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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 UI.

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 said.

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 model.

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 cancers.

"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.