Archive for the ‘Stem Cell Research’ Category

Stem Cells Could Fuel Cancer Growth

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Posted 02 Aug 2012 — by James Street
Category Stem Cell Research, Stem Cell Research

By MALCOLM RITTER AP Science Writer
NEW YORK August 1, 2012 (AP)

 

How can a cancer come back after it’s apparently been eradicated? Three new studies are bolstering a long-debated idea: that tumors contain their own pool of stem cells that can multiply and keep fueling the cancer, seeding regrowth.

If that’s true, scientists will need to find a way to kill those cells, apart from how they attack the rest of the tumor.

Stem cells in healthy tissues are known for their ability to produce any kind of cell. The new research deals with a different kind, cancer stem cells. Some researchers, but not all, believe they lurk as a persisting feature in tumors.

Over the past decade, studies have found evidence for them in tumors like breast and colon cancers. But this research has largely depended on transplanting human cancer cells into mice that don’t have immune systems, an artificial environment that raises questions about the relevance of the results.

Now, three studies reported online Wednesday in the journals Nature and Science present evidence for cancer stem cells within the original tumors. Again, the research relies on mice. That and other factors mean the new findings still won’t convince everyone that cancer stem cells are key to finding more powerful treatments.

But researcher Luis Parada, of the University of Texas Southwestern Medical Center in Dallas, believes his team is onto something. He says that for the type of brain tumor his team studied, “we’ve identified the true enemy.”

If his finding applies to other cancers, he said, then even if chemotherapy drastically shrinks a tumor but doesn’t affect its supply of cancer stem cells, “very little progress has actually been made.”

The three studies used labeling techniques to trace the ancestry of cells within mouse tumors.

Collectively, they give “very strong support” to the cancer stem cell theory, said Jeffrey M. Rosen, a professor of molecular and cellular biology at Baylor College of Medicine in Houston. He did not participate in the work but supports the theory, which he said is widely accepted.

Another scientist who’s skeptical about the theory, and said he has plenty of company, said the new papers did not change his mind.

Parada’s team worked with mice genetically primed to develop a certain type of brain tumor. The scientists genetically labeled particular cells in the tumor and then attacked the cancer with the same drug given to human patients. It kills growing tumor cells and temporarily stops the cancer’s growth.

After treatment, when the tumor started growing again in the mice, the researchers showed that the vast majority, if not all, of its new cells had descended from the labeled cells. Apparently these were the tumor’s cancer stem cells, they concluded.

Parada said his team is now trying to isolate cancer stem cells from mouse brain cancers to study them and perhaps get some leads for developing therapies to eradicate them.

He also said that preliminary study of human brain tumors is producing results consistent with what his team found in the mice.

Parada’s study appears in Nature. In a second Nature report, British and Belgian researchers found evidence for cancer stem cells in early stage skin tumors in mice. And in the journal Science, a Dutch group found such evidence in mouse intestinal polyps, which are precursors to colon cancer.

Scott Kern of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore is skeptical about whether tumors contain cancer stem cells. He said that since the new studies didn’t involve human tumors, it’s not clear how relevant they are to people.

The two European studies focused largely on lesions that can lead to tumors, he said. And as for Parada’s brain cancer study, he said he believed the results could be explained without relying on the cancer stem cell theory.

Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line

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Posted 07 Apr 2012 — by James Street
Category Circulating Tumor Cells, Osteosarcoma, Stem Cell Research

Osteosarcoma is a bone-forming tumor of mesenchymal origin that presents a clinical pattern that is consistent with the cancer stem cell model. Cells with stem-like properties (CSCs) have been identified in several tumors and hypothesized as the responsible for the relative resistance to therapy and tumor relapses.

In this study, we aimed to identify and characterize CSCs populations in a human osteosarcoma cell line and to explore their role in the responsiveness to conventional therapies.

Methods: CSCs were isolated from the human MNNG/HOS cell line using the sphere formation assay and characterized in terms of self-renewal, mesenchymal stem cell properties, expression of pluripotency markers and ABC transporters, metabolic activity and tumorigenicity. Cell’s sensitivity to conventional chemotherapeutic agents and to irradiation was analyzed and related with cell cycle-induced alterations and apoptosis.

Results: The isolated CSCs were found to possess self-renewal and multipotential differentiation capabilities, express markers of pluripotent embryonic stem cells Oct4 and Nanog and the ABC transporters P-glycoprotein and BCRP, exhibit low metabolic activity and induce tumors in athymic mice.

