CONTACT: JENNIFER BROWN
Iowa City IA 52242
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Release: Sept. 4, 2001
Aggressive tumor cells leave trail that affects spread of cancer
IOWA CITY, Iowa -- The environment around and between cells is known as
the extracellular matrix and is full of molecules that play important roles
in how tissues look and behave. In a new study, University of Iowa researchers
and their collaborators have shown that highly aggressive melanoma cells interact
with this matrix differently than less aggressive melanoma cells. These differences
may have important implications for the diagnosis and treatment of melanoma,
as well as other types of aggressive cancers.
The researchers found that aggressive melanoma cells lay down a molecular
track as they interact with their extracellular matrix. These tracks appear
to contain information and cues which, like bread crumbs on a path, contain
information and directions that can be interpreted by less aggressive tumor
cells. These cues may persist in the matrix long after the aggressive tumor
cells have moved on and then cause less aggressive cells, which move into
this area, to become more aggressive.
The UI team, led by Mary J.C. Hendrix, Ph.D., the Kate Daum Research Professor
and head of anatomy and cell biology, and deputy director of the Holden Comprehensive
Cancer Center at the UI, collaborated with researchers at the Scripps Research
Institute in La Jolla, Calif., and researchers at the National Human Genome
Institute and the National Cancer Institute, both parts of the National Institutes
of Health, in Bethesda, Md. Their research findings are reported in the Sept.
1 issue of the journal Cancer Research. Images from the study are featured
on the cover of the journal.
"We wanted to know what these aggressive cancer cells were doing to
their extracellular matrix environment," said Richard E. B. Seftor, Ph.D.,
a research scientist in Hendrix's laboratory and lead author of the paper.
"We found that aggressive melanoma cells could alter their environment
and cause other less aggressive melanoma cells to act more aggressively."
Similar to the example of remodeling your house, cells remodel their extracellular
environment by both knocking down and building up the physical structure they
live in. One of the fundamental building blocks of the extracellular matrix
is produced by cells and is a family of proteins called laminins. Other proteins
produced by cells, called matrix metalloproteinases (MMPs), act to break down
and remodel the extracellular matrix. The interplay of building up and breaking
down the extracellular matrix by cells plays a major role in how wounds heal,
how cancer spreads through the body (metastasis) and how the body deals with
Certain members of the MMP family of proteins contribute to the aggressiveness
of cancer cells. MMPs are important in helping tumor cells leave a primary
tumor and move into and out of the bodys blood (and lymph) vessels.
After entering these vessels, tumor cells can travel to distant parts of the
body and begin growing in new tissues. The ability to spread through the body
and invade new tissues are two features that define a more aggressive and
dangerous cancer. Furthermore, aggressive tumor cells can mimic other cell
types, such as the cells that form vascular networks in the body (a process
called vasculogenic mimicry), while less aggressive tumor cells do not form
"Our investigation aimed to define the intricate interactions between
certain matrix metalloproteinases produced by the aggressive cancer cells,
and a specific extracellular matrix molecule called laminin 5, gamma 2 chain,"
Hendrix said. "We found that this particular laminin is produced almost
exclusively by aggressive, compared to poorly aggressive, melanoma cells.
Furthermore, two specific MMPs (MMP-2 and MMP-14) were also found to be at
higher levels in the aggressive cells."
The study showed that interactions between these two MMPs and this particular
laminin protein, made by the aggressive tumor cells, resulted in a breakdown
of the laminin into fragments that were deposited into discrete tracks in
the extracellular matrix. However, if the MMPs were prevented from breaking
down the laminin protein, then the aggressive tumor cells could not engage
in vasculogenic mimicry.
A key finding was that if the aggressive melanoma cells were grown on the
matrix for only a short period of time and then removed, less aggressive melanoma
cells put onto this matrix were induced to engage in vasculogenic mimicry.
It became apparent that the fragments of the laminin laid down in the matrix
by the aggressive tumor cells were directing the activity of the less aggressive
tumor cells that followed.
"These findings show the importance of specific interactions of particular
molecules in the matrix to support and perpetuate invasion and migration of
tumor cells long after the original aggressive tumor cells have passed through
the matrix," said Hendrix. "The implications of this study suggest
that the matrix of tumors might serve as an excellent target to inhibit tumor
cell signals, which control invasion and metastasis."
"In addition to finding ways to treat cancer cells themselves, we also
have to be concerned with how aggressive cancer cells alter their extracellular
matrix and the effects this might have on subsequent populations of less aggressive
cells, which come into this environment," Seftor added.
In addition to Hendrix and Seftor, the UI researchers on the team included
Elisabeth A. Seftor and Lynn M. G. Gardner. The Scripps Research Institute
researchers included Vito Quaranta, M.D., and his colleagues, Naohiko Koshikawa,
Ph.D. and Martin Bilban, Ph.D. Paul Meltzer, M.D., Ph.D., of the National
Human Genome Research Institute and William G. Stetler-Stevenson, M.D., Ph.D.,
of the National Cancer Institute were also part of the research team.
The research was funded by grants from the National Cancer Institute.
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