Public release date: 2-Aug-2012 [ | E-mail | Share ]

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. Stem cells are special. Nestled in muscle and skin, organ and bone, they bide their time over years or decades until called to replace damaged or lost tissue. One secret to their longevity is an enzyme called telomerase, which stills the relentless ticking of the molecular clock that limits the life span of other cells.

This cellular fountain of youth prevents the progressive shortening of the tips of our chromosomes that occurs with each cell division. But the presence of telomerase can be a double-edged sword: The same activity that ensures long life for stem cells can also keep a cancer cell dividing long after its aging neighbors have thrown in the towel. Conversely, a malfunction can prevent stem cells from doing their job and lead to devastating diseases.

Now, for the first time, researchers at the Stanford University School of Medicine have identified how telomerase is recruited to chromosome ends and figured out a way to block it.

"If telomerase is unable to maintain the ends of the chromosomes, cells will stop multiplying," said professor of medicine Steven Artandi, MD, PhD. "This would be advantageous in cancer cells, but in normal stem cells it can cause severe dysfunction and lead to diseases such as pulmonary fibrosis, aplastic anemia and a genetic condition called dyskeratosis congenita. We want to understand how telomerase works, and to develop therapies for cancer and these other diseases."

Artandi is the senior author of the research, which will be published Aug. 3 in Cell. He is also a member of the Stanford Cancer Institute. Graduate student Franklin Zhong is the first author of the study.

Telomerase is normally expressed in adult stem cells and immune cells, as well as in cells of the developing embryo. In these cells, the enzyme caps off the ends of newly replicated chromosomes, allowing unfettered cell division. Without telomerase, cells stop dividing or die when the ends called telomeres fall below a minimum length. Unfortunately, the enzyme is also active in nearly all cancer cells.

Earlier research in Artandi's lab identified a protein called TCAB1 that brings the telomerase complex (actually a large clump of many proteins) to a processing area in the cell's nucleus called a Cajal body. But no one knew how the complex was then ferried to the ends of telomeres, and research was stymied by the complex's large size, multiple components and relative scarcity.

"This problem has been really intractable," said Artandi. "The enzyme is extremely hard to study. But we've now found that telomerase is recruited to the telomeres through an interaction with a protein called TPP1 that coats the ends of chromosomes." What's more, the researchers have identified the exact region of TPP1 to which telomerase binds a section called an OB-fold.

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Research shows how protein component that enables cell replication gets ferried to chromosome tips

ScienceDaily (Aug. 2, 2012) Stem cells are special. Nestled in muscle and skin, organ and bone, they bide their time over years or decades until called to replace damaged or lost tissue. One secret to their longevity is an enzyme called telomerase, which stills the relentless ticking of the molecular clock that limits the life span of other cells.

This cellular fountain of youth prevents the progressive shortening of the tips of our chromosomes that occurs with each cell division. But the presence of telomerase can be a double-edged sword: The same activity that ensures long life for stem cells can also keep a cancer cell dividing long after its aging neighbors have thrown in the towel. Conversely, a malfunction can prevent stem cells from doing their job and lead to devastating diseases.

Now, for the first time, researchers at the Stanford University School of Medicine have identified how telomerase is recruited to chromosome ends -- and figured out a way to block it.

"If telomerase is unable to maintain the ends of the chromosomes, cells will stop multiplying," said professor of medicine Steven Artandi, MD, PhD. "This would be advantageous in cancer cells, but in normal stem cells it can cause severe dysfunction and lead to diseases such as pulmonary fibrosis, aplastic anemia and a genetic condition called dyskeratosis congenita. We want to understand how telomerase works, and to develop therapies for cancer and these other diseases."

Artandi is the senior author of the research, published Aug. 3 in Cell. He is also a member of the Stanford Cancer Institute. Graduate student Franklin Zhong is the first author of the study.

Telomerase is normally expressed in adult stem cells and immune cells, as well as in cells of the developing embryo. In these cells, the enzyme caps off the ends of newly replicated chromosomes, allowing unfettered cell division. Without telomerase, cells stop dividing or die when the ends -- called telomeres -- fall below a minimum length. Unfortunately, the enzyme is also active in nearly all cancer cells.

Earlier research in Artandi's lab identified a protein called TCAB1 that brings the telomerase complex (actually a large clump of many proteins) to a processing area in the cell's nucleus called a Cajal body. But no one knew how the complex was then ferried to the ends of telomeres, and research was stymied by the complex's large size, multiple components and relative scarcity.

"This problem has been really intractable," said Artandi. "The enzyme is extremely hard to study. But we've now found that telomerase is recruited to the telomeres through an interaction with a protein called TPP1 that coats the ends of chromosomes." What's more, the researchers have identified the exact region of TPP1 to which telomerase binds -- a section called an OB-fold.

"When we mutated this site in TPP1," said Artandi, "we blocked the interaction between the two proteins and prevented telomerase from going to the telomeres. And when we interfered with this interaction in human cancer cells, the telomeres began to shorten." The researchers are now assessing whether the life span of the cancer cells, and their ability to divide unchecked, will also be affected by the treatment.

To confirm their finding, Artandi and his colleagues used cells from patients with pulmonary fibrosis -- a debilitating scarring or thickening of lung tissue associated with telomerase mutations. The disease had been troubling to researchers and clinicians, however, because the patients' mutated telomerase seemed to be fully active when tested in the laboratory. Zhong and Artandi found that the disease-associated mutations occurred in the portion of telomerase that interacted with TPP1, and interfered with their binding. As a result the enzyme, although active, couldn't get to where it was needed.