Compared with parental MNNG/HOS cells, CSCs were relatively more resistant to both chemotherapy and irradiation. None of the treatments have induced significant cell-cycle alterations and apoptosis in CSCs.

Conclusions: MNNG/HOS osteosarcoma cells contain a stem-like cell population relatively resistant to conventional chemotherapeutic agents and irradiation.

This resistant phenotype appears to be related with some stem features, namely the high expression of the drug efflux transporters P-glycoprotein and BCRP and their quiescent nature, which may provide a biological basis for resistance to therapy and recurrence commonly observed in osteosarcoma.

Author: Sara R Martins-NevesAurio O LopesAnalia DO CarmoArtur A PaivaPaulo C SimoesAntero J AbrunhosaCelia M Gomes
Credits/Source: BMC Cancer 2012, 12:139

Treating cancer as a chronic disease

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Posted 31 Mar 2012 — by James Street
Category Educational, General Cancer Research, Stem Cell Research, Understanding Cancer

March 30th, 2012 in Cancer
Treating cancer as a chronic disease

 

Professor Karl Skorecki

New research from the Technion-Israel Institute of Technology Rappaport Faculty of Medicine and Research Institute and the Rambam Medical Center may lead to the development of new methods for controlling the growth of cancer, and perhaps lead to treatments that will transform cancer from a lethal disease to a chronic, manageable one, similar to AIDS.

By placing cancer in and near a growth developed from a population of human , scientists have demonstrated that the cancer cells grow and proliferate more robustly when exposed to than they do in a typical petri dish or mouse model. The cancer cell population is also more diverse than had previously been understood.  The research was published in the current advanced online issue of the journal Stem Cells. Maty Tzukerman, Rambam senior research scientist and the project leader and senior co-author on the report, says that this model will facilitate targeted drug discovery aimed at blocking the cancer cell self-renewal process.

Previous studies have determined that some tumor cells appear to be differentiated, while others retain the self-renewal property that makes cancer so deadly. According to Technion Professor Karl Skorecki, director of Medical Research and Development at Rambam Health Care Campus and senior co-author on the report, this new research attempts to understand how cancer grows, and to find ways to halt the runaway replication.

In order to mimic the environment as closely as possible, the research team developed a teratoma – a tumor made of a heterogenous mix of cells and tissues – by enabling the differentiation of human embryonic stem cells into a variety of normally occuring human cell lines on a carrier mouse. The human cellular teratoma constitutes a new platform of healthy human cells for monitoring the behavior and proliferation of human cancer cells.

For this study, the team took cells from one woman’s ovarian clear cell carcinoma and injected them either into or alongside the human stem cell-derived environment. “We noticed very early on, rather strikingly, that the human cancer cells grow more robustly when they are in the teratoma environment compared to any other means in which we grew them, such as in a mouse muscle or under the skin of a mouse,” says Skorecki.

The scientists were able to tease out six different kinds of self-renewing cells, based on behavior – how quickly they grow, how aggressive they are, how they differentiate – and on their molecular profile. This was a previously unknown finding, that one tumor might have such a diversity of cells with crucial fundamental growth properties. Tzukerman explains that the growth of the cancer cell subpopulations can now be explained by their proximity to the human cell environment.

The researchers cloned and expanded the six distinct cell populations and injected them into the human stem cell teratomas. One key observation is that some cells, which were not self-replicating in any other model, became self-replicating when exposed to the human cells.

Skorecki said that while he wasn’t surprised that the human environment affected the growth, he was in fact surprised by the magnitude of the effect: “We’ve known for years now that cancers are complex organs, but I didn’t think the power of the human stem cell environment would be so robust, that it would make such a big difference in how the cells were grown.”

The researchers point out that they do not yet know the cues that particularly enhance the cancer’s proliferation, and the team is now working on isolating the factors from human cells that promote such plasticity and self-renewing properties. The scientists explain that this may eventually allow physicians to manage cancer as a chronic disease: instead of one therapy against the entire tumor, researchers may develop a method to tease out the variety of self-renewing cell lines of a particular tumor and determine what allows each to thrive, then attack that mechanism.

Skorecki and Tzukerman say that an important next step in this line of cancer research will be to identify and develop ways of blocking the factor or factors that promote this essential self-renewing property of cancer, thus relegating many forms of to controllable, chronic diseases.

This research was supported with grants from the Daniel M. Soref Charitable Trust, the Skirball Foundation, the Richard D. Satell Foundation, the Sohnis and Forman families, and the Science Foundation.

