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Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cells, also called iPS cells, made from easily accessible skin or other adult cells, are ideal for disease modeling, drug discovery and, possibly, cell therapy. That’s because they can be generated in large numbers and grown indefinitely in the laboratory. They also reflect the genetic background of the person from whom they were generated. However, some fundamental questions still remain before they’re ready for the full glare of the clinical limelight. Does it matter what type of starting cells scientists use to create the pluripotent stem cells? And what’s the best control to use when studying the effect of a particular, patient-specific mutation?

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have addressed and answered these questions. Their work was published yesterday in two back-to-back papers in the Journal of the American College of Cardiology. (Each paper is also accompanied by an editorial.) As Wu explained in an e-mail to me:

If your goal is to generate healthy iPS cell derivatives for regenerative therapy, it’s important to know whether the starting material makes a difference. For example, if I’m treating Alzheimer’s disease, is there a benefit to using iPS cell-derived brain cells made from brain cells? Likewise, if I’m treating a skin disorder, is there a benefit to using iPS cell-derived skin cells made from skin cells? As cardiologists, we are asked this quite often and each time, I had to say “I don’t know.” So we decided to do a study comparing the differentiation and functional ability of iPS cell-derived cardiomyocytes generated from two different sources: skin and heart. We also wanted to devise more efficient ways for researchers to quickly and easily create their own “designer” iPS cell lines to study particular mutations.

To answer the first question, the researchers created iPS cells from two types of starter cells: human fetal skin cells and cardiac progenitor cells. Not surprisingly, only the cardiac progenitor cells expressed genes known to be expressed in heart tissue. Wu and his colleagues then exposed the newly created pluripotent stem cells to growing conditions that favor the development of heart muscle cells called cardiomyocytes. They found that, although iPS cells derived from cardiac progenitor cells were more efficient at becoming cardiomyocytes, both types of starting material produced heart muscle cells that functioned similarly after a period of growth in the laboratory. As Wu explained:

These two populations of cells are essentially no different from one another over time. It appears that they lost the memory of their starting material (this memory is stored in the form of chemical tags on the cells’ DNA in a phenomena known as epigenetic marking). This suggests that I could take my own skin cells, make iPS cells and then create specialized brain, heart, liver or kidney cells for cell therapy. This is much easier than biopsying each tissue, and could be a good way to create universal iPS cell lines for research or cell therapy.

In the second paper, Wu and his colleagues devised a way to introduce specific mutations into iPS cells before transforming them into particular tissues. The approach relies on the use of what’s known as “dominant negative” mutations that exert their disruptive effect even when the unmutated gene is still present. This is important because it’s much easier and quicker than previous similar efforts, which required a complicated, time-consuming procedure to snip out and then replace individual genes. The technique also allows researchers to generate two cell lines that are identical except for the mutation under study. That way researchers can be confident that differences between the cell lines are due only to that mutation, which is particularly important when the lines are used to test the effect of therapeutic drugs. Again, from Wu:

Investigators can make their own designer iPS cell lines to study particular mutations with genetically identical controls to use in their experiments. We won’t have to make new iPS cells from each patient, which is laborious and time consuming. Instead we can create standardized lines to study many different mutations alone and in combination. This has the potential to revolutionize the field of disease modeling and drug discovery.

The two papers describe ongoing research in the Wu lab designed to optimize iPS cells for a variety of applications. The group, including graduate student Arun Sharma, recently published research using human iPS cell-derived cardiomyocytes to investigate the effect of various antiviral drugs againse coxsackievirus, a leading cause of an infection of the middle layer of the heart wall in children and the elderly. The research is the first time that iPS cell-derived heart muscle has been used to investigate the mechanisms behind an acquired viral disease.

Previously: A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells, “Clinical trail in a dish” may make common medicines safer, say Stanford scientists and Lab-made heart cells mimic common cardiac disease in Stanford study

Cancer, Research, Science, Stanford News, Stem Cells

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Localized radiation therapy for breast cancer kills cancer cells at the tumor site. But, in a cruel irony, Stanford radiation oncologist Edward Graves, PhD, and research associate Marta Vilalta, PhD, have found that the dying cells in the breast may send out a signal that recruits other cancer cells back to the site of the initial tumor. Their work was published today in Cell Reports. As Graves explained in an e-mail to me:

Cancer spreads by shedding tumor cells into the circulation, where they can travel to distant organs and form secondary lesions.  We’ve demonstrated with this study that cancer radiation therapy may actually attract these circulating tumor cells, or CTCs, back to the primary tumor, which may lead to the regrowth of the tumor after radiation therapy.

