CONTACT: JENNIFER BROWN
Iowa City IA 52242
(319) 335-9917; fax(319) 384-4638
Release: June 19, 2001
UI study investigates embryonic-like ability of aggressive melanoma cells
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. (Click
here to see illustration.)
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,
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
"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. "Its 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
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.
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 www.uihealthcare.com.