Archive for the ‘aneuploidy’ Category

Georgetown researchers identify unique gene mutation causes cancer

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Posted 20 Aug 2011 — by James Street
Category aneuploidy, genetic research, STAG2

Georgetown University scientists have identified a unique gene mutation that leads to cancer. Researchers know that cancer occurs when cells have too many or too few chromosomes, but they haven’t understood what triggers uneven numbers of chromosomes.

In the finding, published in the August 19th issue of Science, the researchers report they’ve identified missing or mutated STAG2 gene, which encodes part of an essential protein that regulates chromosomes in several types of cancer. The new discovery may mean new hope for eradicating some types of cancer.

Twenty percent of glioblastoma multiforme, malignant melanoma and Ewing’s sarcoma examined by the researchers had either a missing or mutated STAG2 gene, which means during cell division an uneven number of chromosomes are likely to appear in offspring, or “daughter” cells.

Todd Waldman, M.D., Ph.D., an associate professor at Georgetown Lombardi said, “In the cancers we studied, mutations in STAG2 appear to be a first step in the transformation of a normal cell into a cancer cell. We are now looking at whether STAG2 might be mutated in breast, colon, lung, and other common human cancers.”

New cancer treatments possible

Study lead author, David Solomon, Ph.D., a student in the M.D. Ph.D. program at Georgetown University School of Medicine says, “We are now attempting to identify a drug that specifically kills cancer cells with STAG2 mutations. Such a drug would be of clinical benefit to the many patients whose tumors have inactivation of STAG2.”

Solomon says he had a “eureka” moment during the study when he found mutations of STAG2 in a few brain cancer cells.

“The day that I did a Western blot of 10 Ewing’s sarcoma tumors, a bone tumor most common in adolescents, and found that 6 out of 10 Ewing’s sarcoma tumors had mutations or deletions of STAG2,” he says. “I knew then that STAG2 was indeed an important tumor suppressor gene in several tumor types. That day I wrote EUREKA! in my lab notebook.”

He also notes the STAG2 gene mutation is only the second to be found on the human sex chromosome. The gene lies on the X chromosome. Men have two copies, and women have one which is active; the other is dormant. What that means is the gene has to undergo just one mutation to lead to cancer, unlike most genes that require two mutations to become inactivated.

The gene is different in other ways too, says Solomon. “It’s not like most tumor suppressor genes, which when mutated lead to either enhanced cell proliferation or decreased cell death. Instead it’s a tumor suppressor gene with a different function — maintaining normal chromosome number and structure.”

The finding lends new insight about the genetic basis for cancer. Identifying cancer tumors with the STAG2 gene mutation might lead to a new approach to eradicating cancer tumors. The Georgetown researchers are now working on finding a drug that specifically kills tumors caused by the newly identified STAG2 gene mutation.

Submitted by Kathleen Blanchard RN on 2011-08-20

“Science”: DOI: 10.1126/science.1203619
“Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer”
David Solomon, et al.
August 19, 2011

A new theory argues that cancers are actually newly evolved, parasitic species, and suggests new ways to treat them

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Posted 28 Jul 2011 — by James Street
Category aneuploidy

A different beast entirely

A different beast entirely

iStockphoto/Henrik5000/Salon

A group of researchers at University of California at Berkeley have proposed a radical new theory that would cast most everything we know about cancer in a new light. While scientists have for years believed that the disease was the result of our own DNA run amok, the truth might be much weirder — that cancer is, maybe, its own separate species.

The science is complex, but it boils down to a shift in thinking about the way in which cancer is born. For years, scientists have believed that the disease begins when a few mutated genes give rise to renegade body cells that multiply beyond control. But the Berkeley team, led by Dr. Peter Duesberg, argues that cancers are actually born from entire chromosomes, the long bands of genetic material that house our genes. What occurs is a process called aneuploidy, in which “disruptions” in chromosomes cause perversions of our genetic material, which can multiply during cell division. As a result, our DNA is rendered nearly unrecognizable.

According to PhysOrg.com:

 

Normally this would be a death sentence for a cell, but in rare cases, [Duesberg] said, such disrupted chromosomes might be able to divide further, perpetuating and compounding the damage. Over decades, continued cell division would produce many unviable cells as well as a few still able to divide autonomously and seed cancer.

The genetic makeup of the cancerous cells, because of aneuploidy, bears strikingly little resemblance to our original DNA. However, the cancer still shows “relatively stable chromosomal patterns.” Those patterns are called karyotypes, and are a hallmark of living organisms.

