Stem Cells Implicated In The Cause Of Bowel Cancer May Also Be Useful In Treating The Disease

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Stem cells in the intestine, which when they mutate can lead to bowel cancers, might also be grown into transplant tissues to combat the effects of those same cancers, the UK National Stem Cell Network (UKNSCN) annual science meeting heard.

Professor Nick Barker of the Institute of Medical Biology in Singapore will explain how he and his team identified that the stem cells which are crucial to maintaining a healthy intestine are also the site at which bowel cancers first begin, and how he also hopes to use healthy stem cells to regenerate tissues to help patients with Crohn's disease and some cancers.

Having discovered a gene that is only turned on in these particular stem cells Professor Barker and his team have been able to isolate the cells in mice and grow small pieces of intestine in the lab. The researchers hope that if they are able to grow larger pieces, they will be able to produce transplant tissues to replace damaged intestines.

Professor Barker explains: "Processing our dinner every day is a tough job so the lining of our intestines quickly get worn out. To keep the intestine working stem cells in little pockets along the surface replace the lining, cell by cell, about once a week.

"We already knew these stem cells existed for a while we didn't know much about them because it was difficult to distinguish them from all of the other types of cells in our intestines. Our team was able to single them out and study them because we discovered a gene that is only turned on in these particular stem cells."

Once the researchers had found this gene they were able to track where the stem cells occur throughout the body finding that, as well as the intestine, the stomach lining and in hair follicles, the cells were also present in bowel tumours.

Professor Barker continues: "We hope that studying these stem cells will be doubly useful: One day we hope to grow large enough pieces in the lab to form replacement tissues for transplant; and by studying the cells we will be able to find new ways to prevent them from mutating and hence leading to cancer.

"Bowel cancer is the third most common type of cancer in England and an estimated 38,000 new cases are diagnosed each year. We know these stem cells are both implicated in causing the cancer but that they also could be useful for treating disease so we hope that studying them will help us to understand how to attack the disease on two fronts.

Source: Biotechnology and Biological Sciences Research Council

Copyright: Medical News Today

Prostate Cancer Spreads To Bones By Overtaking The Home Of Blood Stem Cells

Like bad neighbors who decide to go wreck another community, prostate and breast cancer usually recur in the bone, according to a new University of Michigan study.

Now, U-M researchers believe they know why. Prostate cancer cells specifically target and eventually overrun the bone marrow niche, a specialized area for hematopoietic stem cells, which make red and white blood cells, said Russell Taichman, professor at the U-M School of Dentistry and senior author of the study.

Once in the niche, the cancer cells stay dormant and when they become active again years later, that's when tumors recur in the bone. The implication is that this may give us a window as to how dormancy and recurrence take place.

Taichman and a team of researchers looked in the bone marrow and found cancer cells and hematopoietic stem cells next to one another competing for the same place. The finding is important because it demonstrates that the bone marrow niche plays a central role in bone metastasis---cancers that spread into the bone-- giving researchers a new potential drug target.

Drugs could be developed to keep the types of cancers that likely recur in the bone from returning, Taichman said. For example, these drugs could either halt or disrupt how the cancer cells enter or behave in the niche, or keep the cancer cells from out-competing the stem cells.

Cancer cells act a lot like stem cells in that they must reproduce, so the U-M research group hypothesized that prostate cancer cells might travel to the niche during metastasis. One of the jobs of the niche is to keep hematopoietic stem cells from proliferating---which may be the case for cancer cells, as well, the researchers found.

So why does cancer recur? Say a person has a tumor and surgeons cut it out or do radiation, but it recurs in the bone marrow five years later, Taichman said. Those cancer cells had been circulating in the body well before the tumor was discovered, and one place those cancer cells hid is the niche.

"So what have the cancer cells been doing during those five years? Now we have a partial answer---they've been sitting in this place whose job it is to keep things from proliferating and growing," Taichman said.

"Our work also provides an explanation as to why current chemotherapies often fail in that once cancer cells enter the niche, most likely they stop proliferating," said Yusuke Shiozawa, lead author of the study. "The problem is that most of the drugs we use to try to treat cancer only work on cells that are proliferating."

Metastases are the most common malignant tumors involving the skeleton, and nearly 70 percent of patients with breast and prostate cancer have bone involvements. Roughly 15 percent to 30 percent of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid or kidney cancer have bone lesions.

Researchers aren't quite sure how the cancer cells out-compete the stem cells in the niche. However, they do know the stem cells were displaced because when cancer cells were in the niche scientists also found evidence of immature blood stem cells in the blood stream, instead of in the marrow where they were supposed to be, Taichman said.