The researchers studied mouse and human breast cancer cells growing in a laboratory dish, as well as human breast cancer cells implanted into mice. They found that irradiated cells secreted a molecule called granulocyte macrophage colony stimulating factor, or GM-CSF. Blocking the expression of GM-CSF by the cells inhibited (but didn’t completely block) their ability to recruit other cells to the cancer site. The finding is particularly interesting, since physicians sometimes give cancer patients injections of GM-CSF to enhance the growth of infection-fighting white blood cells that can be damaged during chemotherapy. As Graves explained, “This work has important implications for clinical radiotherapy, and for the use of GM-CSF in treating neutropenia in cancer patients during therapy.”

The researchers say, however, that cancer patients shouldn’t eschew radiation therapy. Rather, the finding may help clinicians devise better ways to fight the disease – perhaps by blocking GM-CSF signaling. Graves concluded:

It should be emphasized that radiation therapy remains one of the most effective treatments for cancer. Our findings will help us to further optimize patient outcomes following this already potent therapy.

Previously: Using 3-D technology to screen for breast cancer, Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers and Common drug class targets breast cancer stem cells, may benefit more patients, says study

Research, Science, Stanford News, Stem Cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

Ford assembly lineIn the early 1900s, Henry Ford was lauded for his use of the assembly line, which allowed the rapid, reliable and uniform production of over 15 million Model T automobiles. By codifying each step of production and using identical, interchangeable parts, he brought car ownership within reach of the average American and changed the face of our country.

Now Stanford cardiologist Joseph Wu, MD, PhD, and instructor Paul Burridge, PhD, have done something similar with stem cells. They’ve devised a way to create large numbers of heart muscle cells called cardiomyocytes from stem cells without using human or animal-derived products, which can vary in composition and concentration among batches. Their technique was published Sunday in Nature Methods. Wu, who is the director of the Stanford Cardiovascular Institute explained to me in an e-mail:

This technique solves an important hurdle for the use of iPS-derived heart cells. In order to fully realize the potential of these cells in drug screening and cell therapy, it’s necessary to be able to reliably generate large numbers at low cost. Due to their chemically defined nature, this system is highly reproducible, massively scalable and substantially reduces costs to allow the production of billions of cardiomyocytes matching a specific patient’s heart phenotype.

Chemically defined cell culture means that scientists know exactly what (and how much) is in the liquid in which the cells are grown. In contrast, many common cell culture methods involve the use of nutrient-rich broth derived from animal or human sources. These liquids are teaming with proteins, some known and some unknown, that can promote stem cell growth. They get the job done, but their components can vary among batches and the outcome isn’t always reproducible.

In the new method, Wu and his colleagues collected cells from the skin or blood of an individual. They used a virus called the Sendai virus encoding four reprogramming genes to create induced pluripotent stem cells. These cells were then grown in a liquid in which everything needed for growth was precisely defined. As Wu explained, “This approach gives us an opportunity to fully understand the molecular and macromolecular requirements for cardiac differentiation and eliminates any animal-derived components that were previously used.”

The researchers found they were able to produce about 100 cardiomyocytes for every one stem cell by following a systematic series of steps and using a growing medium that contained just three well-defined components. They showed the technique worked on 11 different batches of induced pluripotent stem cells. The cardiomyocytes were more than 95 percent pure, making it easier to get large numbers of cells to study disease processes or to test the effects of compounds during drug development. According to Wu:

We can use this approach to assess the effect of a particular medication on a specific patient’s heart cells, to discover new drugs, to better understand the process of heart development and to generate cardiomyocytes for use in regenerative medicine approaches, such as for injection into the heart to aid recovery after a heart attack. The system also serves as a platform to study cardiomyocyte subtype specification and maturation.

Of course, stem cells are nothing like automobiles, and regular people aren’t lining up clamoring for a fresh vial of heart muscle cells. But it’s possible that the ability to reliably generate large numbers of cardiomyocytes for study and therapy could be as transformative to cardiac medicine as the Model T was to our grandparents and great grandparents.

