Newly Discovered Behavior in Cancer Cells Signals Dangerous Metastasis
DURHAM, N.C. -- The most aggressively malignant cancer cells
have a "toggle switch" that enables them to morph into highly
mobile cells that invade other tissues and then nest
comfortably in their new surroundings, a new study in rats
This picture of how cancer cells shift between two
alternating states -- travelers and nesters -- represents a new
understanding of how cancer metastasizes, or spreads to other
parts of the body, said the Duke Comprehensive
Cancer Center researchers who conducted the study.
"Understanding this toggle switch might ultimately enable
scientists to find ways to stop cells from metastasizing, which
is the most deadly trait of cancer," said the study's lead
investigator, Mariano Garcia-Blanco, M.D., Ph.D., professor of
molecular genetics and microbiology.
The researchers will publish their findings in the Sept. 19,
2006, issue of the journal Proceedings of the National Academy
of Sciences, now available on line. The research was funded by
the National Cancer Institute.
Until now, scientists have believed that cancer cells must
transform permanently from stationary epithelial cells into
migratory mesenchymal cells in order to metastasize.
The Duke team discovered that highly malignant cells are
equal parts epithelial and mesenchymal, transitioning between
the two as their surroundings necessitate. The proteins that
the cell produces dictate which way the cell shifts.
In a classic example of survival of the fittest, a cancer
cell's ability to toggle between epithelial and mesenchymal
enables the most malignant cells to aggressively invade and
then peacefully adapt in unfamiliar territory, the scientists
"The prevailing notion has been that the more mesenchymal
the cancer cells, the more mobile and metastatic they would
be," Garcia-Blanco said. "In reality, aggressive cancer cells
are not homogenous, but are extremely versatile in their
ability to adapt as their survival needs shift."
The researchers discovered this transition in cancer cells
when they observed an error in "alternative splicing," a key
element of the genetic copying program inside cells.
Alternative splicing determines how the DNA is chopped into
pieces and then reassembled. The order in which DNA is
reassembled determines which proteins the gene produces.
In cancer cells, the splicing machinery goes awry -- as do
myriad functions within the cells. When the splicing process
proceeds one way, the cells become mesenchymal. Spliced another
way, the cells turn epithelial.
To determine which way a cancer cell would turn, the
scientists constructed a fluorescent "reporter" -- a protein
that illuminates if the cell turns epithelial but lies dormant
if the cell reverts to mesenchymal state.
By following the reporter's illumination within cancer cells
in rats, the team viewed the very process of alternative
splicing as it occurred in the tumors. The researchers were
able to visualize specific portions of DNA, called exons, to
see if they were included or excluded in the splicing process
as the cell transformed.
"We found that the regulation of alternative splicing is
different in mesenchymal versus epithelial cells,"
Garcia-Blanco said. "A particular exon, FGFR2 IIIc, is silenced
in mesenchymal cells but is active in epithelial cells.
"We can visualize the genes as they are dynamically
changing," he said. "We can define the cell types by observing
their splicing patterns."
According to Garcia-Blanco, the cellular switch that is
believed to guide the regulation of splicing is a protein
called Fox. Both mesenchymal and epithelial cells produce Fox,
but the protein is active only in epithelial cells,
Fox also may have an accomplice or "co-factor" in or around
epithelial cells that prompts it to activate, the researchers
said. They speculate that this co-factor could be activated by
contact with stroma --the supporting structural cells of a
tumor -- because the stroma is where the majority of
epithelial-type cancer cells were observed. Their heavy
presence implies that the stroma may have induced the cancer
cells to revert to epithelial when they reached a new
destination, so they could stabilize to populate a new tumor
"Our findings validate that tumors are highly complex in
their behavior and don't necessarily need a gene mutation to
alter their behavior," said Sebastian Oltean, M.D., Ph.D.,
research associate and first author of the journal article.
"Alterations in gene splicing can be much more subtle in nature
but still have a major impact on the cancer cell and can be
targets of therapy."
The team's next step is to determine precisely what controls
the toggle mechanism in cancer cells, Garcia-Blanco said.
Identifying the various steps that occur during the natural
progression of tumors could lead to therapies for blocking
metastasis, he said.