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.
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Cancer Research