Previously: Oh grow up! “Specialized” stem cells tolerated by the immune system, say Stanford researchers, Stem cell medicine for hearts? Yes, please, says one amazing family and “Clinical trial in a dish” may make common medicines safer, say Stanford scientists
Photo by Kyle Harris

Evolution, Genetics, Research, Science, Stanford News, Stem Cells

It’s a blond thing: Stanford researchers suss out molecular basis of hair color

It's a blond thing: Stanford researchers suss out molecular basis of hair color

blond hair, brighter

It’s all over the news today: Blonds aren’t stupid.

Well, that’s what most of the media would have you believe is the take-home message of the latest research by developmental biologist David Kingsley, PhD. And although I’m happy to see such great coverage, I’m hoping that readers realize that Kingley’s study on human hair color, which was published yesterday in Nature Genetics (subscription required), describes something much more subtle, and less superficial. From our release:

The study describes for the first time the molecular basis for one of our most noticeable traits. It also outlines how tiny DNA changes can reverberate through our genome in ways that may affect evolution, migration and even human history.

Kingsley, who is known for his study of a tiny fish called the threespine stickleback, is interested in learning how organism adapt to new environments by developing new traits. He’s found that this type of adaptation is most-often accomplished by changes in DNA regulatory regions that affect when, where and how a gene is expressed, rather than through (possibly disruptive) changes in the genes themselves.

In this case, he and his colleagues turned his attention to the blond hair common to many northern European and Icelanders. A previous study had shown that a single nucleotide change on human chromosome 12 was a major driver in hair color. As explained in the release:

The researchers found that the blond hair commonly seen in Northern Europeans is caused by a single change in the DNA that regulates the expression of a gene that encodes a protein called KITLG, also known as stem cell factor. This change affects how much KITLG is expressed in the hair follicles without changing how it’s expressed in the rest of the body. Introducing the change into normally brown-haired laboratory mice yields an animal with a decidedly lighter coat — not quite Norma Jeane to Marilyn Monroe, but significant nonetheless.

The involvement of KITLG, with its critical role in stem cell biology, is certainly interesting. But there’s also a more global lesson about the specificity of gene expression their effect on phenotype:

The study shows that even small, tissue-specific changes in the expression of genes can have noticeable morphological effects. It also emphasizes how difficult it can be to clearly connect specific DNA changes with particular clinical or phenotypic outcomes. In this case, the change is subtle: A single nucleotide called an adenine is replaced by another called a guanine on human chromosome 12. The change occurs over 350,000 nucleotides away from the KITLG gene and only alters the amount of gene expression about 20 percent — a relatively tiny blip on a biological scale more often assessed in terms of gene expression being 100 percent “on” or “off.”

“What we’re seeing is that this regulatory region exercises exquisite control over where, and how much, KITLG expression occurs,” said Kingsley. “In this case, it controls hair color. In another situation — perhaps under the influence of a different regulatory region — it probably controls stem cell division. Dialing up and down the expression of an essential growth factor in this manner could be a common mechanism that underlies many different traits.”

And now, the hook that excited most of the news media:

[Kingsley] added: “It’s clear that this hair color change is occurring through a regulatory mechanism that operates only in the hair. This isn’t something that also affects other traits, like intelligence or personality. The change that causes blond hair is, literally, only skin deep.”

Previously: Something fishy: Threespine stickleback genome published by Stanford researchers, Hey guys, sometimes less really is more , Tickled by stickle(backs) and Blond hair evolved more than once, and why it matters
Photo by Traci Lawson

Research, Science, Stanford News, Stem Cells

“Alert” stem cells speed damage response, say Stanford researchers

"Alert" stem cells speed damage response, say Stanford researchers

191855419_350c4827a2_zStanford neurologist and longevity researcher Thomas Rando, MD, PhD and his colleagues have found that adult stem cells (those that hang around in mature tissues to facilitate tissue repair) have a surprising ability to notice, and respond, to damage in distant parts of the body. The researchers termed the response an  “alert” state; the cells are no longer resting deeply, but are also not yet committed to possibly unnecessary action. (As I was writing our release, I kept envisioning the stem cells like dogs frozen in a point, waiting for further movement or instructions.)

