June 27, 2001 IOWA CITY, Iowa – University of Iowa researchers and their colleagues have discovered that a protein usually found in endothelial cells (the cells that form blood vessels) is also made by aggressive melanoma cells.
The team's research shows that the protein, Vascular Endothelial Cadherin (VE-Cadherin), plays a key role in the ability of these cancer cells to form primitive vascular networks. The results of the study appear in the June 19 issue of the journal Proceedings of the National Academy of Sciences.
During embryonic development, primitive blood vessels are initially formed by embryonic cells that develop into endothelial cells and establish vascular networks – a process called vasculogenesis. The subsequent growth and remodeling of these networks occurs through angiogenesis, which involves the sprouting of new blood vessels from the existing vascular network.
UI researchers and their collaborators recently discovered that aggressive melanoma cells have the ability to form primitive tubular networks from scratch. The researchers called the process, which resembles embryonic vasculogenesis, vasculogenic mimicry.
The UI researchers and their colleagues have also shown that in addition to their own specific cellular markers, aggressive tumor cells display the molecular and genetic hallmarks of other cell types such as expressing VE-Cadherin, which is normally associated with endothelial cells.
"We are discovering that these tumor cells are really quite flexible in that they can look like or mimic other cell types," said Mary J. C. Hendrix, Ph.D., Kate Daum Research Professor of Anatomy and Cell Biology at the UI and head of the department. "Our studies suggest that highly aggressive melanoma tumors, which can form these primitive networks, have reverted to a more embryonic-like state and have regained a stem cell-like ability to form different types of cells with related functions.
"Thinking about tumors as embryos, or embryonic masses, is a novel way of hypothesizing about how tumor cells behave," added Hendrix, who also is deputy director and associate director of basic research at the UI Holden Comprehensive Cancer Center.
In the latest study, melanoma samples were taken from patients and analyzed. VE-Cadherin was clearly present in the aggressive melanoma cells and completely absent in those that were poorly aggressive. The aggressive melanoma tumors cells were able to form primitive tubular networks, while the poorly aggressive melanoma cells were not able to form the primitive networks. This pattern held true when other aggressive and poorly aggressive melanoma cell samples were analyzed.
"This is such a remarkable on/off expression pattern," Hendrix said. "We’d like to suggest that the presence of VE-Cadherin might represent a vasculogenic switch, which may play an important role in the acquisition of a blood supply needed by a growing tumor."
This interpretation has implications for the treatment of melanoma. If the tumor cells do not make VE-Cadherin, the findings suggest that those melanomas will likely be poorly aggressive. If the cells do make VE-Cadherin, then they will likely be quite aggressive and will require aggressive treatment.
Using a technology called anti-sense DNA to turn off or inhibit the production of the VE-Cadherin protein, the research team went on to prove that the presence of VE-Cadherin protein was essential to the formation of the vasculogenic networks. Without the protein, the cells were no longer able to form primitive vascular network structures.
"This is really direct evidence that the VE-Cadherin molecule is a critical player in the process of vasculogenic mimicry," Hendrix said.
Other recent work from Hendrix's lab with Anil K. Sood, M.D., UI assistant professor of obstetrics and gynecology, has shown that vasculogenic mimicry also occurs in ovarian cancer cells.
"If you think about the clinical significance of our findings, it is both exciting and challenging," Hendrix said. "It’s a challenge because if these highly aggressive melanoma cells and potentially other tumor cells look like normal endothelial cells how do you diagnose them?"
Hendrix added that work in her lab would now focus on developing new detection technologies for identifying and diagnosing these cells accurately. "It is exciting because this research will allow us to investigate the significance of other kinds of cellular markers, in addition to VE-Cadherin, that these tumor cells can make," Hendrix said. "I think it will really open the field to the possibility that tumor cells can mimic other cell types."
In addition to Hendrix, the UI research team included Elisabeth A. Seftor, Lynn M. G. Gardner, Angela R. Hess, Dawn A. Kirschmann, Ph.D., Gina C. Schatteman, Ph.D., and Richard E. B. Seftor, Ph.D. Also part of the team was Paul Meltzer, M.D., Ph.D., of the Cancer Genetics Branch of the National Human Genome Research Institute in Bethesda, Md.
The research was funded by grants from the National Institutes of Health.
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