An unusual collaboration between a University of Iowa cardiologist and cancer biologists at the Holden Comprehensive Cancer Center at the UI, the Scripps Research Institute in California and Kanagawa Cancer Center Hospital and Research Center in Japan utilized a multidisciplinary approach to learn more about how aggressive cancer cells function and how they differ from poorly aggressive cancer cells. The study, which appears in the Sept. 1 issue of Cancer Research, may also suggest potential new therapeutic targets for cancer treatment.
Previous studies have found that aggressive tumor cells express genes that are more normally associated with other cell types, including endothelial cells that line blood vessels. Also, aggressive cancer cells are able to form vascular-like, fluid-conducting networks, an ability known as vasculogenic mimicry that resembles the behavior of embryonic cells that form primitive vascular networks.
Patients' tumors that have fluid-conducting networks are much more aggressive than tumors that do not have those networks.
The present study focuses on just a few of the genes that are expressed by aggressive cancer cells but not by poorly aggressive tumor cells. These genes normally are involved in regulating anticoagulant, or blood-clotting, activity in endothelial cells. The study suggests that the expression of these genes by aggressive tumor cells provides the cells with anticoagulant capabilities that are similar to those in blood vessel cells.
"Essentially our observations indicated that the aggressive melanoma tumor cells behaved in a similar manner as do endothelial cells that form blood vessels," said Mary Hendrix, Ph.D., the Kate Daum Research Professor of Anatomy and Cell Biology and head of the department.
The finding that tumor cells have anticoagulant properties similar to endothelial cells prompted the researchers to analyze whether there was blood flow within these tumors in extravascular spaces lined by tumor cells.
UI cardiologist, Robert Weiss, M.D., associate professor of internal medicine and a staff physician at the Iowa City Veterans Affairs Medical Center, used Doppler imaging to analyze blood flow within tumors. The researchers saw an exchange of blood from the normal vasculature (blood vessels) at the periphery of the tumor through tumor-cell-lined extravascular spaces within the aggressive tumor.
Although the precise role of the extravascular intra-tumoral network remains unclear, one possibility might be that the meshwork may provide a nutritional exchange for aggressive tumors that might prevent cell death within the tumor.
The observation that aggressive tumor cells over-express key anticoagulation pathway genes may help to explain how blood could flow through aggressive tumors prior to the growth of new blood vessels within the tumor compartment.
"This is yet another example of the plasticity of aggressive melanoma tumor cells in that they can mimic other cell types, such as endothelial cells, and our study provides a mechanistic example of how they do it," Hendrix said.
Hendrix added that this "chameleon-like" ability of aggressive tumor cells raises some clinically important issues.
"This plasticity represents a clinical challenge in trying to detect aggressive tumor cells," Hendrix said. "But it also provides new insights on how we might target them more effectively."
In addition to Hendrix and Weiss, the research team included Wolfram Ruf, M.D., associate professor of immunology at the Scripps Research Institute (TSRI), and lead author of the study, Ramona Petrovan, Ph.D., also at TSRI, Yohei Miyagi, M.D., at Kanagawa Cancer Center Hospital and Research Center, and UI researchers Elisabeth Seftor, Lynn Gruman, Naira Margaryan, D.V.M., Ph.D., and Richard Seftor, Ph.D.
The study was funded in part by grants from the National Institutes of Health.
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