Their study was published last week in Nature. As I explained:

The researchers were studying the response of mouse muscle stem cells, or satellite cells, to muscle injury. Conventional wisdom holds that adult stem cells are by nature quiescent — a term that indicates a profound resting state characterized by small size and no cell division. It’s a kind of cellular deep freeze. In contrast, most other cells cycle through rounds of DNA replication and cell division in discrete, well-defined phases. A quiescent stem cell can “wake up” and enter the cell cycle in response to local signals of damage or other regeneration needs.

Rando and his colleagues were studying this activation process in laboratory mice by watching how muscle stem cells in one leg respond to a nearby muscle injury in the same leg. (Mice were anesthetized prior to a local injection of muscle-damaging toxin; they were given pain relief and antibiotics during the recovery period.) The researchers had planned to observe the quiescent muscle stem cells in the uninjured leg as a control for their experiment. However, they instead saw something unexpected.

“The muscle stem cells in the uninjured leg had definitely changed,” said Rando, who is director of the Rehabilitation Research & Development Center of Excellence at the Veterans Affairs Palo Alto Health Care System. “They were very clearly biochemically different from completely dormant, quiescent cells, and from fully activated stem cells. We termed this state an ‘alert’ state of quiescence.”

These alert stem cells were able to respond to subsequent, nearby damage much more quickly and efficiently than completely quiescent cells, the researchers found. They also learned that the stem cells’ response encompasses several tissue types in addition to the one in which the injury occurred. More from the release:

Surprisingly, the muscle stem cells also became alert in response to bone or minor skin injuries — injuries in which the cells are not known to play any regenerative role.

Conversely, other non-muscle adult stem cells, including hematopoietic stem cells in the bone marrow and mesenchymal stem cells in the muscle, became alert in response to muscle damage.

“It is clear that this alert state is a systemic response,” said Rando.

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Cardiovascular Medicine, Immunology, Research, Science, Stanford News, Stem Cells

Oh, grow up! “Specialized” stem cells tolerated by immune system, say Stanford researchers

Oh, grow up! "Specialized" stem cells tolerated by immune system, say Stanford researchers

3075268200_419b9e73b7_zMany of us know by now that stem cells are remarkably fluid in the types of cells they can become. But this fluidity, or pluripotency, comes with a price. Several studies have shown that the body’s immune system will attack and reject even genetically identical transplanted stem cells, making it difficult to envision their usefulness for long-term therapies.

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have shown that coaxing the stem cells to become more-specialized (a process known as differentiation) before transplantation allows the body to recognize and tolerate the cells. Their research was published today in Nature Communications (subscription required).

From our release:

In a world teeming with microbial threats, the immune system is a necessary watchdog. Immune cells patrol the body looking not just for foreign invaders, but also for diseased or cancerous cells to eradicate. The researchers speculate that the act of reprogramming adult cells to pluripotency may induce the expression of cell-surface molecules the immune system has not seen since the animal (or person) was an early embryo. These molecules, or antigens, could look foreign to the immune system of a mature organism.

Previous studies have suggested that differentiation of iPS cells could reduce their tendency to inflame the immune system after transplantation, but this study is the first to closely examine, at the molecular and cellular level, why that might be the case.

Postdoctoral scholars Patricia Almeida, PhD, and Nigel Kooreman, MD, and assistant professor of medicine Everett Meyer, MD, PhD, share lead authorship of the study. They found that laboratory mice accepted grafts of endothelial cells made from stem cells much more readily than they did the stem cells themselves. As Wu, who also directs the Stanford Cardiovascular Institute said in our release:

This study certainly makes us optimistic that differentiation — into any nonpluripotent cell type — will render iPS cells less recognizable to the immune system. We have more confidence that we can move toward clinical use of these cells in humans with less concern than we’ve previously had.

Previously: New technique prevents immune-system rejection of embryonic stem cells and Overcoming immune response to stem cells essential for therapies, say Stanford researchers
Photo by Umberto Salvagnin

Stanford News, Stem Cells, Surgery, Videos

Stanford reconstructive surgeon Jill Helms reminds us that “beauty isn’t defined by our faces alone”

Stanford reconstructive surgeon Jill Helms reminds us that "beauty isn't defined by our faces alone"

Jill Helms, PhD, a professor of plastic and reconstructive surgery at Stanford, leads a team of scientists that are working on methods to activate a patient’s own stem cells at the site of an injury to speed up tissue healing. In this TEDxStanford video, Helms discusses how surgical scars can sometimes impede growth of a patient’s body, such as the repair of a child’s cleft palate, and the potential of using stem cells to enhance the body’s natural healing process.

