When human lung epithelial cells are exposed to equivalent doses of nano-sized (left) or micro-sized (right) metallic nickel particles, activated HIF-1 alpha pathways (stained green) appear mostly with the nanoparticles. Image: Brown University
All the excitement about nanotechnology comes down to
this: Structures of materials at the scale of billionths of a meter take on
unusual properties. Technologists often focus on the happier among these
newfound capabilities, but new research by an interdisciplinary team of
scientists at Brown
University finds that
nanoparticles of nickel activate a cellular pathway that contributes to cancer
in human lung cells.
“Nanotechnology has tremendous potential and promise for
many applications,” says Agnes Kane, chair of the Department of Pathology and
Laboratory Medicine in The Warren Alpert Medical School of Brown University. “But the lesson is that we have to learn to be able to design them more
intelligently and, if we recognize the potential hazards, to take adequate
Kane is the senior author of the study published online
in Toxicological Sciences.
Nickel nanoparticles had already been shown to be
harmful, but not in terms of cancer. Kane and her team of pathologists,
engineers and chemists found evidence that ions on the surface of the particles
are released inside human epithelial lung cells to jumpstart a pathway called
HIF-1 alpha. Normally the pathway helps trigger genes that support a cell in
times of low oxygen supply, a problem called hypoxia, but it is also known to
encourage tumor cell growth.
“Nickel exploits this pathway, in that it tricks the cell
into thinking there’s hypoxia but it’s really a nickel ion that activates this
pathway,” says Kane, whose work is supported by a National Institues of Health
Superfund Research Program Grant. “By activating this pathway it may give
premalignant tumor cells a head start.”
The research team, led by postdoctoral research associate and first author Jodie
Pietruska, exposed human lung cells to nanoscale particles of metallic nickel
and nickel oxide, and larger microscale particles of metallic nickel. A key
finding is that while the smaller particles set off the HIF-1 alpha pathway,
the larger metallic nickel particles proved much less problematic.
In other words, getting down to the nanoscale made the
metallic nickel particles more harmful and potentially cancer-causing. Kane
says the reason might be that for the same amount of metal by mass, nanoscale particles
expose much more surface area and that makes them much more chemically reactive
than microscale particles.
Another important result from the work is data showing a
big difference in how nickel nanoparticles and nickel oxide nanoparticles react
with cells, Pietruska says. The nickel oxide particles are so lethal that the
cells exposed to them died quickly, leaving no opportunity for cancer to
develop. Metallic nickel particles, on the other hand, were less likely to kill
the cells. That could allow the hypoxia pathway to lead to the cell becoming
“What is concerning is the metallic nickel nanoparticles
caused sustained activation but they were less cytotoxic,” Pietruska says. “Obviously a dead cell can’t be transformed.”
Although Kane said the findings should raise clear
concerns about handling nickel nanoparticles, for instance to prevent airborne
exposure to them in manufacturing, they are not all that’s needed to cause
cancer. Cancer typically depends on a number of unfortunate changes, Kane says.
Also, she says, the study looked at the short-term effects of nickel
nanoparticle exposure in cells in a lab, rather than over the long term in a
Still, in her lab Kane employs significant safeguards to
keep researchers safe.
“We handle all these materials under biosafety level 2 containment
conditions,” she says. “I don’t want anyone exposed. We’re handling them as
though they were an airborne carcinogen.”