 

[Duesberg] and his colleagues analyzed several cancers, clearly demonstrating that the karyotype is amazingly similar in all cells of a specific cancer line, yet totally different from the karyotypes of other cancers and even the same type of cancer from a different patient.

Translation: Each different case of cancer is a unique, parasitic species. And these species are flexible, adaptable, immortal and autonomous — as long as the host survives, of course.

In a press release, Duesberg said:

 

Cancer is comparable to a bacterial level of complexity, but still autonomous, that is, it doesn’t depend on other cells for survival; it doesn’t follow orders like other cells in the body, and it can grow where, when and how it likes. That’s what species are all about … Once a cell has crossed that barrier of autonomy, it’s a new species.

What’s the point of all this hypothesizing, though? What are the possible benefits? Duesberg argues that gene therapy — which attempts to prevent the genetic mutations that many believe cause cancer — has been ineffective because it doesn’t deal with the central problem of aneuploidy. Remember that in the Berkeley theory, chromosomes themselves mutate with a very low success rate, until they reach a stable karyotype, causing cancer. It could be that a treatment that budged cancer cells off from their stable genetic footing, urged them to keep reconfiguring and evolving, would be significantly more successful in curing patients of the disease rather than current treatment.

Exploiting cancer cells’ weaknesses

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Posted 30 May 2011 — by James Street
Category aneuploidy, Chemotherapy, Drugs, Epigenetics, genetic research

Professor of Biology Angelika Amon
Photo – Photo: Donna Coveney
Team identifies potential drugs that enhance stress caused by too many chromosomes.
Anne Trafton, MIT News Office

March 7, 2011

When designing new cancer drugs, biologists often target specific gene mutations found only in cancer cells, or in a subset of cancer cells. A team of MIT biologists is now taking a slightly different approach, targeting a trait shared by nearly all cancer cells — they have too many chromosomes.

MIT biology professor Angelika Amon has been studying this peculiarity, known as aneuploidy, for several years. In developing fetuses, aneuploidy causes death or birth defects. However, in cancer cells, aneuploidy appears to confer a survival advantage.

“We’re interested in this because the vast majority of human cancers are aneuploid,” says Amon, a member of the David H. Koch Institute for Integrative Cancer Research. “The question arises, can we exploit the fact that all tumor cells are aneuploid for treatment? Compounds that selectively kill aneuploid cells would be effective against a broad spectrum of human tumors.”

In a study published Feb. 18 in the journal Cell, Amon and her colleagues identified three such compounds, and they are now running a large-scale screen of thousands of compounds, with researchers from Harvard, to identify even more drug candidates. Lead author of the paper is Yun-Chi Tang, a postdoctoral fellow at the Koch Institute.

Cell stress

Amon has previously shown that aneuploid cells divide very slowly and grow too large. Aneuploidy also puts significant stress on cells: It takes a lot of energy to replicate all of that extra genetic material, and to produce the proteins encoded by those extra genes. Furthermore, the cells then have to break down all those proteins, since they’re not needed. “Cells have a limited number of tools available to deal with extra proteins,” Amon says. “These pathways get stressed and they can’t keep up.”

In the Cell study, Amon selected about 20 potential drug compounds that might exploit those weaknesses. “We said, maybe we can enhance those stresses and induce lethality. The hope is to enhance it to a level that does not affect normal cells but would affect aneuploid cells more,” she says.

The researchers tested the compounds in mouse embryonic fibroblasts that have an extra chromosome, and then in human cancer cells. They identified three compounds that preferentially targeted the aneuploid cells (both human and mouse): chloroquine, a drug commonly used to treat malaria, and two other compounds called AICAR and 17-AAG.

AICAR stresses cells by activating an enzyme called AMPK, which cranks up cellular metabolism. 17-AAG inhibits the production of a protein involved in stabilizing other proteins that cancer cells need to grow. Chloroquine acts by blocking a cancer cell’s ability to rid itself of damaged proteins and cell structures.

Amon says she believes the drugs are exaggerating the stresses of aneuploidy, but more experiments are needed to show that.

All three compounds induce human cancer cells to kill themselves, but they work much better when two are used together. 17-AAG is already in clinical trials for leukemia, but these new data suggest that it would be better used in combination with other drugs, Amon says.

AICAR is not approved for human use, but a similar drug called metformin is used to treat diabetes. However, metformin did not perform as well in this study as AICAR.

Pumin Zhang, professor of molecular physiology at Baylor College of Medicine, says the results represent a significant step toward finding drugs that specifically target cancer cells, unlike most of the chemotherapy drugs now available. “It shows there is a clear difference between normal cells and aneuploid cancer cells, and we can exploit that difference,” says Zhang, who was not involved in this research.