As previously mentioned here, Helms delivered a talk on the topic of beauty reconsidered, and she reminds us at the end of the video that “beauty isn’t defined by our faces alone.” She says, “Beauty is compassion, kindness and warmth, and that’s internal beauty. That’s the most important beauty.”

Previously: A spotlight on TEDxStanford’s “awe-inspiring” and “deeply moving” talks and Stanford study shows protein bath may rev up sluggish bone-forming cells

Research, Stanford News, Stem Cells

Studying the inner ear and advancing research in developmental biology

Studying the inner ear and advancing research in developmental biology

hellerResearcher Stefan Heller, PhD, came to Stanford in 2005 from Harvard. His laboratory focuses on inner ear development and works on approaches to regenerate sensory hair cells, scarce sensory receptor cells that are essential for our senses of hearing and balance.

As I explained in an article about his arrival, Heller’s goal was to come here and collaborate with others to devise “a variety of possible cures for deafness from drug therapy treatment – which could be as simple as an application of ear drops-to stem cell transplantation into the inner ear to remedy hearing loss.” Since then, his lab has continued to add to the body of research on the inner ear’s early development and to pave the way towards regenerative therapies for hearing loss. The researchers’ most recent milestone (subscription required) – during which they designed the most detailed 3-D model to date of the otocyst, the embryonic structure in vertebrates that develops into the inner ear in the adult – was published online this month in the journal Cell.

In a video on the journal website, Heller and the lead author of the study, Robert Durruthy-Durruthy, a PhD candidate, describe the mathematical method used that allows the 3-D reconstruction of the developing inner ear. Russ Altman, PhD and Assaf Gottlieb, PhD, from Stanford bioengineering were collaborators of the study.

Heller recently described to me how microfluidics technology developed in the lab of Stanford bioengineering professor Stephen Quake, PhD, was essential to analyze single cells in order to develop the blue prints for their 3-D model. The approach is new in biology, Heller said. Much like dismantling the engine of a car into its smallest parts, taking apart a simple organ into single cells results in the challenge of putting the pieces back together.  “Our new method provides a good strategy for such reconstructions,” Heller said.

Heller also explained how this advancement will help as he continues researching early ear development and working on growing inner ear sensory hair cells, the linchpin for hearing. (Hair cells exist in limited numbers in human ears and once they are gone, hearing loss occurs.) He said:

This [paper] gives us deep insight into how this organ forms in early development. It identifies the different cell types and defines them in much more detail than previously known. It provides details about the inner ear progenitor cells that we are trying to generate from stem cells. Having this blue print will help us to generate sensory hair cells more efficiently and hopefully to regenerate hair cells at some time in the future.

The technology, Heller said, can also benefit others: “It can be used to reconstruct all kinds of things, other simple organs, perhaps even simple multicellular organisms, or structures like tumors.”

Previously: Regenerating sensory hair cells to restore hearing to noise-damaged ears, Stanford chair of otolaryngology discusses future regenerative therapies for hearing loss, Stefan Heller discusses stem cell research on Science Friday and Growing new inner ear cells a step toward a cure for deafness
Photo by Steve Fisch

Aging, Mental Health, Neuroscience, Research, Stanford News, Stem Cells

The rechargeable brain: Blood plasma from young mice improves old mice’s memory and learning

The rechargeable brain: Blood plasma from young mice improves old mice's memory and learning

brain battery“Maybe Ponce de Leon should have considered becoming a vampire,” I noted here a few years ago. In a related Stanford Medicine article, I elaborated on that point (i.e. Dracula may have been on to something):

Count Dracula may have been bloodthirsty, but nobody ever called him stupid. If that practitioner of what you could call “the Transylvanian transfusion” knew then what we know now, it’s a good bet he was keeping his wits as sharp as his teeth by restricting his treats to victims under the age of 30.

I was referring then to an amazing discovery by Stanford brain-degeneration expert Tony Wyss-Coray, PhD, and his then-graduate student Saul Villeda, PhD, who now has his own lab at the University of California-San Francisco. They’d found that something in an old mouse’s blood could somehow exert an aging effect on the capabilities of a young mouse’s brain, and you know that ain’t good. They’d even pinpointed one specific substance (eotaxin) behind this effect, implying that inhibiting this naturally produced and sometimes very useful chemical’s nefarious action – or, if you’re a vampire, laying off the old juice and  getting your kicks from preteens when available – might be beneficial to aging brains.