Provided by American Technion Society

Diverse approach to cancer research need of the hour, stresses professor

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Posted 14 Mar 2012 — by James Street
Category General Cancer Research, Stem Cell Research
 

Prof Weissman

Profoundly different approaches are needed for cancer research, the Qatar International Conference on Stem Cell Science and Policy 2012, has been told by an expert in cancer stem cell (CSC) biology.
Professor Irving Weissman, director, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, was delivering a keynote address on ‘Normal and neoplastic stem cells’ yesterday.
“Self-renewal is the principal property that distinguishes stem cells from their daughter cells,” he said while explaining that when stem cells divide they give rise to stem cells (by self-renewal) and progenitors (by differentiation).
The balance between self-renewal and differentiation is what generates, and then maintains, tissues enabling them to respond to injury or other stressors.
Studies identifying hematopoietic stem cells (HSC) – which form blood and immune cells – and progenitors, have made hematopoiesis one of the best systems for studying the molecular changes in cell fate decision-making and creation of cancer.
Further, it serves as a paradigm for finding preclinical and clinical platforms for tissue and organ replacement and regeneration.
Stem cell isolation and transplantation is the basis for regenerative medicine. Self-renewal is dangerous and therefore strictly regulated.
Poorly regulated self-renewal can lead to the genesis of CSC — the only cells within a tumour or leukaemia that have the ability to self renew, and therefore the cells that maintain the cancer.
“Thus, it is predicted that CSC elimination is required for cure. This prediction necessitates profoundly different approaches to cancer research, compelling investigators to prospectively isolate CSCs and to characterise the molecular pathways regulating their behaviour in order to identify targeted and truly effective therapies,” Weissman added.
A founder of three companies – SyStemix, Cellerant, and Stem Cells Inc – all focused on bringing stem cell therapies into the clinic, Weissman has authored more than 700 scientific articles and has been an editor of multiple scientific journals.

Brain Cancer Blood Vessels Not Substantially Tumor-Derived

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Posted 11 Mar 2012 — by James Street
Category antiangiogenesis, Avastin, Brain, Stem Cell Research

ScienceDaily (Mar. 8, 2012) — Johns Hopkins scientists have published laboratory data refuting studies that suggest blood vessels that form within brain cancers are largely made up of cancer cells. The theory of cancer-based blood vessels calls into question the use and value of anticancer drugs that target these blood vessels, including bevacizumab (Avastin).

“We don’t question whether brain cancer cells have the potential to express blood vessel markers and may occasionally find their way into blood vessels, but we do question the extent to which this happens,” says Charles Eberhart, M.D., Ph.D., chief of neuropathology at the Johns Hopkins University School of Medicine. “In general, we find no evidence in our study that these vessels contain substantial amounts of cancer cells.”

Eberhart, professor of pathology, ophthalmology and oncology at Johns Hopkins, said he first encountered claims about the cancerous nature of tumor blood vessels about a year ago when he was invited to join students at a journal club meeting, a forum for discussing studies published in medical journals. “My first reaction to this research was ‘How could this be true?’” says Eberhart. “Our clinical experience examining tissue from brain cancers does not support it.”

Studies have long demonstrated that malignant brain tumors contain large numbers of blood vessels to feed their growing demand for nutrients. The blood vessels are formed when tumors pump out growth factors that increase vessel production. Such studies opened the door to treatment strategies that specifically targeted blood-vessel growth and the vessel cells themselves.

More recently, scientists in Italy and the Memorial Sloan Kettering Cancer Center in New York published results of studies suggesting that these tumor blood vessels are made by primitive types of brain cancer cells that are a form of stem cells. In their studies, they found tumor markers on blood vessel cells in 20 to 90 percent of their brain cancer samples. The U.S./Italian research teams said their findings also suggested that the cancerlike blood vessels were more prone to drug resistance, potentially explaining why drugs like bevacizumab yield tumor-shrinking responses, but only for short periods. Bevacizumab is currently approved by the U.S. Food and Drug Administration for use in patients with colorectal, lung, kidney and brain cancers.

Eberhart said pathologists, including those who work on brain tissue, use certain tissue-based techniques to distinguish cancer cells from normal ones. When evaluating specimens of brain tissue removed during surgery for suspected cancer, he said, most pathologists agree that blood vessel cells in these specimens consistently lack the molecular changes associated with cancer cells, according to Eberhart. In fact, they often use these blood vessel cells as “normal controls” to compare with potentially cancerous ones.

After the journal club experience, Eberhart teamed up with fellow neuropathologist Fausto Rodriguez, M.D., and colleagues at the Dana Farber Cancer Institute and Harvard Medical School in Boston to look more closely at the molecular features of blood vessel cells in brain cancer samples. They tested more than 100 samples from patients at Johns Hopkins and Dana Farber for EGFR and IDH1 markers, two common genes altered in brain cancer.

