Stem cell study holds out promise for kidney disease

Kidney failure

Image via youtube.com

Kidney failure is the Rodney Dangerfield of diseases, it really doesn’t get the respect it deserves. An estimated 660,000 Americans suffer from kidney failure and around 47,000 people die from it every year. That’s more than die from breast or prostate cancer. But now a new study has identified a promising stem cell candidate that could help in finding a way to help repair damaged kidneys.

Kidneys are the body’s waste disposal system, filtering our blood and cleaning out all the waste products. Our kidneys have a limited ability to help repair themselves but if someone suffers from chronic kidney disease then their kidneys are slowly overwhelmed and that leads to end stage renal disease. At that point the patient’s options are limited to dialysis or an organ transplant.

Survivors hold out hope

Italian researchers had identified some cells in the kidneys that showed a regenerative ability. These cells, which were characterized by the expression of a molecule called CD133, were able to survive injury and create different types of kidney cells.

Researchers at the University of Torino in Italy decided to take these findings further and explore precisely how CD133 worked and if they could take advantage of that and use it to help repair damaged kidneys.

In their findings, published in the journal Stem Cells Translational Medicine, the researchers began by working with a chemotherapy drug called cisplatin, which is used against a broad range of cancers but is also known to cause damage to kidneys in around one third of all patients. The team found that CD133 was an important factor in helping those damaged kidneys recover. They also found that CD133 prevents aging of kidney progenitor cells, the kind of cell needed to help create new cells to repair the kidneys in future.

Hope for further research

The finding opens up a number of possible lines of research, including exploring whether infusions of CD133 could help patients whose kidneys are no longer able to produce enough of the molecule to help repair damage.

In an interview in DD News, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine – praised the research:

“This is an interesting and novel finding. Because the work identifies mechanisms potentially involved in the repair of tissue after injury, it suggests the possibility of new therapies for tissue repair and regeneration.”

CIRM is funding several projects targeting kidney disease including four clinical trials for kidney failure. These are all late-stage kidney failure problems so if the CD133 research lives up to its promise it might be able to help people at an earlier stage of disease.

UC Irvine scientists engineer stem cells to “feel” cancer and destroy it

By blocking cell division, chemotherapy drugs take advantage of the fact that cancer cells multiply rapidly in the body. Though this treatment can extend and even save the lives of cancer patients, it’s somewhat like destroying an ant hill with an atomic bomb: there’s a lot of collateral damage. The treatment is infused through the blood so healthy cells that also divide frequently – like those in hair follicles, the intestines and bone marrow – succumb to the chemotherapy. To add insult to injury, cancers often become resistant to these drugs and metastasize, or invade, other parts of the body. Sadly, this spreading of a cancer is responsible for 90% of cancer deaths.

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UCI doctoral students Shirley Zhang, left, and Linan Liu are co-leading authors of the study. Photo: UC Irvine

Developing more specific, effective anti-cancer therapies is the focus of many research institutes and companies. While some new strategies target cell surface proteins that are unique to cancer cells, a UC Irvine (UCI) team has devised a stem cell-based technique that can seek out and destroy breast cancer cells that have metastasized in the lungs of mice by sensing the stiffness of the surrounding tissue. The CIRM-funded study was published this week in Science Translational Medicine.

While cells make up the tissues and organs of our bodies, they also secrete proteins and molecules that form a scaffold between cells called the extracellular matrix. This cell scaffolding is not just structural, it also plays a key role in regulating cell growth and other functions. And previous studies have shown that at sites of tumors, accumulation of collagen and other proteins in the matrix increases tissue stiffness and promotes metastasis.

Based on this knowledge, the UCI team aimed to create a cell system that would release chemotherapy drugs in response to increased stiffness. It turns out that mesenchymal stem cells – which give rise to bone, muscle, cartilage and fat – not only migrate to tumors in the body but also activate particular genes in response to the stiffness of their local cellular environment.  The researchers engineered mesenchymal stem cells to carry a gene that codes for a protein involved in the activation of a chemotherapy drug which is given by mouth. They also designed the gene to turn on only when it encounters stiff, cancerous tissue. They called the method a mechanoresponsive cell system (MRCS).

To test the MRCS, mice were infused with human breast cancer cells, which metastasized or spread to the lung. The MRCS-engineered mesenchymal stem cells were infused through the blood and homed to the lungs where they activated the chemotherapy drug which caused localized killing of the tumor cells with minimal damage to lung tissue. When the MRSC stem cells were given to mice without tumors, no increase in tissue damage was seen, proving that the MRSC-induced chemotherapy drug is only activated in the presence of cancerous tissue and has few side effects.