But I was premature. While the dynamic duo had shown that old blood is bad for young brains and had also demonstrated that old mice’s brains produce more new nerve cells (presumably a good thing) once they’ve had continuous exposure to young mice’s blood, the researchers hadn’t yet definitively proven that the latter translated into improved intellectual performance.

This time out they’ve gone and done just that, in a study (subscription required) published online yesterday in Nature Medicine. First they conducted tricky, sophisticated experiments to show that when the old mice were continuously getting blood from young mice, an all-important region in a mouse’s brain (and yours) called the hippocampus perks up biochemically, anatomically and physiologically: It looks and acts more like a younger mouse’s hippocampus. That’s big, because the hippocampus is not only absolutely essential to the formation of new memories but also the first brain region to go when the early stirrings of impending dementia such as Alzheimer’s start subtly eroding brain function, long before outwardly observable symptoms appear.

Critically, when Wyss-Coray, Villeda and their comrades then administered a mousey IQ test (a standard battery of experiments measuring mice’s ability to learn and remember) to old mice who’d been injected with plasma (the cell-free part of blood) from healthy young mice, the little codgers far outperformed their peers who got crummy old-mouse plasma instead.

Slam dunk.

“This could have been done 20 years ago,” Wyss-Coray told me when I was assembling my release on this study. “You don’t need to know anything about how the brain works. You just give an old mouse young blood and see if the animal is smarter than before. It’s just that nobody did it.”

Previously: When brain’s trash collectors fall down on the job, neurodegeneration risk picks up, Brain police: Stem cells’ fecund daughters also boss other cells around, Old blood + young brain = old brain and Might immune response to viral infections slow birth of new nerve cells in brain?
Photo by Takashi Hososhima

Cancer, Research, Science, Stanford News, Stem Cells

Cellular culprit identified for invasive bladder cancer, according to Stanford study

Cellular culprit identified for invasive bladder cancer, according to Stanford study

Beachy image resizedInvasive bladder cancer is a grim disease that is expensive to treat and requires ongoing monitoring due to its high probability of recurrence. Stanford developmental biologist Philip Beachy, PhD, and urologist Michael Hsieh, MD, PhD, wanted to know how the cancer starts, and what makes it so intractable. Their research was published yesterday in Nature Cell Biology (subscription required).

As Beachy explained in the release I wrote:

We’ve learned that, at an intermediate stage during cancer progression, a single cancer stem cell and its progeny can quickly and completely replace the entire bladder lining. All of these cells have already taken several steps along the path to becoming an aggressive tumor. Thus, even when invasive carcinomas are successfully removed through surgery, this corrupted lining remains in place and has a high probability of progression.

In the photo above, the blue cells are progeny of just one cancer-initiating cell in the basal cell layer of the bladder lining. They’ve “elbowed out” their neighbors to take over the lining. The cells, and the cancers that arise, have a distinctive gene-expression profile. More from our release:

Although the cancer stem cells, and the precancerous lesions they form in the bladder lining, universally express an important signaling protein called sonic hedgehog, the cells of subsequent invasive cancers invariably do not — a critical switch that appears vital for invasion and metastasis. This switch may explain certain confusing aspects of previous studies on the cellular origins of bladder cancer in humans. It also pinpoints a possible weak link in cancer progression that could be targeted by therapies.

Hsieh, who has treated many patients with this type of bladder cancer, explained to me the significance of the finding:

This could be a game changer in terms of therapeutic and diagnostic approaches. Until now, it’s not been clear whether bladder cancers arise as the result of cancerous mutations in many cells in the bladder lining as the result of ongoing exposure to toxins excreted in the urine, or if it’s due instead to a defect in one cell or cell type. If we can better understand how bladder cancers begin and progress, we may be able to target the cancer stem cell, or to find molecular markers to enable earlier diagnosis and disease monitoring.

Previously: Is the worm turning? Early stages of schistosomiasis bladder infection charted, Mathematical technique used to identify bladder cancer marker and Bladder infections–How does your body repair the damage?
Photo by Kunyoo Shin, PhD

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