“We also used a marker called CD34 to differentiate vascular [blood vessel] cells from other types of cells,” says Rodriguez, assistant professor of pathology at Johns Hopkins. The research teams found no more than 10 percent of their samples contained vascular cells with EGFR or IDH1 cancer markers, and in those rare tumor samples, only a few cells exhibited those markers. The Johns Hopkins-Dana Farber-Harvard team tested all parts of the vessel walls for presence of the cancer markers.

Results of the team’s laboratory experiments were published in the online journal Oncotarget in January.

Although the two groups used different markers to identify vessel cells, Rodriguez says “there is no marker that is absolute for each cell.”

Eberhart and Rodriguez noted that the U.S./Italian research teams focused mainly on cell-by-cell research techniques in dissociated specimens to evaluate cancer markers, losing associations that can be made by looking at a cell’s shape and physical relationship within clusters of cells. The Johns Hopkins and Dana Farber researchers conducted studies examining cells in intact tissue.

“Pathologists with extensive experience in examining cells become accustomed to quickly identifying a blood vessel cell from a normal cell, and we can gain a lot of information when we look at how cells connect with other cells in real-life examples,” notes Rodriguez, who says that his team’s findings could potentially apply to any cancer thought to contain stem cells.

In addition to Eberhart and Rodriguez, the research team included Brent Orr from Johns Hopkins and Keith Ligon from the Dana Farber Cancer Institute/Harvard Medical School.

Funding for the study was provided by a National Institutes of Health postdoctoral fellowship (T32CA067751) to Orr and a grant (5R01NS055089) to Eberhart.

Scientists use old theory to discover new targets

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Posted 18 Feb 2012 — by James Street
Category Stem Cell Research
By SALK INSTITUTE FOR BIOLOGICAL STUDIES

Similarities between genetic signatures in developing organs and breast cancer could predict and personalize cancer therapies.

La Jolla, CA – Reviving a theory first proposed in the late 1800s that the development of organs in the normal embryo and the development of cancers are related, scientists at the Salk Institute for Biological Studies have studied organ development in mice to unravel how breast cancers, and perhaps other cancers, develop in people. Their findings provide new ways to predict and personalize the diagnosis and treatment of cancer.

In a paper published February 3 in Cell Stem Cell, the scientists report striking similarities between genetic signatures found in certain types of human breast cancer and those of stem cells in breast tissue in mouse embryos. These findings suggest that cancer cells subvert key genetic programs that guide immature cells to build organs during normal growth.

“Stem cells in a healthy developing embryo have a GPS system to alert them about their position in the organ,” says Geoffrey Wahl, a professor in Salk’s Gene Expression Laboratory, who led the research. “The system depends on internal instructions and external signals from the environment to tell the stem cell what to do and where to go in the body. It stimulates the stem cells to grow and form more stem cells, or to change into different cells that form complex organs, such as the breast. Our findings tell us that this GPS system is broken during cancer development, and that may explain why we detect stem-like cells in breast cancers.”

The relationship between cancer and embryonic tissues was first proposed in the 1870s by Francesco Durante and Julius Cohnheim, who thought that cancers originated from cells in adults that persist in an immature, embryonic-like state. More recently, scientists including Benjamin Spike, a co-first author on the current work and post-doctoral fellow in the Wahl lab, have discovered that tumors often contain cells with stem cell characteristics revealed by their genetic signatures.

As a result, many scientists and physicians are pursuing ways to destroy stem-like cells in cancer, since such cells may make cancer more resistant to treatment and may lead to cancer recurrence. The Salk scientists are now characterizing the stem-like cells in certain forms of breast cancer to arrest their growth.

Studying the genetic activity of organ-specific stem cells is very difficult because the cells are very rare, and it is hard to separate them from other cells in the organ. But, by focusing on tissue obtained from mouse embryos, the Salk researchers were able for the first time to identify and isolate a sufficiently large number of fetal breast stem cells to begin to understand how their GPS works.

The Salk scientists first made the surprising finding that these fetal breast stem cells were not fully functional until just prior to birth. This observation suggested that a very special landscape is needed for a cell to become a stem cell. The breast stem cells at this late embryonic stage were sufficiently abundant to simplify their isolation. This enabled their genetic signature to be determined, and then compared to that of the stem-like cells in breast cancers.

