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An Unlikely Dynamic Duo

Dr. Stephen Baylin in the lab.
Dr. Stephen Baylin, professor
of oncology and medicine at
the Johns Hopkins University
School of Medicine.

The latest medical news portrays stem cells as plucky heroes, swooping in to save the day—and someday, you—from aging, illness or injury. Their dastardly antithesis is cancer, the ultimate villain intent on stealing health and lives. But what if this superhero and villain share more than just the news pages? What if stem cells and cancer have an uncanny likeness, a similarity hammered onto their genetic material? By getting a better understanding of what makes stem cells so special and potentially useful, scientists might also discover new vulnerabilities to exploit in cancer.

Ferreting out this similarity and understanding what it means for the future of cancer treatment is one of the driving forces behind the lab of Stephen Baylin, M.D., a professor of oncology and medicine at the Johns Hopkins University School of Medicine. Baylin and his colleagues’ work centers on a phenomenon known as epigenetics, a laying down of instructions on top of the genome that tells some genes to constantly remain on while others are permanently shut off. His results show that stem cells and cancer have some remarkable similarities at the epigenetic level, a finding that he and his team are already exploiting in efforts to change cancer cells’ epigenetic patterns to look more like their healthy brethren.

How Good Cells Go Bad

Scientists have long noticed superficial similarities between stem cells and cancer.  Both cancer and stem cells—developmentally primitive cells that spur organ development early in life and remain present in nearly all the body’s organs later to repair or replace injured and aging tissues—are immortal, resisting the programmed cell death that keeps the growth of healthy cells in check. Both cell populations also tend to have a biological wanderlust, with selected cells driven by both internal and external  forces  to migrate elsewhere in the body.

In recent years, this paradigm has extended even further into the idea that cancerous tumors have their own population of “cancer stem cells.”  While scientists previously thought of all cells in a tumor having similar capabilities, some research has shown that a fraction of cells seem to carry more of the load for growing the tumor and causing it to spread to other sites.

Based on these similarities, some researchers have speculated that cancer might spring from the healthy stem cells responsible for maintaining mature tissue.  For some cancers, that may indeed be true, Baylin says. Several research teams have reported that when tissue is chronically inflamed—which spurs healthy stem cells to kick into high gear to reproduce more and faster to repair damage—it’s more likely to become cancerous. For example, there’s a close association between chronic hepatitis, which inflames the liver, and liver cancer. However, Baylin notes, that connection doesn’t appear to hold true for all cancers.  Many researchers have shown that even more mature cell populations can become cancerous.

Baylin and his colleagues have been studying a different connection between stem cells and cancer that might explain why cancer can arise from both developmentally primitive and more mature cells.  Years ago, his lab was one of the first to report that cancer cells often have abnormal patterns of epigenetic –or, “above the genome”—marks.  These chemical marks, or methyl  groups, attach to DNA and contribute to preventing  genes from being turned on.  If a gene isn’t being used to make a protein, it’s the equivalent of being turned off. 

Baylin and his team have found that many genes are abnormally  methylated in cancer cells, and some of these are  known as  tumor suppressor genes, whose job is keeping cell division in check—and therefore, keeping cancer at bay.

Turning Cancer Back Down the Straight and Narrow

The finding could explain why healthy stem cells might turn into cancer, Baylin explains, especially in conditions in which these cells are spurred to reproduce quickly. Developmentally immature cells gain or lose methyl marks as they grow up and differentiate into more mature cells.  The function of these marks is to turn on only the genes that a cell needs to do its particular job—acting as a muscle or nerve cell, for example—and turn off genes important for stem cells, such as unlimited division.  When healthy stem cells are reproducing quickly, they may be more likely to make mistakes in assigning these epigenetic marks, accidently placing methyl groups on genes that shouldn’t be turned off or genes where the normal turn of signals do not involve DNA methylation. 

“If a gene important for keeping cell division rates low is methylated so it can’t be expressed, the result is a cell that divides out of control,” Baylin explains.

In isolation, these epigenetic mistakes don’t necessarily cause cancer.  But several mistakes, or epigenetic mistakes combined with genetic mutations, might be the key early signals that cause cells to turn cancerous.

Baylin and his colleagues recently revealed why these epigenetic mistakes may arise in mature cells too.   Two years ago, he and his team discovered that many of the genes that acquire abnormal methyl marks in cancer are the same ones that are marked during the embryonic stage of development with proteins known as polycomb group proteins.  These proteins are a special signal that holds genes in a state of suspended animation of low function, poised to turn on or off at any time.  Normally, these proteins regulate genes for low function without relying on DNA methylation in the process.  The researchers aren’t sure why, but this poised state seems to linger for some genes in abnormal states of cell division such as in chronic inflammation,  causing such genes  to have a higher chance of being mistakenly methylated in mature cells.

In terms of clinical significance, these methylation marks aren’t just a signal that cells have gone bad, says Baylin.  Additional research by his lab and collaborators shows that methylation may also be a useful clue for determining prognosis.  He and principally Hopkins researchers Malcolm Brock, M.D.,  and James Herman, M.D., have shown that samples of human lung cancer with particular methylation patterns behave as if they’re in the later stages of the disease, advancing aggressively, even if pathologists who view these tissues report that they’re in an earlier stage.

“Being able to accurately assess a cancer’s aggressiveness is critical for delivering the best treatment,” Baylin says.

He and his team also have found that all isn’t lost, even if abnormal methyl marks are present.  In multiple cancer types the team has shown that when they use chemicals to knock methyl groups off of genes, the cells begin to behave more like normal, healthy cells.  Scientists are currently using drugs known to remove methyl groups from  DNA to effectively treat a form of pre-leukemia and may eventually develop new cancer drugs that work by directly altering methylation patterns, he says.

The end result: turning the devious villain cancer back toward the straight and narrow path to health.

--by Christen Brownlee

 
 
 
 
 
 

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