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Penn State College of Medicine research isolates liver cancer stem cells prior to tumor formation
September 18, 2009HERSHEY, PA- Penn State College of Medicine researchers, in collaboration with colleagues at the University of Southern California, have taken an important step in understanding the role of stem cells in development of liver cancer. Using a unique approach that involves study of individual cells, the team, led by C. Bart Rountree, M.D., has demonstrated for the first time a population of cancer stem cells in the liver prior to tumor formation. The research, published in the journal Stem Cells, shows a potential link between liver stem cells and liver cancer.
Using a liver-specific PTEN (phosphatase and tensin homolog deleted on chromosome 10) mouse model allowed Rountree and his colleagues to study the microenvironment of the liver without affecting the rest of the mouse.
"The PTEN knock-out mouse is one model of chronic liver injury that ultimately leads to liver cancer. During chronic injury, liver stem cells proliferate, and at times of healthy liver, the liver stem cells are very rare," Rountree said. "We were initially looking for what is driving liver stem cell proliferation during chronic liver injury.
"We started investigating liver stem cells in many different liver injury models with the idea we may be able to help people with liver disease, but we discovered that some cells we isolated were malignant," Rountree said. "It was quite a surprise for us because there were not any tumors in the mice when we isolated the cells."
The liver is the only organ in the body that is able to fully regenerate itself. The cells of the liver, including hepatocytes and cholangiocytes, can divide and repopulate themselves. With chronic liver injury, including by a virus or alcoholism, the hepatocytes lose the ability to make more of themselves. In that setting, liver stem cells proliferate and can make either of the cell types. However, patients with chronic injury also develop liver cancer, opening the possibility that the stem cells are involved in tumor formation.
"There's been a groundswell of interest in understanding the role of specific stem cells in the development of liver cancer," Rountree said. "There is a cancer stem cell lurking out there that may be very bad. It has stem cell properties and is malignant, resistant to chemotherapy. These properties make it harder to treat these cancers.
"What we ended up doing was shifting our understanding of liver stem cells and their role in malignancy," Rountree said. "All work previously done was looking at patients, animal models or cell lines after the tumor already developed. What we did was identify malignant stem cells before there is evidence of the primary tumor. This gave us a new perspective on not only what the potential of stem cells for therapy is, but also in terms of what's driving cancer formation. Imagine treating a cancer before a primary malignancy forms."
Researchers created ten cell lines to study using a single-cell isolation technique. Cells that make a unique surface protein called CD133 were separated by placing them in a liquid medium and running through a flow cytometer. Once identified, a robot took a single CD133-positive cell and placed it in a single drop into one well of a culture dish. Doing this several hundred times, the cell lines were established.
These single cells, when expanded up, had stem cell characteristics, having markers of both hepatocytes and cholangiocytes. When these lines were injected into a mouse with a deficient immune system, the tumors then formed.
Rountree said there is interest in targeting these stem cells with malignant potential. "Can we target these cells in patients with hepatitis B or C, either before or after their cancer forms?" Rountree said. "The broader implication is very powerful. If you look at a patient with chronic injury and find a way to specifically target cells with malignant potential, you may be able to prevent liver cancer in the first place."
Penn State Hershey Medical Center, Penn State College of Medicine
"We started investigating liver stem cells in many different liver injury models with the idea we may be able to help people with liver disease, but we discovered that some cells we isolated were malignant," Rountree said. "It was quite a surprise for us because there were not any tumors in the mice when we isolated the cells."
The liver is the only organ in the body that is able to fully regenerate itself. The cells of the liver, including hepatocytes and cholangiocytes, can divide and repopulate themselves. With chronic liver injury, including by a virus or alcoholism, the hepatocytes lose the ability to make more of themselves. In that setting, liver stem cells proliferate and can make either of the cell types. However, patients with chronic injury also develop liver cancer, opening the possibility that the stem cells are involved in tumor formation.
"There's been a groundswell of interest in understanding the role of specific stem cells in the development of liver cancer," Rountree said. "There is a cancer stem cell lurking out there that may be very bad. It has stem cell properties and is malignant, resistant to chemotherapy. These properties make it harder to treat these cancers.
"What we ended up doing was shifting our understanding of liver stem cells and their role in malignancy," Rountree said. "All work previously done was looking at patients, animal models or cell lines after the tumor already developed. What we did was identify malignant stem cells before there is evidence of the primary tumor. This gave us a new perspective on not only what the potential of stem cells for therapy is, but also in terms of what's driving cancer formation. Imagine treating a cancer before a primary malignancy forms."
Researchers created ten cell lines to study using a single-cell isolation technique. Cells that make a unique surface protein called CD133 were separated by placing them in a liquid medium and running through a flow cytometer. Once identified, a robot took a single CD133-positive cell and placed it in a single drop into one well of a culture dish. Doing this several hundred times, the cell lines were established.
These single cells, when expanded up, had stem cell characteristics, having markers of both hepatocytes and cholangiocytes. When these lines were injected into a mouse with a deficient immune system, the tumors then formed.
Rountree said there is interest in targeting these stem cells with malignant potential. "Can we target these cells in patients with hepatitis B or C, either before or after their cancer forms?" Rountree said. "The broader implication is very powerful. If you look at a patient with chronic injury and find a way to specifically target cells with malignant potential, you may be able to prevent liver cancer in the first place."
Penn State Hershey Medical Center, Penn State College of Medicine
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Stem cell research is making great strides. This is yet again illustrated by a study carried out by the I-STEM* Institute (I-STEM/ Inserm UEVE U861/AFM), published in the Lancet on 21 November 2009. The I-STEM team, directed by Marc Peschanski has just succeeded in recreating a whole epidermis from human embryonic stem cells.
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The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells.
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Embryonic stem (ES) cells, known for their capacity to proliferate indefinitely and differentiate into almost all types of cells including hepatocytes, have raised the hope of cellular replacement therapy for liver failure.
Paradoxical protein might prevent cancer
One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.
U of M researchers find 2 units of umbilical cord blood reduce risk of leukemia recurrence
A new study from the Masonic Cancer Center, University of Minnesota shows that patients who have acute leukemia and are transplanted with two units of umbilical cord blood (UCB) have significantly reduced risk of the disease returning.
The use of stem cells in regenerative medicine may also be detrimental for health
The use of stem cells in regenerative medicine is not always beneficial for human health, it may even be harmful according to a work done by the University of Granada and University of León. Scientists have demonstrated that transplantation of human mononuclear cells isolated from umbilical cord blood exerted a deleterious effect in rats with liver cirrhosis.
Penn Study Provides First Clear Idea of How Rare Bone Disease Progresses
An international team of scientists, led by researchers at the University of Pennsylvania School of Medicine, is taking the first step in developing a treatment for a rare genetic disorder called fibrodysplasia ossificans progressiva (FOP), in which the body's skeletal muscles and soft connective tissue turns to bone, immobilizing patients over a lifetime with a second skeleton.
Iowa State University researcher discovers key to vital DNA, protein interaction
A researcher at Iowa State University has discovered how a group of proteins from plant pathogenic bacteria interact with DNA in the plant cell, opening up the possibility for what the scientist calls a "cascade of advances."
Scientists successfully reprogram blood cells
Researchers have transplanted genetically modified hematopoietic stem cells into mice so that their developing red blood cells produce a critical lysosomal enzyme -preventing or reducing organ and central nervous system damage from the often-fatal genetic disorder Hurler's syndrome.
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