The signatures of the breast stem cells in the fetus were stunningly similar to the stem-like cells found in aggressive breast cancers, including a significant fraction of a virulent cancer subtype known as “triple-negative.” This is important as this type of breast cancer has until now lacked the molecular targets useful for designing personalized therapeutic strategies.

“The cells that fuel the development of tumors in the adult are unlikely to ‘invent’ entirely new patterns of gene expression,” says Benjamin Spike. “Instead, some cancer cells seem to reactivate and corrupt programs that govern fetal tissue stem cell function, including programs from their neighboring cells that constitute the surrounding fetal stem cell landscape, or microenvironment.” The discovery of the shared genetic signatures provides a new avenue for scientists to explore the links between development and cancer. By uncovering new biological markers, the scientists hope to develop tests that individualize treatment by showing how the GPS system of a tumor operates. This should help doctors to determine which patients may benefit from treatment, and the correct types of treatment to administer.

Doctors are already using drugs, such as Herceptin, that specifically target malfunctioning genetic pathways in tumors, but no such therapies are currently available for certain aggressive forms of the disease, such as the triple negative subtype.

Although triple negative cancer cells lack the three critical genetic markers that are currently used to guide breast cancer treatment, the scientists’ analysis suggests a strong reliance on signaling through pathways similar to those that affect fetal breast stem cell growth.

They found that the fetal breast stem cells are sensitive to a class of targeted therapies that already exists, so these therapies might also work in triple negative breast cancers. Laboratory studies and clinical trials are currently underway to test this possibility.

“Substantial effort is being expended to personalize cancer treatment by gaining a better understanding of the genetics of an individual patient’s cancer,” Wahl says. “Our findings offer a way to discover new targets and new drugs for humans by studying the primitive stem cells in a mouse.”

In addition to Spike, Dannielle Engle and Jennifer Lin, both postdoctoral researchers in Wahl’s laboratory, were also co-first authors on the paper.

The research was sponsored by the Breast Cancer Research Foundation, the US Department of Defense, the G. Harold & Leila Y. Mathers Foundation and Susan G. Komen for the Cure.

About the Salk Institute for Biological Studies

The Salk Institute for Biological Studies is one of the world’s preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer’s, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.

This article was first published on www.newswise.com.

Chemo drug drives growth of some tumors

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Posted 31 Jan 2012 — by James Street
Category Adriamycin, doxorubicin, Ovarian, Stem Cell Research
Ovarian cancer stem cells stimulated by common treatment
Web edition : Monday, January 23rd, 2012
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Chemotherapy drugs designed to kill tumors may actually encourage ovarian cancer by stimulating the growth of cells that give rise to the malignancy, a new study finds.

“It was quite a surprise, actually, that chemotherapy could stimulate growth,” says Kenneth Nephew, a cancer biologist at the Indiana University School of Medicine in Bloomington, who was not involved in the new work. “When clinicians see this paper it may raise a few eyebrows.”

Researchers led by Patricia Donahoe and Xiaolong Wei of Massachusetts General Hospital and Harvard Medical School found that the common chemotherapy agent doxorubicin actually encourages the growth of ovarian cancer stem cells. The immature cells make up less than 1 percent of an ovarian cancer, but just a few left behind after surgery can reestablish a tumor.

But the study, published online the week of January 23 in the Proceedings of the National Academy of Sciences, also offers hope. The researchers found that a protein called Müllerian inhibiting substance, or MIS, halts growth of cancer stem cells. Made by male fetuses and boys until puberty, the protein reverses the growth of tissues that would otherwise develop into fallopian tubes.

MIS treatment might be combined with chemotherapy (which does kill most mature ovarian cancer cells) to stop growth of all the cancer cells, says Charles Landen, a gynecologic oncologist at the University of Alabama at Birmingham. Since humans naturally produce the potential anti-stem cell treatment, it would probably be safe to use in a clinical setting, he says.

Such therapy is still a long way off, says Donahoe. The researchers are able to produce only enough Müllerian inhibiting substance for use in a laboratory setting. Making enough of the protein to test in clinical trials will probably require a commercial partner.

Other researchers have identified different types of ovarian cancer stem cells, but Donahoe and her colleagues “have defined what may be the most aggressive subset of tumor cells,” says Landen.

It’s not clear if the MIS protein can stop all types of ovarian cancer stem cells.

December 19, 2011 Monday – 11:50 am EST inShare 1 Text Size Smaller Normal Larger E-mail Print ‘Fantastic Potential’: Researchers Keep Cells Alive Away From Body

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Posted 20 Dec 2011 — by James Street
Category Diagnostic, Personalized, Stem Cell Research, Targeted Cancer Therapy

December 19, 2011 Monday – 11:50 am EST

By Adam Daley

Georgetown researchers say they have just significantly changed biomedical research.

