Aggressive Tumor Cells Leave A Trail In Their Environment That AffectsThe Spread Of Cancer Posted Tuesday, September 4, 2001 by ctustis
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 inflammation.

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 body's 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 these networks.

"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.

University of Iowa Health Care describes the partnership between the UI
College of Medicine and the UI Hospitals and Clinics and the patient
care, medical education and research programs and services they provide.
Visit UI Health Care online at http://www.uihealthcare.com

Note: This story has been adapted from a news release issued by
University Of Iowa for journalists and other members of the public. If
you wish to quote from any part of this story, please credit University
Of Iowa as the original source. You may also wish to include the
following link in any citation:
http://www.sciencedaily.com/releases/2001/09/010903091625.htm