In collaboration with the husband and wife team of Dr. Barnhill, professor of pathology and Dr. Lugassy, associate professor of pathology, the study was published March 6, 2014 in the journal Nature. Lugassy and Barnhill's team at UCLA collaborated with a team from the University of Bonn, Germany, led by Dr. Thomas Tuting.
It is well established that melanoma cells can spread through the blood to accumulate and form new tumors (metastases) in other parts of the body away from the original tumor. Thus, a small skin cancer becomes life-threatening by spreading to the brain, lungs, liver, or other organs.
Lugassy and Barnhill began studying the way cancer, especially melanoma, spreads (metastasizes) more than fifteen years ago, when they conceived and developed a process that they termed extravascular migratory metastasis (EVMM). They found that besides traveling in the bloodstream, melanoma cells could also move along the abluminal, or outside, surface of blood vessels by way of angiotropism, a biological interaction between the cancer cells and the blood vessel cells. Lugassy and Barnhill continue to assemble a body of scientific studies confirming the reality of this metastatic pathway of cancer cells.
With angiotropism and EVMM, the cancer cells may replace a type of cell called a pericyte, which normally resides on the outsides of blood vessels. While imitating the tendril-like pericytes, which Lugassy and Barnhill called pericytic mimicry, the melanoma cells creep along the length of blood vessels like spiders until they reach an organ or other point where they accumulate to form new tumors, "potentially explaining the delay between the detection of the primary cancer and the appearance of distant metastasis," Barnhill said.
"At first our idea was controversial," Lugassy said. "But mounting evidence confirming angiotropism and EVMM has revolutionized the knowledge of how cancer spreads through the body to the point that other scientists have confirmed the process in other solid tumor cell types such as pancreatic cancer."
In this new Nature study, EVMM was observed again by Tuting, Lugassy, Barnhill, and colleagues in a genetically engineered mouse model. The researchers also found that when the mice with melanoma were exposed to ultraviolet radiation (UV light) their immune systems responded with inflammation that accelerated the angiotropism, increasing the amount of EVMM, and leading to more lung metastases in the mice than those not exposed to UV light. This very exciting new study has been performed in the Laboratory for Experimental Dermatology in Bonn, Germany, under the direction of Dr. Tuting.
"We have known for a long time that UV radiation is a factor in the development of melanoma," Barnhill said, "but in this study the melanoma was already present in the mice." Tuting observed that UV light provoked inflammation at the site of the tumor, which caused the mouse immune system to attract neutrophils, a type of white blood cell, and the neutrophils promoted angiotropism.
With this knowledge and the confirmation of the works of Lugassy and Barnhill on angiotropism and EVMM, the researchers in the scientific community can now begin looking for a drug target that will interfere with this EVMM process, with the hope of creating a treatment that would stop EVMM. Because the danger of melanoma comes from its metastasis from the skin to the vital organs, being able to slow down or stop metastasis could turn a disease that was often a death sentence into a manageable chronic illness with relatively little risk of death.
This research was supported by The Melanoma Research Network, Jurgen Manchot Stiftung, the AIRC and the DFG.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.
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