In a press release, team leader Weian Zhao, explained that these promising results could have wide application:

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Weian Zhao
Photo: UC Irvine

“This published work is focused on breast cancer metastases in the lungs. However, the technology will be applicable to other metastases as well, because many solid tumors have the hallmark of being stiffer than normal tissue. This is why our system is innovative and powerful, as we don’t have to spend the time to identify and develop a new genetic or protein marker for every kind of cancer.”

 

The team envisions even more applications. The MRCS could be engineered to carry genes that would enable detection with imaging technologies like PET scans. In this scenario, the MRCS could act as a highly sensitive detection system for finding areas of very early metastases when current techniques would miss them. They could also design the MRCS to activate genes that code for proteins that can break down and soften the stiff cancerous tissues which may inhibit the ability for a tumor to spread.

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.”

Sleep inducing hormone puts breast cancer cells to rest  

It’s pretty easy to connect the dots between a lack of sleep and an increased risk of a deadly car crash. But what about an increased risk of cancer? A 2012 study of 101 women newly diagnosed with breast cancer found that those with inadequate sleep were more likely to have more aggressive tumors. Though the results of this survey were statistically significant, the biological connection between sleep and breast cancer is not well understood.

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Melatonin, the sleep hormone, may help fight cancer. Image Credit

Now, a report in Genes and Cancer by a Michigan State University research team shows that the interplay between melatonin, a hormone involved in sleep-wake cycles, and breast cancer stem cells may provide an explanation. And, more importantly, the study points to melatonin’s potential use as a cancer therapeutic.

Mammospheres: cancer in a more natural environment
To carry out their lab experiments, the researchers grew breast cancer cells into three-dimensional aggregates, called mammospheres, that resemble the tumor cell composition seen in an actual tumor in the body. This cell mix includes breast cancer stem cells which are thought to drive the uncontrolled tumor growth and reccurrence. David Arnosti, a MSU professor and co-author on the study, used a helpful analogy in a university press release to explain the importance of using the mammosphere technique:

“You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild. Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That’s what is so special about this work.”

 

Melatonin fighting cancer cells via their stem cell-like properties
The cancer cells used in this study are also categorized as so-called estrogen receptor (ER) -positive cells. This classification means that the cancer growth is largely stimulated by the hormone estrogen.  The first round of experiments analyzed melatonin’s effects on estrogen’s ability to increase the growth and size of the mammospheres. The team also tested Bisphenol A (BPA), a chemical used in the plastics industry that mimics estrogen’s effects. While estrogen or BPA alone caused a large increase in mammosphere size and number, addition of melatonin stunted these effects.

Next, the team went deeper and looked at melatonin’s impact from a genes and proteins perspective. Estrogen is a steroid hormone that acts by passing through the cell wall and binding to the estrogen receptor inside the cell. Once bound by estrogen, the receptor travels to a cell’s nucleus and binds particular regions of DNA which can activate genes. One of those activated genes is responsible for producing OCT4, a protein that plays a critical role in a stem cell’s ability to indefinitely makes copies of itself and to maintain its unspecialized, stem cell state. This cellular pathway is how estrogen helps drives the growth of ER-positive breast cancer cells. The researchers showed that estrogen- and BPA-stimulated binding of the estrogen receptor to the OCT4 gene in the mammospheres was inhibited when melatonin was added to the cells.

Melatonin: putting cancer stems to bed?
Putting these observations together, melatonin appears to suppress breast tumor growth by directing inhibiting genes responsible for driving the stem cell-like properties of the breast cancer stem cells within the mammosphere. Melatonin is produced by the brain’s pineal gland which is only active at night. Once released, melatonin helps induce sleep. So a disrupted sleep pattern, like insomnia, would reduce melatonin levels and as a consequence the block on estrogen driven cancer growth is removed. ­

James Trosko, whose MSU lab perfected the mammosphere technique, sees these breast cancer results in a larger perspective:

“This work establishes the principal by which cancer stem cell growth may be regulated by natural hormones, and provides an important new technique to screen chemicals for cancer-promoting effects, as well as identify potential new drugs for use in the clinic.”

 

Keep in mind that these are very preliminary studies and more work is needed before a potential clinical application sees the light of day. In the meantime, have a good day and get a good night’s sleep.