"Eventually the entire blood system is going to collapse," he said. "For example, the patient ultimately becomes anemic, gets infections, and has bleeding problems. We really don't know why people with prostate cancer die. They end up dying from different kinds of complications in part because the marrow is taken over by cancer."

The next step is to find out how the tumor cell gets into the niche and becomes dormant, and exactly what they do to the stem cells when they are there. Researchers also want to know if other types of cancer cells, such as breast cancer, also go to the niche.

The study, "Prostate Cancer Metastases Target the Hematopoietic Stem Cell Niche to Establish Footholds in Marrow," appears online in the Journal of Clinical Investigation.

Source: University of Michigan

 

Studies Track Protein Relevant To Stem Cells, Cancer

Last year, a research team at the University of North Carolina at Chapel Hill discovered one way the protein Tet 1 helps stem cells keep their pluripotency - the unique ability to become any cell type in the body. In two new studies, the team takes a broad look at the protein's location in the mouse genome, revealing a surprising dual function and offering the first genome-wide location of the protein and its product, 5-hydroxymethylcytosine - dubbed the "sixth base" of DNA.

UNC biochemist Yi Zhang, PhD, whose team conducted the studies, called the findings an important step in understanding the molecular mechanisms behind cell differentiation and the development of cancer. The findings appear in two recent papers, published March 30, 2011 online in Nature and in the April 1, 2011 issue of Genes & Development.

"There is no doubt that Tet proteins are relevant to cancer," said Zhang, Kenan distinguished professor of biochemistry and biophysics. Zhang is also an investigator of the Howard Hughes Medical Institute and a member of the UNC Lineberger Comprehensive Cancer Center. Tet proteins were initially discovered in leukemia as fusion proteins, which are commonly found in cancer cells, where they may function as oncoproteins.

In addition, Zhang said, "Tet is likely to be one of the important players for stem cell reprogramming." Learning to "reprogram" cells in the adult body to make them behave like stem cells has long been a goal for stem cell researchers; understanding how Tet proteins operate could help advance stem-cell based treatments.

Tet proteins are known to help stem cells stay pluripotent. Zhang's team analyzed Tet1's occupancy across the entire mouse embryonic stem cell genome. They found that the protein works by using a two-pronged approach to maintain the mouse embryonic stem cell state.

"On one hand, it silences the genes that are important for differentiation. On the other hand, it also activates pluripotency genes," said Zhang.

The team then focused its attention on the Tet1-catalyzed reaction product,5-hydroxymethylcytosine. 5-hydroxymethylcytosine is a modified version of cytosine - the "C" in the four main DNA bases, A, T, G, and C. 5-methylcytosine and 5-hydroxymethylcytosine have been called the fifth and sixth bases of DNA, but since 5-hydroxymethylcytosine was discovered only recently, scientists know little about it.

"Everybody is trying to understand what 5-hydroxymethylcytosine is doing," said Zhang. "Is it an intermediate, or is it an end product? What is its biological function?" Zhang's team mapped the distribution of 5-hydroxymethylcytosine across the genome, offering new insights to its role in development and disease.

"It's the first time we have the whole picture of where this new modification is in embryonic stem cells," said Zhang. "We found that its role in regulating transcription is complicated. It's not simply activating or repressing genes - it depends on the context."

Like much of science, the research answers some questions while raising others. "This study is just beginning," said Zhang. Although Tet1 is known to generate 5-hydroxymethylcytosine, there are places where one exists without the other. Further investigation could reveal more about the relationship between the two and whether other enzymes may play a role. In addition, scientists need to examine how Tet1 and 5-hydroxymethylcytosine function in animal models.

Notes:

Study collaborators include UNC postdoctoral researchers Ana D'Alessio, Shinsuke Ito, and Kai Xia, as well as Yi Sun and Hao Wu of the University of California, Los Angeles School of Medicine; Zhibin Wang of the Johns Hopkins School of Public Health; and Kairong Cui and Keji Zhao of the National Heart, Lung, and Blood Institute.

Source:
Les Lang
University of North Carolina School of Medicine

 

Potential Treatment For Chemotherapy-Resistant Chronic Myeloid Leukaemia

Speaking at the UK National Stem Cell Network conference in York later today (31 March), Professor Tessa Holyoake from the University of Glasgow will discuss a brand new approach to treating chronic myeloid leukaemia (CML) in which a small number of cancer cells persist despite effective therapy thus preventing cure.