Researchers know that normal cells don’t last long once removed from a human, dividing only a few times in a laboratory setting. Common cancers won’t grow in a lab.

That’s about to change.

Senior investigator, Richard Schlegel, M.D., Ph.D., and chairman of the department of pathology at Georgetown Lombardi Comprehensive Cancer Center, has discovered a way to keep normal cells as well as tumor cells taken from an individual cancer patient alive in the laboratory. The technique could be a critical advance, ushering in a new era of personalized cancer medicine, and has potential application in regenerative medicine.

“Because every tumor is unique, this advance will make it possible for an oncologist to find the right therapies that both kills a patient’s cancer and spares normal cells from toxicity,” said Dr. Schlegel. “We can test resistance as well chemosensitivity to single or combination therapies directly on the cancer cell itself.”

The research team found that inserting a Rho kinase (ROCK) inhibitor and fibroblast feeder cells to cancer and normal cells in a laboratory pushes them to morph into stem-like cells. The cells visibly changed their shape as they reverted to a stem-like state.

“In short, we discovered we can grow normal and tumor cells from the same patient forever, and nobody has been able to do that,” said Dr. Schlegel. “Normal cell cultures for most organ systems can’t be established in the lab, so it wasn’t possible previously to compare normal and tumor cells directly.”

“Today, pathologists don’t work with living tissue. They make a diagnosis from biopsies that are either frozen or fixed and embedded in wax,” added Dr. Schlegel. “In the future, pathologists will be able to establish live cultures of normal and cancerous cells from patients, and use this to diagnose tumors and screen treatments. That has fantastic potential.”

The study, which was funded by grants from the National Institutes of Health, Department of Defense fellowship funding, and an internal grant from Georgetown Lombardi’s Cancer Center Support Grant from the National Cancer Institute, is published online today in the American Journal of Pathology.

Cancer Stem Cells

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Posted 25 Oct 2011 — by James Street
Category Stem Cell Research, tocotrienol
October 24, 2011
Volume 89, Number 43
pp. 41 – 43

Researchers zero in on the pathways that allow cancer to bounce back after treatment

Aaron A. Rowe

Take some cells from a tough-to-treat tumor, sort them, and inject each fraction into a different immunodeficient mouse, and only a small percentage of those cells will thrive and form tumors.

This sort of experiment illustrates a concept that has been gaining traction within the cancer research community. Tumors contain a diverse mixture of cells, and only a handful of them can bounce back after treatment. That deadly minority can reproduce indefinitely and differentiate into a wide variety of cell types, just like stem cells. And often they express many of the same genes that are active in induced or embryonic stem cells and inactive in mature tissue.

Not all cancers fit seamlessly into this paradigm. Until recently, the hypothesis that stemlike cells are at the root of cancer recurrence was mired in controversy. But in the past few years, a great deal of evidence has shown that it holds true in many types of leukemia, breast cancer, and brain cancer. In these diseases, the proportion of cancer cells with a stemlike character can sometimes be as high as 40%. On the other hand, some cancers don’t contain any cells that exhibit stem cell behavior.

Many of today’s cancer treatments can wipe out the most vulnerable cells in a tumor, but they often leave behind cells with tremendous regenerative ability. It’s like mowing down a field of dandelions but leaving their roots intact, says William Matsui, an oncologist from Johns Hopkins University School of Medicine who studies cancer stem cells. He explains that measuring the shrinkage of tumors is an awful way to gauge the effectiveness of a cancer treatment. Statistics from large-scale studies of cancer patients show little correlation between how much their tumors shrink and how long they live. Instead, Matsui argues, cancer treatments should be evaluated for the ability to prevent relapses.

Emetine

Many scientists are becoming convinced that targeting cancer stem cells is the key to preventing relapses. But finding drugs with a robust effect on cancer stem cells isn’t easy. Some stem cells are inherently drug resistant because they replicate slowly compared with mature cancer cells and express proteins that pump out or otherwise eliminate small molecules. Even worse, some stem cells can continue replicating even after traditional anticancer drugs shut down their primary cancer-causing mutation.

Despite these obstacles, many cancer research groups have begun to hunt for molecules that target stem cell pathways or developmental pathways that influence the fate of stemlike cells in tumors. They are approaching the problem with many classes of therapeutics, from small RNAs and hormones to natural products.