 

 

Breast cancer: Piecing together early detection and treatment

Developing therapies for disease is kind of like trying to put together a series of incredibly complex puzzles. Scientists collect lots of “puzzle pieces”, in the form of data, through experiments in the lab and clinic or by reading up on other researchers’ results. Each piece gives researchers a tidbit of insight but the breakthroughs rely on connecting the pieces to see the whole picture.

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This is how the story has played out for a research team studying breast cancer at the Medical College of Georgia at Augusta University. Reporting last Friday in the American Journal of Pathology, the researchers connected the origin of several cell types present in breast tumor tissue to a common mutant precursor stem cell that is likely responsible for helping tumors thrive.

This finding was made possible by the identification of a mutation in the gene, GT198, that may not only provide a diagnostic tool for early breast cancer detection but also a totally new target for therapies. This is hopeful news for the one in eight women in the U.S. who will develop invasive breast cancer during their lifetime.

The GT198 gene carries the code for a protein that activates other genes in the presence of the hormone, estrogen. In its mutated form, GT198 protein no longer relies on estrogen to function and instead get stuck in the “on” position. Analyzing 249 human breast cancer tissues and 11 healthy samples, the researchers detected GT198 protein in breast tumor stromal tissue but not in the healthy samples.

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Anatomy of the breast. The cells of the stroma produce connective tissue and fat which support the lobules and ducts, structures that produce and deliver milk.

The stroma (meaning “mattress” in Greek) contains various cell types, some of which are responsible for producing fat and connective tissue, that provide structural support for the milk producing glands and ducts in the breast. But the presence of mutated GT198 in the tumor stromal tissue is thought to sabotage the cells into providing a favorable microenvironment for tumor growth. For instance, in one cell culture experiment, the team showed that mutant GT198 but not normal GT198 leads to increased angiogenesis, or new blood vessel growth, and fat production – activities associated with cancer initiation.

The presence of the mutant GT198 in not just one but several of the tumor stromal cell types, strongly suggests that they all come from the same stem cell or progenitor cell. Among the cells harboring the GT198 mutation, the pericytes – found in the stromal capillary blood vessels – also have significant amounts of CD44, a marker for progenitor cells, the progeny of stem cells. So the team hypothesizes that mutant pericytes are the precursor cells that give rise to the other mutant cells found in breast cancer stromal tissue.

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GT198 protein (brown staining) is specifically detected in various cell types found in breast cancer stroma. Tumor cells outside the stroma (panel K) don’t have GT198. Blue color indicates DNA.
Am J Pathol 2016, 186: 1-11

In an interview with MedicalResearch.com, senior author Kan Lo described the implications of these findings:

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Dr. Kan Lo

“In breast cancer, the progenitor cells are mutated leaving mutant stromal cell offspring with altered activities to induce tumor. Mutant stem or progenitor cells may have longer lifespan than their mutant descendants so that they can fuel cancer growth for years. Eliminating those mutant progenitors at the source, at least in theory, will efficiently stop cancer.”

 

One way of getting rid of those mutant progenitors could be by developing drugs that block the GT198 protein. Another exciting use of GT198 is as a diagnostic. Since the mutant stromal cells are important for providing the right conditions for tumor growth, it’s likely that they are present in the early stages of the cancer. So testing for the presence GT198 could be a tool for catching breast cancer early.

Sounds like we need to put together a few more puzzles before scientists can understand the full story of GT198 and breast cancer.

Stem cell stories that caught our eye: Parkinson’s trial revived, aspirin kills cancer stem cells and a stem cell role in mother-child obesity

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.

Parkinson’s clinical trials back on track.
After nearly 20 years of being stuck on the clinical trial “bookshelf”, an international team from Cambridge, UK revived a cell therapy for Parkinson’s disease.

In an announcement picked up this week by the Genetic Literacy Project, the team reported they had treated their first patient. Specifically, fetal brain cells were injected into the brain of a man in his mid-50’s with the disease.

Neurons derived from human embryonic stem cells

A fluorescent microscopic image of numerous dopaminergic neurons (the type of neurons that are degenerated in Parkinson’s disease patients) generated from human embryonic stem cells. Image courtesy of the Xianmin Zeng lab at the Buck Institute for Age Research.

In Parkinson’s, nerve cells controlling movement die for poorly understood reasons. An accumulation of data through the 60’s and 70’s suggested transplantation of fetal brain cells into the Parkinson’s brain would replace the lost nerve cells and restore movement control. After initial promising results in the 80’s and 90’s, larger clinical trials showed no significant benefit and even led to a worsening of symptoms in some patients.

