. So, it’s best for a company’s bottom line and, more importantly, for patient safety to figure out sooner rather than later if a therapy has dangerous toxic side effects.

Researchers at Stanford reported this week in Science Translational Medicine on a method they devised that could help weed out cancer drugs with toxic effects on the heart before the treatment is tested in people.

In the lab, the team grew beating heart muscle cells, or cardiomyocytes, from induced pluripotent stem cells derived from both healthy volunteers and kidney cancer patients. A set of cancer drugs called tyrosine kinase inhibitors which are known to have a range of serious side effects on the heart, were added to the cells. The effect of the drugs on the heart cell function were measured with several different tests which the scientists combined into a single “safety index”.

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A single human induced pluripotent stem cell-derived cardiomyocyte. Cells such as these were used to assess tyrosine kinase inhibitors for cardiotoxicity in a high-throughput fashion. Credit: Dr. Arun Sharma at Dr. Joseph Wu’s laboratory at Stanford University

They found that the drugs previously shown to have toxic effects on patients’ hearts had the worst safety index values in the current study. And because these cells were in a lab dish and not in a person’s heart, the team was able to carefully examine cell activity and discovered that the toxic effects of three drugs could be alleviated by also adding insulin to the cells.

As lead author Joseph Wu, director of the Stanford Cardiovascular Institute, mentions in a press release, the development of this drug safety index could provide a powerful means to streamline the drug development process and make the drugs safer:

“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients. It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects”

Worm feeds off of plants by taking control of their stem cells
In what sounds like a bizarre mashup of a vampire movie with a gardening show, a study reported this week pinpoints how worms infiltrate plants by commandeering the plants’ own stem cells. Cyst nematodes are microscopic roundworms that invade and kill soybean plants by sucking out their nutrients. This problem isn’t a trivial matter since nematodes wreak billions of dollars of damage to the world’s soybean crops each year. So, it’s not surprising that researchers want to understand how exactly these critters attack the plants.

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A nematode, the oblong object on the left, activates the vascular stem cell pathway in the developing nematode feeding site on a plant root. Credit: Xiaoli Guo, University of Missouri

Previous studies by Melissa Goellner Mitchum, a professor at the University of Missouri, had shown that the nematodes release protein fragments, called peptides, near a plant’s roots that help divert the flow of plant nutrients to the worm.

“These parasites damage root systems by creating a unique feeding cell within the roots of their hosts and leeching nutrients out of the soybean plant. This can lead to stunting, wilting and yield loss for the plant,” Mitchum explained in a press release.

In the current PLOS Pathogens study, Mitchum’s team identified another peptide produced by the nematode that is identical to a plant peptide that instructs stem cells to form the plant equivalent of blood vessels. This devious mimicking of the plant peptides is what allows the nematode to trick the plant stem cells into building vessels that reroute the plants’ nutrients directly to the worm.

Mitchum described the big picture implications of this fascinating discovery:

“Understanding how plant-parasitic nematodes modulate host plants to their own benefit is a crucial step in helping to create pest-resistant plants. If we can block those peptides and the pathways nematodes use to overtake the soybean plant, then we can enhance resistance for this very valuable global food source.”

Finding vulnerabilities in treatment-resistant esophageal cancer stem cells

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Illustration of radiation therapy for esophageal cancer.
Credit: Cancer Research UK

The incidence of esophageal cancer has increased more than any other disease over the past 30 years. And while some patients respond well to chemotherapy and radiation treatment, most do not because the cancer becomes resistant to these treatments.

Focusing on cancer stem cells, researchers at Trinity College Dublin have identified an approach that may overcome treatment resistance.

Within tumors are thought to lie cancer stem cells that, just like stem cells, have the ability to multiply indefinitely. Even though they make up a small portion of a tumor, in some patients the cancer stem cells evade the initial rounds of treatment and are responsible for the return of the cancer which is often more aggressive. Currently, there’s no effective way to figure out how well a patient with esophageal cancer will response to treatment.

In the current study published in Oncotarget, the researchers found that a genetic molecule called miR-17 was much less abundant in the esophageal cancer stem cells. In fact, the cancer stem cells with the lowest levels of miR-17, were the most resistant to radiation therapy. The researchers went on to show that adding back miR-17 to the highly resistant cells made them sensitive again to the radiation. Niamh Lynam-Lennon, the study’s first author, explained in a press release that these results could have direct clinical applications:

“Going forward, we could use synthetic miR-17 as an addition to radiotherapy to enhance its effectiveness in patients. This is a real possibility as a number of other synthetic miR-molecules are currently in clinical trials for treating other diseases.”