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How protein component that enables cell replication gets ferried to chromosome tips

Multicolored intestine tissue in genetically modified mice allow scientists to track which cells give rise to tumors. Image: A. G. Schepers et al., Science (2012)

By Gretchen Vogel, ScienceNOW

All too often, cancer that seems to have been wiped out by treatment comes back. Some scientists have blamed so-called cancer stem cells, a subset of cancer cells that might be able to remain dormant, evading chemotherapy or radiation treatments, only to form new tumors months or years later. The idea has been controversial, but three papers published today report evidence that in certain brain, skin, and intestinal tumors, cancer stem cells are the source of tumor growth.

The cancer stem cell model differs from the traditional idea that tumor growth is equal opportunitythat is, any and all cancerous cells can divide and cause the tumor to grow and spread. The stem cell model says that tumor growth is more hierarchical, mainly driven by a subset of cells that can make new copies of themselves and give rise to the other cell types the tumor contains. Some of the first evidence for cancer stem cells came from studies of leukemia in the 1990s, which showed that only a small subset of the cancerous blood cells could propagate the disease in mice. But it has been harder to test whether cancer stem cells fuel the growth of tumors in other tissues.

In the new studies, three independent groups used genetic cell-marking techniques to trace the proliferation of certain cells within growing tumors. The method gives researchers a glimpse of what happens in the real life of a tumor, says Cdric Blanpain, a stem cell researcher at the Universit Libre de Bruxelles in Belgium. He and his colleagues report online in Nature that in mouse papilloma tumors, a precursor to skin cancer, most of the tumor growth came from a few cells, which in some ways resembled the stem cells that maintain healthy skin.

In a second paper, also published online today in Nature, developmental biologist Luis Parada and his colleagues at the University of Texas Southwestern Medical Center (UTSMC) in Dallas show that in mice that develop glioma, a form of brain cancer, tumor growth seems to come from a small subset of cells in the tumor. They find that the cells can remain dormant during chemotherapy that kills off most of the cancer and can give rise to new tumors once the drug treatment stops.

And in the third paper, published online today in Science, developmental biologists and stem cell researchers Hugo Snippert, Arnout Schepers, Hans Clevers, and their colleagues at the Hubrecht Institute in Utrecht, the Netherlands, used mice with multicolored intestines to look at the kinds of cells that form intestinal adenomas, a precursor to intestinal cancer. The rodents, which the scientists have nicknamed confetti mice, carry genetic markers that can label intestinal cells blue, green, red, or yellow depending on which cell they originate from. The team reports that the adenomas grow from cells that express a gene called Lgr5+, which is also active in normal intestinal stem cells. The tumor is really like a caricature of normal tissue, Snippert says.

Such cell-tracing techniques are the right approach to test the cancer stem cell model, says Sean Morrison, who studies stem cells and cancer at UTSMC and who was not involved in any of the studies. There is now enough evidence to be fairly sure that the model explains at least some types of cancer, he says. Morrison cautions, however, that the studies on papilloma and adenoma looked at precancerous tumors. Indeed, when Blanpain and his colleagues examined mice with squamous cell carcinoma, a malignant outgrowth of the papilloma, they found that most of the cells were actively dividing, not just a small subset of stem-cell-like cells.

Understanding which cancers might grow fromor simply harborcancer stem cells is key to more effective treatments, the researchers say. That is no easy task, however. Morrison notes that tumor growth differs even among patients with the same type of cancer. Still, says Parada, having three examples in which tumors seem to harbor cancer stem cells suggests there will be more. I hope it will bolster and stimulate the community to figure out how to better study the cancer stem cell model, he says. Lets bring this level of scrutiny to all solid tumors.

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Cancer Stem Cells Can Fuel Tumor Growth

(AP) Why does cancer come back after a tumor has been seemingly eradicated? Three new studies from American, Belgian, British and Dutch researchers may have an answer.

Study: Stem cells boost brain tumor treatments

The studies bolster 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 target and 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.

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Stem cells in tumors may fuel cancer regrowth, new studies suggest

Featured Article Academic Journal Main Category: Cancer / Oncology Also Included In: Stem Cell Research;Biology / Biochemistry Article Date: 02 Aug 2012 - 2:00 PDT

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Papers on all three studies appeared online on Wednesday, two in Nature and one in Science.

In all three studies, the teams used genetic cell-marking techniques to track cell lineage and show that a restricted cell population appears to be the source of new tumor cells, in much the same way as stem cells are the "master builders" of new healthy cells.

GBM is a type of brain cancer that is currently considered incurable. It is a fast-growing tumor with a median survival of about 15 months. Although initially it responds to chemotherapy, the cancer nearly always comes back.

In their study, Parada and colleagues used genetically engineered mice bred to develop GBM and found that the resting tumor cells act more like stem cells.

They used a genetic marker that labels healthy adult neural stem cells, but not their more specialized descendants, to see if it would do the same for cancer stem cells in GBM. When they did so, they found all the tumors contained at least a few labelled cells, which they presumed to be stem cells.

The tumors also contained unlabelled cells, which could be killed with standard chemotherapy, but then the tumors came back soon afterwards. When they tested them again, they found the tumors contained unlabelled cells that came from labelled predecessors.

When they applied chemotherapy with a technique that suppressed the labelled cells, the researchers found the tumors shrank back to what Parada described to Nature NEWS as "residual vestiges" that bore no resemblance to GBM.

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Cancer Stem Cells May Drive Tumor Growth