Cells don’t like to be alone. In the early stages of tumor formation, a
cell might be pushed out of its normal home environment due to
excessive growth. But a cell normally responds to this homeless state
by dismantling its nucleus, packing up its DNA, and offering itself to
be eaten by immune system cells. Simply put, the homeless cell kills
itself. This process, known as apoptosis, typically stops potential
cancer cells before they have a chance to proliferate.
Now, researchers from the lab of Harvard Medical School
professor of cell biology Joan Brugge have uncovered another mechanism
that kills these precancerous, homeless cells. By studying two
different types of human breast epithelial cells, the researchers found
that when separated from their natural environment, these cells lose
their ability to harvest energy from their surroundings. Eventually,
they starve.
“We originally thought that in order for cells to survive
outside their normal environment, they would simply need to suppress
apoptosis,” says Brugge, senior author on the paper, which appeared
August 19 online in Nature.
“But our studies indicate that this activity is not sufficient to
prevent the demise of homeless cells. Even if they escape apoptosis,
these cells can’t transport enough glucose to sustain an energy
supply.”
Surprisingly, metabolic function is restored if antioxidant
activity is increased inside the cells, allowing the cells to use
energy pathways that don’t rely on glucose.
“It raises the interesting idea that antioxidants, which are
typically thought to be protective because they prevent genomic damage,
might be allowing these potentially dangerous cells to survive,” says
first author Zachary Schafer, assistant professor at the University of
Notre Dame and a former postdoc in Professor Brugge’s lab.
The authors caution against extrapolating too far from their
data, which were based on experiments in laboratory cell culture. They
also emphasize that the experiments were not designed to mimic the
effect of dietary antioxidants in the body. The researchers used two
specific antioxidant compounds – which are chemically distinct from
those found in food and supplements – only in order to understand how
oxidants contributed to the metabolic defects.
“We think that genes with antioxidant activity play a much
bigger role than antioxidant compounds administered from outside the
body,” says Brugge. “What happens with dietary antioxidants is much
more complicated and not what we were trying to study.”
Beyond cell suicide
The researchers had previously reported that when cells were
endowed with a cancer-causing gene that prevents them from committing
suicide, they still died when cut off from their extracellular
environment. This puzzled researchers, who have long thought that
apoptosis was the only way the cells could die.
In the recent study, Schafer and colleagues took a closer
look, measuring the levels of proteins and molecules associated with
metabolic activity in the displaced, but apoptosis-resistant, cells.
They found that the cells had become incapable of taking up glucose,
their primary energy source. Under the microscope, the cells also
displayed telltale signs of oxidative stress, a harmful accumulation of
oxygen-derived molecules called reactive oxygen species (ROS). The end
result was a halt in the production of ATP, the molecular lifeblood
that transports energy in the cells. The unmoored cells were literally
starving to death.
“The idea that a lack of extracellular matrix can prevent
cells from accessing nutrients hasn’t been shown conclusively before,”
says Schafer. “Loss of glucose transport, decreased ATP production,
increased oxidative stress – all those things turn out to be
interrelated.”
To figure out what was wrong, the researchers took a
straightforward approach – they tried to fix it. Schafer engineered the
homeless cells to express high levels of a gene, HER2, known to be
hyperactive in many breast tumors. He also treated the cells with
antioxidants in an attempt to relieve oxidative stress and help the
cells survive.
Both strategies worked. The cells with the breast cancer gene
regained glucose transport, preventing ROS accumulation, and recovered
their ATP levels. The antioxidant-treated cells also survived, but by
using fatty acids instead of glucose as an energy source.
“Our results raise the possibility that antioxidant activity
might allow early-stage tumor cells to survive where they otherwise
would die from these metabolic defects,” says Schafer.
The researchers are currently planning to test the effects of
antioxidant genes, some of which are abnormally regulated in human
tumors, and a wider range of antioxidants in animal models. They also
plan on characterizing the metabolic consequences of matrix detachment
in more detail.
“Ultimately,” Brugge says, “we want to understand enough about
the metabolism of tumor cells so that new types of drugs can be
designed to target them.”
Notes:
This research was funded by the National Cancer Institute and the National Institutes of Health.
Written by Jue Wang
“Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment”
Zachary T. Schafer(1,†), Alexandra R. Grassian(1,*), Loling
Song(1,*), Zhenyang Jiang(1), Zachary Gerhart-Hines(2,3), Hanna Y.
Irie(1), Sizhen Gao(1), Pere Puigserver(1,2), & Joan S. Brugge(1)
1-Department of Cell Biology, Harvard Medical School, Boston, MA
2-Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
3-Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD
*These authors contributed equally to this work.
†Present address: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN
Source:
David Cameron
Harvard Medical School