Stories that caught our eye: new target for killing leukemia cancer stem cells and stem cell vesicles halt glaucoma

New stem cell target for acute myeloid leukemia (Karen Ring).  A new treatment for acute myeloid leukemia, a type of blood cancer that turns bone marrow stem cells cancerous, could be in the works in the form of a cancer stem cell destroying antibody.

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Acute Myeloid Leukemia (Credit: Medscape)

Scientists from the NYU Langone Medical Center and the Memorial Sloan Kettering Cancer Center identified a protein called CD99 that appears more abundantly on the surface of abnormal blood cancer stem cells compared to healthy blood stem cells. They developed an antibody that specifically recognizes and kills the CD99 wielding cancer stem cells while leaving the healthy blood stem cells unharmed.

The CD99 antibody was effective at killing human AML stem cells in a dish and in mice that were transplanted with the same type of cancer stem cells. Further studies revealed that the CD99 antibody when attached to the surface of cancer stem cells, sets off a cascade of enzyme activity that causes these cells to die. These findings suggest that cancer stem cells express more CD99 as a protective mechanism against cell death.

In an interview with Genetic Engineering and Biotechnology News, Chris Park, senior author on the Science Translational Medicine study, explained the importance of their work:

“Our findings not only identify a new molecule expressed on stem cells that drive these human malignancies, but we also show that antibodies against this target can directly kill human AML stem cells. While we still have important details to work out, CD99 is likely to be an exploitable therapeutic target for most AML and MDS patients, and we are working urgently to finalize a therapy for human testing.”

While this work is still in the early stages, Dr. Park stressed that his team is actively working to translate their CD99 antibody therapy into clinical trials.

“With the appropriate support, we believe we can rapidly determine the best antibodies for use in patients, produce them at the quality needed to verify our results, and apply for permission to begin clinical trials.”

 

Peculiar stem cell function may help treat blindness (Todd Dubnicoff). Scientists at the National Eye Institute (NEI) have uncovered a novel function that stem cells use to carry out their healing powers and it may lead to therapies for glaucoma, the leading cause of blindness in United States. Reporting this week in Stem Cells Translational Medicine, the researchers show that stem cells send out regenerative signals by shedding tiny vesicles called exosomes. Once thought to be merely a garbage disposal system, exosomes are now recognized as an important means of communication between cells. As they bud off from the cells, the exosomes carry proteins and genetic material that can be absorbed by other cells.

Microscopy image shows exosomes (green) surrounding retinal ganglion cells (orange and yellow). Credit: Ben Mead

Microscopy image shows exosomes (green) surrounding retinal ganglion cells (orange and yellow). Credit: Ben Mead

The researchers at NEI isolated exosomes from bone marrow stem cells and injected them into the eyes of rats with glaucoma symptoms. Without treatment, these animals lose about 90 percent of their retinal ganglion cells, the cells responsible for forming the optic nerve and for sending visual information to the brain. With the exosome treatment, the rats only lost a third of the retinal ganglion cells. The team determined that microRNAs – small genetic molecules that can inhibit gene activity – inside the exosome were responsible for the effect.

Exosomes have some big advantages over stem cells when comes to developing and manufacturing therapies which lead author Ben Mead explains in a press release picked up by Eureka Alert:

“Exosomes can be purified, stored and precisely dosed in ways that stem cells cannot.”

We’ll definitely keep our eyes on this development. If these glaucoma studies continue to look promising it stands to reason that there would be exosome applications in many other diseases.

Stem Cell Profiles in Courage: Karl’s Fight with Cancer

Karl Trede

Karl Trede

When I think of a pioneer I have an image in my head of people heading west across the Americans plains in the 18th century, riding in a covered wagon pulled by weary oxen.

Karl Trede doesn’t fit that image at all. He is a trim, elegant man who has a ready smile and a fondness for Hawaiian shirts. But he is no less a pioneer for all that. That’s why we profiled him in our 2016 Annual Report.