So far, protein-based strategies have shown the most promise. One example is a protein called granulocyte colony-stimulating factor. G-CSF can force stem cells to differentiate into mature cells. It’s often used to increase the effectiveness of bone marrow or cord blood transplants. In 2003, a team of European researchers showed that G-CSF can also increase the disease-free survival times of patients with acute myeloid leukemia (New Eng. J. Med., DOI: 10.1056/NEJMoa025406). It wipes out the leukemia stem cells by forcing them to become granulocytes and other mature cells.

Antibodies also show promise as a means of eradicating cancer stem cells. In 2003, Michael F. Clarke and colleagues at Stanford University showed that breast cancer stem cells can be identified by their expression of CD44, a well-known cell-surface marker. They founded a company called OncoMed and have advanced two antibodies (OMP-21M18 and OMP-59R5) into the clinic. More recently, ImmunoCellular Therapeutics, a Los Angeles-based cancer vaccine start-up, has been developing cancer vaccines that target the stem cell subpopulation in tumors. They reported that their flagship product increased long-term survival in 55% of glioblastoma patients who enrolled in a Phase I trial.

The hunt for small molecules that exclusively target cancer stem cells remains at an even earlier stage, according to Waldemar Priebe, a professor of medicinal chemistry at the University of Texas M. D. Anderson Cancer Center. His group recently identified and modified a natural product that inhibits STAT3, a transcription factor that is upregulated in both cancer cells and embryonic stem cells. The modified natural product, dubbed WP1066, halts the growth of both normal and stemlike cancer cells, while preventing them from secreting molecules that suppress the immune system.

WP1066

Hoping to expedite the small-molecule hunt, many cancer researchers have tested Food & Drug Administration-approved drugs for their effect on cancer stem cells. In animal experiments, the immunosuppressant rapamycin has shown promise in defeating neuroblastoma stem cells and the diabetes drug metformin helped doxorubicin wipe out breast cancer stem cells.

Meanwhile, a handful of labs are testing new substances that act on well-studied developmental pathways. Blocking developmental signals can interfere with cancer stem cells’ ability to reproduce, according to Margaret A. Read, a senior product developer at Infinity Pharmaceuticals.

The company has already found one such compound. Infinity’s IPI-926 inhibits Smoothened, a regulator of the hedgehog signaling pathway that is well-known for its role in developmental biology. IPI-926 has completed Phase I trials and is being evaluated in several other Phase I and II trials for indications including pancreatic cancer, squamous cell carcinoma, and chondrosarcoma.

A few academic research groups have started looking for drug targets within developmental pathways that aren’t nearly as famous as hedgehog. For instance, at the University of California, San Diego, Tannishtha Reyaand her group have found that disrupting the Musashi-Numb signaling axis could knock out the stem cells behind chronic myelogenous leukemia (Nature, DOI: 10.1038/nature09171). By blocking the production of the Musashi protein with short hairpin-shaped RNA molecules, they prevented leukemia cells from adopting a particularly aggressive and deadly phenotype. Her team is now beginning to screen small-molecule inhibitors of this pathway to find leukemia drug leads.

To further accelerate the drug hunt, some researchers are looking for cancer stem cell stand-ins that might prove viable test beds for screening new cancer therapies. At the Whitehead Institute, Robert A. Weinbergand his collaborators have found ways to generate a large number of mesenchymal stem cells. Derived from epithelial cells, mesenchymal cells are thought to be potential precursors to cancer stem cells. His team has used these cells to screen potential anticancer drugs. They’ve identified several lead compounds, including salinomycin, which destroys cancer stem cells 100 times more efficiently than paclitaxel does (Cell, DOI: 10.1016/j.cell.2009.06.034). Weinberg and colleagues Piyush B. Gupta and Eric S. Lander have cofounded a company, Verastem, to pursue these leads.

Another group has begun screening compounds on cultures with an enriched population of cancer stem cells. Harley Kornblum and colleagues at UCLA, recently screened 31,624 compounds and narrowed the pool down to four leads. In addition to looking at the effect of the compounds on cell growth, they analyzed the effects on the expression of four genes that are correlated with a poor clinical outcome for cancer patients (Mol. Cancer Ther., DOI: 10.1158/1535-7163.MCT-11-0268). One of the four leads discovered in their study was emetine, an antiprotozoal drug.

RNA interference has proven itself a useful tool for validating targets within cancer stem cells. It has been particularly useful in targeting the same transcription factors that are used to generate induced pluripotent stem cells. Many in the cancer stem cell field think these transcription factors could become important cancer drug targets.

