CONTACT: JENNIFER BROWN
Iowa City IA 52242
(319) 335-9917; fax(319) 384-4638
Release: Feb. 1, 2002
UI study: aggressive melanoma cells form blood vessels in tissue that
requires blood supply
Cancer researchers at the University of Iowa and Loyola University in Chicago
have demonstrated that aggressive human melanoma cells form new blood vessels
when placed in living tissue that is in need of a blood supply. The researchers
also found that these aggressive melanoma cells make the same molecules that
direct the formation of new blood vessels in embryos. The results may have
implications for the diagnosis of aggressive tumor cells and for new therapeutic
strategies to treat cancers.
The team used a novel experimental strategy to challenge aggressive melanoma
cells to make cell-fate decisions based on cues from their local environment.
Aggressive melanoma cells were injected into the limb of a mouse, where damaged
blood vessels had resulted in a lack of blood-flow to the limb (called ischemia).
After five days, the tumor cells were clearly included in the new blood vessels
that were forming in response to the limb's need for blood. A three-dimensional
image of the new vessels can be seen at http://www.anatomy.uiowa.edu/pages/directory/faculty/images/vert_plane.avi
. After five days, there was normal vascular flow to the muscle. The results
of the UI-based study appear in the Feb. 1 issue of Cancer Research and also
are featured on the journal's cover.
"We challenged the metastatic melanoma cells to a microenvironment
that required blood vessels," said Mary J.C. Hendrix, Ph.D., the Kate
Daum Research Professor of Anatomy and Cell Biology at the UI and head of
the department. "And, the melanoma cells rose to the occasion by responding
to the appropriate biological signals and participating in the formation of
new blood vessels. This study demonstrates that aggressive melanoma tumor
cells are very plastic; they are remarkably flexible in their ability to respond
to environmental cues."
After 20 days, tumor cells were no longer found in the blood vessel system
(also called the vasculature). Instead, the researchers found tumor cells
outside of the vasculature, and they formed a melanoma tumor.
"Our hypothesis is that after normal blood flow was restored, the environmental
cues shut down and the tumor cells commence forming tumors," said Hendrix,
who also is deputy director of the Holden Comprehensive Cancer Center at the
Previous studies conducted by Hendrix and her colleagues had revealed the
plasticity of aggressive melanoma cells. The UI team found that aggressive
tumor cells, in addition to their own specific cellular markers also display
the molecular and genetic hallmarks of other cell types. In particular, they
express VE-cadherin, a gene that is normally associated with blood vessel
cells (called endothelial cells).
These aggressive tumor cells not only look like endothelial cells, but also
behave like blood vessel cells and can form primitive vascular networks in
experimental cell models. The term "vasculogenic mimicry" has been
used to describe this behavior because it resembles the behavior of embryonic
cells forming the networks that become vasculature.
"Our results support the exciting new concept that highly aggressive
tumor cells have a plasticity which is similar to a stem cell," Hendrix
As expected, based on their varied gene expression pattern, non-aggressive
cells were not capable of forming new vessels in the mice.
The current findings in ischemic mice highlight the powerful influence that
local cellular environment has on the fate of flexible cells.
"We also learned that the melanoma tumor cells turned on the expression
of Notch proteins," Hendrix said.
Notch proteins are known to play a role in the formation of blood vessel
systems. This family of proteins prompts endothelial cells to become vascular
networks and these molecules are integrally involved in the cell-fate decisions
of stem cells.
"The aggressive tumor cells express Notch molecules that also are expressed
by early vascular-like stem cells, and the tumor cells appear to utilize the
same cellular decision-making program as vascular stem cells," said Hendrix.
These results reinforce the idea that aggressive melanoma cells may resemble
embryonic cells in some aspects.
Hendrix noted that collaborating with the Loyola researchers, who have been
addressing the role of Notch molecules in cancer progression, gave the team
the opportunity to investigate the importance of Notch proteins in this melanoma
Commenting on the significance of the team's findings, Hendrix explained
that a greater understanding of the workings of aggressive melanoma cells
could improve the ability to recognize and diagnose these tumor cells that
might be disguised as other cell types.
Hendrix also indicated that the results could potentially lead to novel
therapeutic strategies. In particular, understanding how environmental cues
stimulate tumor cells to participate in blood vessel formation might suggest
ways to inhibit the process. Hendrix also suggested that altering the expression
of molecules shown to be important for plasticity in aggressive melanoma cells
might alter the fate of the cells and, hence, the clinical consequences of
"These findings have important implications for how we study tumor
cells and provide new insights into the flexibility of an aggressive tumor
cell phenotype," Hendrix said.
In addition to Hendrix, the UI researchers involved in the study were Richard
E. B. Seftor, Ph.D.; Elisabeth A. Seftor; Lynn M. Gruman; Lisa M. L. Lee;
Gina C. Schatteman, Ph.D.; and Don D. Sheriff, Ph.D. Two researchers at Loyola
University were also part of the research team: Brian J. Nickoloff, M.D.,
Ph.D., professor of pathology, and Lucio Miele, M.D., Ph.D., assistant professor
of pathology, biochemistry and molecular biology.
The study was funded in part by grants from the National Cancer Institute,
the National Institute of Diabetes and Digestive and Kidney Diseases and the
National Heart, Lung, and Blood Institute.
The Holden Comprehensive Cancer Center is Iowa's only National Cancer Institute
(NCI)-designated comprehensive cancer center. NCI-designated comprehensive
cancer centers are recognized as the leaders in developing new approaches
to cancer prevention and cancer care, conducting leading edge research and
educating the public about cancer. Visit the center online at http://www.uihealthcare.com/depts/cancercenter.
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.