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Molecular marker identifies normal stem cells as intestinal tumor source
December 18, 2008St. Jude scientists show for the first time that normal stem cells can act as the source of tumors in mature solid tissues
Scientists at St. Jude Children's Research Hospital have answered a central question in cancer biology: whether normal stem cells can give rise to tumors. Stem cells are immature cells that can renew themselves and give rise to mature differentiated cells that compose the range of body tissues. In recent years, researchers have developed evidence that cancers may arise from mutant forms of stem cells.
Like a brand-name product instantly identifiable by its trademarked logo, normal and cancerous stem cells display on their surface characteristic proteins, including Prominin1 or CD133. A key question in cancer biology has been whether these so-called cancer stem cells arise from normal stem cells or more mature cancer cells that somehow reacquire the characteristics of stem cells.
In the advanced, online issue of the journal Nature, St. Jude investigators show that Prominin1 marks normal intestinal stem cells and that these cells, when mutated, give rise to intestinal tumors. The finding could also aid in identifying the source of cancer stem cells in the lung, kidney, brain, pancreas and other tissues.
"The idea that cancers might arise from mutant stem cells is an attractive one; but until now the link between normal and cancer stem cells in solid tissues like the intestine was not known," said Richard Gilbertson, M.D., Ph.D., associate member of the St. Jude Developmental Neurobiology and Oncology departments and the paper's senior author. "Our work provides the first direct link between normal solid tissue stem cells and cancer. The fact that this occurs in the intestine is particularly interesting since human intestinal tumors contain Prominin1-expressing cancer stem cells."
In addition to providing insights into the origins of cancer, the work might help scientists identify more effective treatments. "Normal stem cells are designed to withstand environmental insults," Gilbertson said. "Thus cancer stem cells might use these same mechanisms to resist chemotherapy and radiotherapy. Remnant cancer stem cells might therefore cause tumors to relapse and re-grow following treatment. If we could kill these cancer stem cells, we might be able to prevent relapse. Understanding the link between normal and cancerous stem cells should help us target the latter while preserving the former."
Working with mice, the researchers inserted a genetic switch that enabled them to selectively turn on a colored tracer molecule only in cells that were expressing, or had expressed, Prominin1. These tracer experiments revealed that Prominin1 cells generate the covering of the entire small intestine and are therefore the stem cell of this tissue.
Next, the researchers switched on cancer-producing machinery in the Prominin1 intestinal stem cells and used a fluorescent tracer to follow the offspring of these cells. Those studies revealed that the stem cells stopped making normal intestine and made tumors instead. "We saw a dramatic change in these laboratory models," Gilbertson said. "The tumorous tissue ultimately replaced the entire normal intestine. In terms of clinical importance, now that we have isolated both the normal, parental stem cells and the cancer stem cells, we can begin screening compounds that will affect the malignant stem cell but not the normal stem cell."
More broadly, Prominin1 might prove to be a useful marker to trace cancer stem cells in the kidney, brain, pancreas and other tissues. The researchers are also exploring the use of stem cell markers in diseases other than cancer. "As we develop these kinds of characteristic markers for stem cells, we might be able to use them to isolate stem cells capable of regenerating healthy tissue in patients who suffer diabetes or other diseases due to organ failure," Gilbertson said.
St. Jude Children's Research Hospital
In the advanced, online issue of the journal Nature, St. Jude investigators show that Prominin1 marks normal intestinal stem cells and that these cells, when mutated, give rise to intestinal tumors. The finding could also aid in identifying the source of cancer stem cells in the lung, kidney, brain, pancreas and other tissues.
"The idea that cancers might arise from mutant stem cells is an attractive one; but until now the link between normal and cancer stem cells in solid tissues like the intestine was not known," said Richard Gilbertson, M.D., Ph.D., associate member of the St. Jude Developmental Neurobiology and Oncology departments and the paper's senior author. "Our work provides the first direct link between normal solid tissue stem cells and cancer. The fact that this occurs in the intestine is particularly interesting since human intestinal tumors contain Prominin1-expressing cancer stem cells."
In addition to providing insights into the origins of cancer, the work might help scientists identify more effective treatments. "Normal stem cells are designed to withstand environmental insults," Gilbertson said. "Thus cancer stem cells might use these same mechanisms to resist chemotherapy and radiotherapy. Remnant cancer stem cells might therefore cause tumors to relapse and re-grow following treatment. If we could kill these cancer stem cells, we might be able to prevent relapse. Understanding the link between normal and cancerous stem cells should help us target the latter while preserving the former."
Working with mice, the researchers inserted a genetic switch that enabled them to selectively turn on a colored tracer molecule only in cells that were expressing, or had expressed, Prominin1. These tracer experiments revealed that Prominin1 cells generate the covering of the entire small intestine and are therefore the stem cell of this tissue.
Next, the researchers switched on cancer-producing machinery in the Prominin1 intestinal stem cells and used a fluorescent tracer to follow the offspring of these cells. Those studies revealed that the stem cells stopped making normal intestine and made tumors instead. "We saw a dramatic change in these laboratory models," Gilbertson said. "The tumorous tissue ultimately replaced the entire normal intestine. In terms of clinical importance, now that we have isolated both the normal, parental stem cells and the cancer stem cells, we can begin screening compounds that will affect the malignant stem cell but not the normal stem cell."
More broadly, Prominin1 might prove to be a useful marker to trace cancer stem cells in the kidney, brain, pancreas and other tissues. The researchers are also exploring the use of stem cell markers in diseases other than cancer. "As we develop these kinds of characteristic markers for stem cells, we might be able to use them to isolate stem cells capable of regenerating healthy tissue in patients who suffer diabetes or other diseases due to organ failure," Gilbertson said.
St. Jude Children's Research Hospital
Stem Cells Current Events and Stem Cells News RSSPhysician-scientist proves stem cells heal lungs of newborn animals
Dr. Bernard Thébaud lives in two very different worlds. As a specialist in the Stollery Children's Hospital's Neonatal Intensive Care Unit at the Royal Alexandra Hospital, he cares for tiny babies, many of whom struggle for breath after being born weeks before they are due.
New discovery about the formation of new brain cells
The generation of new nerve cells in the brain is regulated by a peptide known as C3a, which directly affects the stem cells' maturation into nerve cells and is also important for the migration of new nerve cells through the brain tissue, reveals new research from the Sahlgrenska Academy published in the journal Stem Cells.
Umbilical cord blood stem cell transplant may help lung, heart disorders
Two separate studies published in the current issue of Cell Transplantation (18:8), - now freely available on-line have shown that transplanted human-derived umbilical cord blood (UCB) stem cells transplanted in an animal model had positive therapeutic effects on specific lung and heart disorders the animal models.
Gene mismatch influences success of bone marrow transplants
A commonly inherited gene deletion can increase the likelihood of immune complications following bone marrow transplantation, an international team of researchers reports in the November 22 advance online issue of Nature Genetics.
New research shows versatility of amniotic fluid stem cells
For the first time, scientists have demonstrated that stem cells found in amniotic fluid meet an important test of potential to become specialized cell types, which suggests they may be useful for treating a wider array of diseases and conditions than scientists originally thought.
First reconstitution of an epidermis from human embryonic stem cells
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.
Bone Implant Offers Hope for Skull Deformities
A synthetic bone matrix offers hope for babies born with craniosynostosis, a condition that causes the plates in the skull to fuse too soon.
Your Own Stem Cells Can Treat Heart Disease
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.
Is hepatic differentiation of embryonic stem cells induced by valproic acid and cytokines?
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.
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