Due to these outcomes, the research community shelved the approach. Insights gained in the interim pointed to more ideal brain injection sites in order to help avoid side effects. Also, follow up on patients beyond the two-year run of those early trials suggested that positive effects of the cell therapy may not emerge for at least three to five years. So this latest trial will run longer to capture this time window.

One remaining snag for this therapeutic strategy is the limited number of available cells for each transplant. So in the meantime, scientists including some of our grantees are working hard at getting embryonic stem cell- or iPS cell-based therapies to the clinic. Since stem cells divide indefinitely, this approach could provide an off-the-shelf, limitless supply of the nerve cells. Stay tuned.

Targeting cancer stem cells with the Wonder Drug.
Aspirin: it’s the wonder drug that may turn out to be even more wonderful.

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Ball and stick model of aspirin, the wonder drug: relieves pain and prevents cancer

Famous for relieving pain and preventing heart attacks, aspirin may add breast cancer-killer to its resume. This week a cancer research team at the Kansas City (Mo.) Veteran Affairs Medical Center published experiments picked up by Eureka Alert showing a daily dose of aspirin could put the brakes on breast cancer.

The analysis attributed this anti-cancer effect to aspirin’s capacity to reduce the growth of cancer stem cells. These cells make up a tiny portion of a tumor but if chemotherapy or radiation treatment leaves any behind, it’s thought the cells’ stem cell-like ability for unlimited growth drives cancer relapse and spread (metastasis).

In the study, mice with tumors given a daily low dose of aspirin for 15 days had, on average, tumors nearly 50% smaller than the aspirin-free mice. In another set of experiments, the team showed aspirin could prevent tumors as well. Mice were given aspirin for 10 days before exposing them to cancer cells. After another 15 days, the aspirin treated animals had significantly less tumor growth compared to an untreated group.

Senior author Sushanta Banerjee stands behind these findings: he’s been taking an aspirin a day for three years but stresses that you should consult with your doctor before trying it yourself.

A stem cell link to the passing on of obesity from mom to child?
It’s been observed that children of obese moms have a high risk for obesity and diabetes. You might conclude that genetics are the culprit as well as lifestyle habits passed down from parent to child. But research published this week by researchers at the University of Colorado School of Medicine suggests another mechanism: they conclude the mere presence of the growing embryo in the uterus of an obese mother may instruct the child’s cells to take on more fat.

The team’s reasoning is based on an analysis of umbilical cord blood stem cells collected from babies born to 12 obese mothers and 12 normal weight mothers. In the lab, the stem cells were specialized into fat and muscle cells. The cells from babies of obese mothers showed increased fat accumulation and a lower production of proteins important for uptake of blood sugar (a state that could eventually tip the scales towards diabetes).

Certainly it’s a leap to link the property of cells in a dish to the eventual health of a child. But the results are intriguing enough that the researchers intend to follow the children as they get older to look for more connections between the state of the kids’ stem cells and their health profile.

Cancer Cells Mimic Blood Vessels to Colonize the Body’s Farthest Reaches

Scientists at Cold Spring Harbor Laboratory have just uncovered the latest dirty trick in the cancer playbook—one that spurs the cancer cells to spread throughout the body and evade treatment. But importantly, they believe they may have found a way to counter it.

Reporting today in the journal Nature, Cold Spring Harbor researchers describe how tumor cells can form tubular networks that mimic blood vessels. It is this mimicry, the team argues, that plays a key role in helping the cancer spread throughout the body—and a significant hurdle to successfully treating the disease.

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Using mouse models of breast cancer, the team—led by Simon Knott—identified this phenomenon, called ‘vascular mimicry,’ and revealed that two genes, called Serpine2 and Slpi, were driving it. Made up of tumor cells literally stacked together, these tubular networks allowed oxygen and other nutrients to reach far-flung tumor cells throughout the body. This kept the tumor cells healthy, and helped them spread.

In today’s press release, Knott explained his initial reactions to this critical discovery:

“It’s very neat to watch and see cells evolve to have these capacities, but on the other hand it’s really scary to think that these cells are sitting there in people doing this.”

In laboratory experiments, the team found that boosting levels of Serpin2 and Slpi boosted the cancer’s ability to build these networks. Conversely, shutting down these two genes appeared to do the opposite. Knott argues that targeting the proteins that these two genes produce, as a way of shutting them off, may be a winning strategy:

“Targeting them might provide therapeutic benefits,” said Knott, “but we’re not sure yet.”