CML is a type of blood cancer caused by the infamous "Philadelphia Chromosome" genetic abnormality. It is usually treated using a class of drugs called Tyrosine Kinase Inhibitors and in the majority of cases this treatment is successful, with around 90% of patients recovering from the disease. However in the majority of patients a subset of cancer cells - CML stem cells - are resistant to Tyrosine Kinase Inhibitors.

"At the moment we are working with 9 patients who still have low level evidence of CML despite Tyrosine Kinase Inhibitor treatment. They are helping us to test the use, in principle, of a new type of drug that specifically deals with the resistant CML stem cells," said Professor Holyoake.

"The drug we are using in the trial is hydroxychloroquine - a well established antimalarial drug that has been used commonly since the 1950s and is also used in rheumatoid arthritis. This will allow us to test the principle of using similar drugs to treat CML patients.

"Unfortunately hydroxychloroquine may not be suitable for very long term treatment because of side effects. In particular there is a very low risk of temporary or permanent eye problems. In our trial the patients will take the drug for up to 12 months with very close monitoring of their eye health, which will allow us to intervene at the very earliest sign of an adverse effect," Professor Holyoake continued.

The patients in the trial have already taken a Tyrosine Kinase Inhibitor drug for at least a year, which has reduced the number of cancer cells in their blood to a very low level.

Professor Holyoake's team discovered that CML stem cells avoid the impact of Tyrosine Kinase Inhibitor treatments by going into a state called autophagy in response to the drug. This means that they begin to shut down and use nutrients from within the cell to survive in what is effectively suspended animation. In this state the drug cannot kill them and so later they can initiate a resurgence of the disease. Hydroxychloroquine has been shown to kill cells that are undergoing autophagy and the trial is designed to test whether this is a potential route for treatment in patients.

Professor Holyoake concluded "Although hydroxychloroquine probably isn't the final answer for treating resistant CML stem cells, we are aware that there is interest from the pharmaceuticals industry in developing new drugs that target cells undergoing autophagy. We are therefore very hopeful that once we can prove that in principle this approach works, it could lead relatively quickly to a new treatment for patients for whom Tyrosine Kinase Inhibitors don't provide a full cure."

Source:
Mike Davies
Biotechnology and Biological Sciences Research Council

 

Comparing The Quality And Quantity Of Dental Pulp Stem Cells Using Two Different Techniques

During the 89th General Session & Exhibition of the International Association for Dental Research, held in conjunction with the 40th Annual Meeting of the American Association for Dental Research and the 35th Annual Meeting of the Canadian Association for Dental Research, lead researcher C. Paganellii presented a poster titled "Influence of Pulp Extraction Technique on DPSCs Quality and Quantity."

The objective of this study was to compare the quality and quantity of dental pulp stem cells (DPSC) obtained from permanent teeth using two different pulp extraction techniques. In this study, 28 upper premolars, with no caries or periodontal problems and extracted for orthodontic reasons, were randomly divided in two different groups. Teeth of group A were longitudinally cut in two half parts with a rotating diamond disc under cool water irrigation whereas in the group B, after the creation of a 3mm deep and 40° angled notch covering all the tooth perimeter obtained thanks to the use of a dedicated bur, an Instron Testing Machine was used in order to create a fragile fracture after the application of a controlled load.

During the study, pulp tissue was removed, digested in collagenase and dispase, filtered and cells were cultured in alpha-modified minimum essential culture medium, supplemented with 20% FCS, 100µM 2P-ascorbic acid and 2 mM L-glutamine. The researchers were able to extract and cultivate DPSC's from every dental element. The stem cell integrity, growth rate, quality and quantity were higher in group B samples.

Notes:

This study was supported by a Italian Ministry of Research grant (20082KAZKN).

This is a summary of abstract #3327 "Influence of Pulp Extraction Technique on DPSCs Quality and Quantity," presented by C. Paganellii at the San Diego Convention Center.

Source:
Ingrid L. Thomas
International & American Association for Dental Research

 

3-D Lab Experiments Provide Greater Versatility Of Adult Stem Cells

A type of adult stem cell is now proving itself more versatile for research and therapies thanks to revolutionary 3D experiments. These cells have already shown great promise for repairing damaged bone and cartilage but until now have been fairly limited in the types of cells they can form in the laboratory.