For example, researchers who study induced pluripotent stem cells quickly learned that c-Myc, one of the transcription factors, causes the cells to become cancerous if c-Myc is left active indefinitely. So they’ve learned to only transiently turn it on. Using hairpin-shaped short RNA molecules to knock down c-Myc, Jeremy Rich of the Cleveland Clinic and colleagues from Duke University showed that it is required for the upkeep of glioma stem cells (PLoS One, DOI: 10.1371/journal.pone.0003769). Another group of researchers, led by Ivan Stamenkovic of the University of Lausanne in Switzerland, showed that three more of these transcription factors, Oct4, SOX2, and Nanog, are active in Ewing’s sarcoma (Genes Dev., DOI: 10.1101/gad.1899710).

The logic of pursuing therapies that might zero in on cancer stem cells is compelling to many. But the methods to evaluate such therapies’ effectiveness, or to personalize cancer treatments according to stem cell markers, are not nearly as well developed. Without an array of proper markers, it’s hard to tell whether drugs that target cancer stem cells are working as intended.

Only recently, genetic markers of cancer stem cells have started showing promise. Some of the most rigorous work in this field was done by John E. Dick of the University of Toronto and colleagues. Using blood samples from 16 patients with acute myeloid leukemia, they identified a gene expression signature that signals the aberrant behavior characteristic of cancer stem cells and a poor prognosis for patients (Nat. Med., DOI: 10.1038/nm.2415). Similarly, Stephen R. Quake, Irving L. Weissman, and colleagues at Stanford University are developing methods to measure gene expression in single stem cells (Nat. Biotechnol., DOI: 10.1038/nbt.1977). This sort of analysis will be particularly useful for studying cancer stem cells, because they are in the minority and the gene expression patterns can easily be masked when cancer cells are analyzed in bulk, rather than individually.

Things are looking up for genetic analysis, but the poor reliability of cancer stem-cell-surface markers remains a confounding problem. For nearly a decade, biologists have known that antigens such as CD133 can be found on the surfaces of cancer stem cells. But these markers are not particularly specific. It would be nice if the newest technologies for monitoring circulating tumor cells via surface markers could be adapted to monitor cancer stem cell populations during clinical trials, says Inifinity’s Read.

But for solid tumors, which account for about 85% of all cancer diagnoses, the search for such stem-cell-surface markers is still in the early days. In such cancers, Read notes, cell-surface markers can vary from one type of cancer to another or even from one cell within a tumor to another. Until better markers are discovered, she adds, the cancer stem cell field will remain somewhat embryonic.

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Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society

Stems cells are potential source of cancer-fighting T cells

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Posted 21 Sep 2011 — by James Street
Category Immune System, Stem Cell Research

Tuesday, September 20, 2011

HERSHEY, Pa. — Adult stem cells from mice converted to antigen-specific T cells — the immune cells that fight cancer tumor cells — show promise in cancer immunotherapy and may lead to a simpler, more efficient way to use the body’s immune system to fight cancer, according to Penn State College of Medicine researchers.

“Cancer immunotherapy is a promising method to treat cancer patients,” said Jianxsun Song, assistant professor of microbiology and immunology. “Tumors grow because patients lack the kind of antigen-specific T cells needed to kill the cancer. An approach called adoptive T cell immunotherapy generates the T cells outside the body, which are then used inside the body to target cancer cells.”

It is complex and expensive to expand T cell lines in the lab, so researchers have been searching for ways to simplify the process. Song and his team found a way to use induced pluripotent stem (iPS) cells, which are adult cells that are genetically changed to be stem cells.

“Any cell can become a stem cell,” Song explained. “It’s a very good approach to generating the antigen-specific T cells and creates an unlimited source of cells for adoptive immunotherapy.”

By inserting DNA, researchers change the mouse iPS cells into immune cells and inject them into mice with tumors. After 50 days, 100 percent of the mice in the study were still alive, compared to 55 percent of control mice, which received tumor-reactive immune cells isolated from donors.

Researchers reported their results and were featured as the cover story in a recent issue of the journal Cancer Research.

A limitation of this potential therapy is that it currently takes at least six weeks for the iPS cells to develop into T cells in the body. In addition, potential side effects need to be considered. iPS cells may develop into other harmful cells in the body.

Researchers are now studying how to use the process in human cells.

Other researchers on this paper are Fengyang Lei and Rizwanul Haque of the Department of Microbiology and Immunology; and Lynn Budgeon and Neil D. Christensen of the Department of Pathology, Penn State College of Medicine.

This study was funded through the Pennsylvania Department of Health using Tobacco Settlement Funds, the W.W. Smith Charitable Trust and the Melanoma Research Foundation.

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