Indeed, research efforts over the past decade or more have tried to curb the production of these tubular networks of tumor cells, but with limited success. These drugs, called angiogenesis inhibitors, may not have worked as well as originally hoped because the underlying mechanism that creates this vascular mimicry—namely the genes Serpin2 and Slpi—was not targeted. Postdoctoral researcher Elvin Wagenblast, the paper’s first author, thinks they might have more success now:

“Maybe by targeting angiogenesis and also vascular mimicry at the same time we might actually have a better benefit in the clinic in the long run.”

This strategy is ultimately the goal of the team, but much work remains. Their most immediate next steps are to understand the process by which tumor cells pass through these tubular networks and infiltrate new areas of the body. But armed with this new-found knowledge of vascular mimicry, these and other researchers may be well on their way to outsmarting cancer, at least some of the time.

Breast Cancer Tumors Recruit Immune Cells to the Dark Side

We rely on our immune system to stave off all classes of disease—but what happens when the very system responsible for keeping us healthy turns to the dark side? In new research published today, scientists uncover new evidence that reveals how breast cancer tumors can actually recruit immune cells to spur the spread of disease.

Some forms of breast cancer tumors can actually turn the body's own immune system against itself.

Some forms of breast cancer tumors can actually turn the body’s own immune system against itself.

Breast cancer is one of the most common cancers, and if caught early, is highly treatable. In fact, the majority of deaths from breast cancer occur because the disease has been caught too late, having already spread to other parts of the body, a process called ‘metastasis.’ Recently, scientists discovered that women who have a heightened number of a particular type of immune cells, called ‘neutrophils,’ in their blood stream have a higher chance of their breast cancer metastasizing to other tissues. But they couldn’t figure out why.

Enter Karin de Visser, and her team at the Netherlands Cancer Institute, who announce today in the journal Nature the precise link between neutrophil immune cells and breast cancer metastasis.

They found that some types of breast tumors are particularly nefarious, sending out signals to the person’s immune system to speed up their production of neutrophils. And then they instruct these newly activated neutrophils to go rogue.

Rather than attack the tumor, these neutrophils turn on the immune system. They especially focus their efforts at blocking T cells—the type of immune cells whose job is normally to target and attack cancer cells. Further examination in mouse models of breast cancer revealed a particular protein, called interleukin 17 (or IL17) played a key role in this process. As Visser explained in today’s news release:

“We saw in our experiments that IL17 is crucial for the increased production of neutrophils. And not only that, it turns out that this is also the molecule that changes the behavior of the neutrophils, causing them to become T cell inhibitory.”

The solution then, was clear: block the connection, or pathway, between IL17 and neutrophils, and you can thwart the tumor’s efforts. And when Visser and her team, including first author and postdoctoral researcher Seth Coffelt, did this they saw a significant improvement. When the IL17-neutrophil pathway was blocked in the mouse models, the tumors failed to spread at the same rate.

“What’s notable is that blocking the IL17-neutrophil route prevented the development of metastases, but did not affect the primary tumor,” Visser added. “So this could be a promising strategy to prevent the tumor from spreading.”

The researchers are cautious about focusing their efforts on blocking neutrophils, however, as these cells are in and of themselves important to stave off infections. A breast cancer patient with neutrophil levels that were too low would be at risk for developing a whole host of infections from dangerous pathogens. As such, the research team argues that focusing on ways to block IL17 is the best option.

Just last month, the FDA approved an anti-IL17 based therapy to treat psoriasis. This therapy, or others like it, could be harnessed to treat aggressive breast cancers. Says Visser:

“It would be very interesting to investigate whether these already existing drugs are beneficial for breast cancer patients. It may be possible to turn these traitors of the immune system back towards the good side and prevent their ability to promote breast cancer metastasis.”

Combination Cancer Therapy Gives Cells a Knockout Punch

For some forms of cancer, there really is no way to truly eradicate it. Even the most advanced chemotherapy treatments leave behind some straggler cells that can fuel a relapse.

By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable. [Credit: Aaron Goldman]

By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable.
[Credit: Aaron Goldman]

But now, scientists have devised a unique strategy, something they are calling a ‘one-two punch’ that can more effectively wipe out dangerous tumors, and lower the risk of them ever returning for a round two.