Dr Paul Genever from the University of York will be speaking later today (31 March) at the annual UK National Stem Cell Network science meeting. He will tell the gathered audience of world-class scientists about his work to grow mesenchymal stem cells (MSCs) - currently one of the leading candidates to be used in stem cell therapies - as tiny spheres. Under these conditions MSCs show potential to become a variety of different cell types including, possibly, the early precursors to heart muscle cells. The work is funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and Smith & Nephew.

MSCs are common in children and adults and quite easy to find in blood, bone marrow, and many other tissues. They are already being used to repair bone in a small number of patients with severe fractures or bone disease.

Dr Genever's experiments hope to recreate the microscopic 3D environment that stem cells would normally occupy inside our bodies and so give an accurate approximation of the factors that might influence the ability of MSCs to eventually produce different types of cell for regenerative medicine.

Dr Genever said "In the past we've grown MSCs in 2D layers in the lab and they are only really strongly inclined to become bone, fat or cartilage - they are very useful for research and therapy, but in both cases would largely be limited to these three cell types.

"Our 3D technique aims to recreate the nutrients, oxygen levels and mechanical forces that these cells would normally experience inside our bodies. By growing the cells as 3D spheres of microscopic size instead of in a 2D layer, they specialise their roles more rapidly and more completely and also appear to be able to become a greater range of cell types. This shows that they are quite a bit more versatile than we thought and so are a very exciting prospect for the use of these cells in therapies."

The spheres used are made of aggregates of MSCs and are tiny, measuring only 200-300 micrometers across - about half the size of a dust mite. Within these spheres it is possible to monitor the effects of interactions between several cells and between cells and other supporting structures. The MSCs can also be combined with other types of cells that they would usually be associated with such as endothelial cells, which are found on the surfaces of blood vessels.

Professor Douglas Kell, Chief Executive, BBSRC said "Stem cells are a vital part of normal development and healthy repair. Stem cell biology is subtle and complicated and this discovery will help to ensure that results from laboratory experiments offer a good approximation of what is happening with stem cells under normal circumstances inside humans and other animals."

Source:
Mike Davies
Biotechnology and Biological Sciences Research Council

 

Stemedica Treats First Patient With Ischemic Allogeneic Mesenchymal Stem Cells

Stemedica Cell Technologies, Inc., a leader in adult allogeneic stem cell manufacturing, research and development, announced today that its specially formulated ischemic adult allogeneic mesenchymal stem cells have been successfully used to treat the first patient in an ischemic stroke study conducted at the University of California, San Diego (UCSD). A total of 35 patients will be enrolled in the clinical trial entitled: "A Phase I/II, Multi-Center, Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of a Single Intravenous Dose of Allogeneic Mesenchymal Bone Marrow Cells to Subjects with Ischemic Stroke."

The goal of this study, led by principle investigator Michael Levy, MD, PhD, FACS, chief of pediatric neurosurgery at Children's Hospital San Diego (CHSD) and professor of neurological surgery at UCSD, is to determine tolerance and therapeutic outcomes for intravenously-delivered adult allogeneic mesenchymal stem cells and to hopefully pave the way for a new therapeutic category of treatment for ischemic stroke. When asked about the first patient in the study, Dr. Levy said, "The treatment went smoothly; no side effects were observed, and the patient was released from the hospital the next day."

"This clinical trial marks a significant achievement in the treatment of debilitating ischemia-related pathologies including ischemic stroke," said Nikolai Tankovich, MD, PhD, president and chief medical officer of Stemedica. "We believe these specially designed mesenchymal stem cells are able to tolerate, survive and repair ischemic tissues caused by an infarction of the brain, heart, kidney, retina and other organs. In addition, these mesenchymal stem cells are capable of up regulating an array of important genes that are essential for the synthesis of critical proteins involved in recovery."

Lev Verkh, PhD, Stemedica's chief regulatory and clinical development officer, commented: "Many years of research and hard work by the Stemedica team culminated today in the treatment of the first patient using our uniquely designed stem cells to be effective under ischemic condition. We are proud to be the first company to initiate a study such as this under a clinical protocol approved by the U.S. Food and Drug Administration (FDA)."

Dr. Verkh continued, "Patients in this study have significant functional or neurologic impairment that confines them to a wheelchair or requires home nursing care or assistance with the general activities of daily living and have received the ischemic stroke diagnosis at least six months prior to enrollment in this study. Information on enrolling in the study can be found here."

More than 800,000 Americans suffer a stroke annually and according to the American Heart Association, stroke is the fourth leading cause of death - costing an estimated $73.7 billion in 2010 for stroke-related medical costs and disability.

Source:
Stemedica Cell Technologies, Inc.