In 2006 Karl was diagnosed with cancer of the throat. He underwent surgery to remove his vocal chords and thought he had beaten the cancer. A few years later, it came back. That was when Karl became the first person ever treated in a CIRM-funded clinical trial testing a new anti-tumor therapy targeting cancer stem cells that so far has helped hold the disease at bay.

Here is Karl’s story, in his own words:

“I had some follow-up tests and those showed spots in my lungs. Over the course of several years, they saw those spots grow, and we knew the cancer had spread to my lungs. I went to Stanford and was told there was no effective treatment for it, fortunately it was slow growing.

Then one day they said we have a new clinical trial we’re going to start would you be interested in being part of it.

I don’t believe I knew at the time that I was going to be the first one in the trial [now that’s what I call a pioneer] but I thought I’d give it a whirl and I said ‘Sure’. I wasn’t real concerned about being the first in a trial never tested in people before. I figured I was going to have to go someday so I guess if I was the first person and something really went wrong then they’d definitely learn something; so, to me, that was kind of worth my time.

Fortunately, I lasted 13 months, 72 treatments with absolutely no side effects. I consider myself really lucky to have been a part of it.

It was an experience for me, it was eye opening. I got an IV infusion, and the whole process was 4 hours once a week.

Dr. Sikic (the Stanford doctor who oversees the clinical trial) made it a practice of staying in the room with me when I was getting my treatments because they’d never tried it in people, they’d tested it in mice, but hadn’t tested it in people and wanted to make sure they were safe and nothing bad happened.

The main goals of the trial were to define what the side effects were and what the right dose is and they got both of those. So I feel privileged to have been a part of this.

My wife and I (Vita) have four boys. They’re spread out now – two in the San Francisco Bay Area, one in Oregon and one in Nevada. But we like to get together a few times a year. They’re all good cooks, so when we have a family get together there’s a lot of cooking involved.

The Saturday after Thanksgiving, in 2015, the boys decided they wanted to have a rib cook-off for up to around 30 people and I can proudly say that I kicked their ass on the rib cook-off. I have an electric cooker and I just cook ‘em slow and long. I do a cranberry sauce, just some home made bbq sauces

I’m a beef guy, I love a good steak, a good ribeye or prime rib, I make a pretty mean Oso bucco, I make a good spaghetti sauce, baked chicken with an asparagus mousse that is pretty good.

I just consider myself a lucky guy.”

Karl Trede with CIRM President Randy Mills at the 2016 December Board meeting.

Karl Trede with CIRM President Randy Mills at the 2016 December Board meeting.


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Cured by Stem Cells

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To get anywhere you need a good map, and you need to check it constantly to make sure you are still on the right path and haven’t strayed off course. A year ago the CIRM Board gave us a map, a Strategic Plan, that laid out our course for the next five years. Our Annual Report for 2016, now online, is our way of checking that we are still on the right path.

I think, without wishing to boast, that it’s safe to say not only are we on target, but we might even be a little bit ahead of schedule.

The Annual Report is chock full of facts and figures but at the heart of it are the stories of the people who are the focus of all that we do, the patients. We profile six patients and one patient advocate, each of whom has an extraordinary story to tell, and each of whom exemplifies the importance of the work we support.

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Brenden Whittaker: Cured

Two stand out for one simple reason, they were both cured of life-threatening conditions. Now, cured is not a word we use lightly. The stem cell field has been rife with hyperbole over the years so we are always very cautious in the way we talk about the impact of treatments. But in these two cases there is no need to hold back: Evangelina Padilla Vaccaro and Brenden Whittaker have been cured.

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Evangelina: Cured

 

In the coming weeks we’ll feature our conversations with all those profiled in the Annual Report, giving you a better idea of the impact the stem cell treatments have had on their lives and the lives of their family. But today we just wanted to give a broad overview of the Annual Report.

The Strategic Plan was very specific in the goals it laid out for us. As an agency we had six big goals, but each Team within the agency, and each individual within those teams had their own goals. They were our own mini-maps if you like, to help us keep track of where we were individually, knowing that every time an individual met a goal they helped the Team get closer to meeting its goals.

As you read through the report you’ll see we did a pretty good job of meeting our targets. In fact, we missed only one and we’re hoping to make up for that early in 2017.

But good as 2016 was, we know that to truly fulfill our mission of accelerating treatments to patients with unmet medical needs we are going to have do equally well, if not even better, in 2017.

That work starts today.