Reporting in the latest issue of the journal Nature Communications, bioengineers at Brigham and Women’s Hospital (BWH) in Boston describe how treating breast cancer cells with a targeted drug immediately after chemotherapy was effective at killing the cancer cells and preventing a recurrence. According to lead scientist Shiladitya Sengupta, these findings were wholly unexpected:

“We were studying the fundamentals of how [drug] resistance develops and looking to understand what drives [cancer] relapse. What we found is a new paradigm for thinking about chemotherapy.”

In recent years, many scientists have suggested cancer stem cells are one of the biggest hurdles to curing cancer. Cancer stem cells are proposed to be a subpopulation of cancer cells that are resistant to chemotherapy. As a result, they can propagate the cancer after treatment, leading to a relapse.

In this work, Sengupta and his colleagues treated breast cancer cells with chemotherapy. And here is where things started getting interesting.

After chemotherapy, the breast cancer cells began to morph into cells that bore a close resemblance to cancer stem cells. For a brief period of time after treatment, these cells were neither fully cancer cells, nor fully stem cells. They were in transition.

The team then realized that because these cells were in transition, they may be more vulnerable to attack. Testing this hypothesis in mouse models of breast cancer, the team first zapped the tumors with chemotherapy. And, once the cells began to morph, they then blasted them with a different type of drug. The tumors never grew back, and the mice survived.

Interestingly, the team did not have similar success when they altered the timing of when they administered the therapy. Treating the mice with both types of drugs simultaneously didn’t have the same effect. Neither did increasing the time between treatments. In order to successfully treat the tumor they had a very slim window of opportunity.

“By treating with chemotherapy, we’re driving cells through a transition state and creating vulnerabilities,” said Aaron Goldman, the study’s first author. “This opens up the door: we can then try out different combinations and regimens to find the most effective way to kill the cells and inhibit tumor growth.”

In order to test these combinations, the researchers developed an ‘explant,’ a mini-tumor derived from a patient’s biopsy that can be grown in an environment that closely mimics its natural surroundings. The ultimate goal, says Goldman, is to map the precise order and timing of this treatment regimen in order to move toward clinical trials:

“Our goal is to build a regimen that will be [effective] for clinical trials. Once we’ve understood specific timing, sequence of drug delivery and dosage better, it will be easier to translate these findings clinically.”

Breast Cancer Commandeers Mammary Stem Cells for Own, Nefarious Purposes

Most instances of breast cancer happen later in life—often after menopause. In many cases, the cancer progresses slowly, over a period of months or even years, often giving physicians precious time to implement a treatment plan, successfully battling that cancer into remission.

A section from a mammary 'outgrowth' harvested at lactation. [Credit: UC San Diego School of Medicine]

A section from a mammary ‘outgrowth’ harvested at lactation. [Credit: UC San Diego School of Medicine]

But there is another far more aggressive form of breast cancer that tends to develop earlier, often immediately following pregnancy. And now, researchers at the University of California, San Diego (UCSD) have discovered how this form of cancer hijacks a woman’s own stem cells to grow quickly and spread throughout the body.

Reporting in the latest issue of the journal Developmental Cell, UCSD stem cell researchers Drs. David Cheresh and Jay Desgrosellier and their teams have found a link between the molecular signaling switches that spur this aggressive, post-pregnancy breast cancer—and mammary stem cells that are normally activated during pregnancy.

These findings, say Cheresh, offer key insight into how scientists may develop better treatments for this form of breast cancer. As he stated in a news release:

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated.”

Normally, pregnancy activates a special group of stem cells in the mammary gland. Their job is to ready the expectant mother for feeding the newborn baby. By the time the baby is born, however, these stem cells go back into hibernation.

However, in some women, these mammary stem cells get hijacked by cancer cells. Rather than the mammary stem cells shutting down by the time milk production begins, cancer cells keep them switched on—which then contributes to the progression of cancer.

These findings shed much-needed light on the complex relationship between breast cancer and pregnancy. However, the authors caution that these findings don’t imply that becoming pregnant causes breast cancer. Rather, as Cheresh explained:

“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated.”

Cheresh, who has received CIRM support for related work, has pinpointed a protein called CD61 that may promote the progression of breast cancer. CD61 has already been implicated in cancer metastasis and resistance to cancer drugs, so it makes sense that it would play a role in breast cancer as well.

Importantly, the discovery of a potential connection between CD61 and this form of breast cancer may ultimately open up new avenues for treating this type of cancer more successfully.

“Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

Want to learn more about breast cancer and stem cells? Check out our Solid Tumor Fact Sheet.