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The Cutting Edge

UV Light Aids Creeping Cancer Cells

A new study by UCLA scientists and colleagues in Germany adds further proof to earlier findings that deadly melanoma cells can spread through the body by creeping like tiny spiders along the outside of blood vessels without ever entering the bloodstream. The research also demonstrates that this process is accelerated when the skin-cancer cells are exposed to ultraviolet light.

UV Light

The histopathological images show angiotropism of tumor cells (A) some distance from the primary melanoma in a melanoma patient. At higher magnification (B), one can observe dark-purple melanoma cells cuffing the external surface of the vessel (V). The diagrams describe how angiotropic melanoma cells spread from the main primary-tumor mass and migrate progressively along the external surfaces of vessels without entering the bloodstream, defining pericytic mimicry (C) and EVMM (D). During EVMM, once a solid tumor becomes invasive, cells at the advancing front of the tumor acquire migratory properties, migrate away from the primary tumor and embark upon an extensive continuous migration to reach their metastatic secondary sites.
Illustration: Courtesy of Drs. Claire Lugassy and Raymond Barnhill

It is well-known that melanoma cells from an initial tumor can travel through the bloodstream to other parts of the body to form new tumors. Through such metastasis, a small skin cancer can become lifethreatening by spreading to the brain, lungs, liver or other organs. Fifteen years ago, Claire Lugassy, MD, and Raymond Barnhill, MD, both professors of pathology at UCLA’s Jonsson Comprehensive Cancer Center, discovered and described an alternative metastatic process, which they called extravascular migratory metastasis (EVMM), by which melanoma cells move along the outside surface of blood vessels by way of angiotropism — a biological interaction between the cancer cells and the blood vessel cells. Since then, Drs. Lugassy and Barnhill have continued this line of research to confirm the existence of this metastatic pathway of cancer cells.

With angiotropism and EVMM, the cancer cells may replace tendril-like cells called pericytes, which are normally found on the outsides of blood vessels. Imitating the pericytes, the melanoma cells creep along the length of blood vessels until they reach an organ or other point where they accumulate to form new tumors, the researchers say. “At first our idea was controversial,” Dr. Lugassy says. “But mounting evidence confirming angiotropism and EVMM has revolutionized the knowledge of how cancer spreads through the body; other scientists have confirmed the process in other solid-tumor cell types, such as pancreatic cancer.”

The scientists observed the process in a genetically engineered mouse model of melanoma. The researchers also found that the immune systems of mice exposed to ultraviolet radiation responded with inflammation that accelerated the angiotropism, increasing the level of EVMM and leading to more lung metastases than among the mice not exposed to UV light.

“We have known for a long time that UV radiation is a factor in the development of melanoma,” Dr. Barnhill says. “But in this study, the melanoma was already present in the mice.”

Their colleague, Thomas Tüting, of the Laboratory of Experimental Dermatology at the University of Bonn (Germany), observed that UV light provoked inflammation at the site of the tumor, which caused the mouse immune system to attract a type of common white blood cells known as neutrophils, which, in turn, promoted angiotropism. With this new knowledge — and the confirmation of Drs. Lugassy and Barnhill’s research on angiotropism and EVMM — researchers in the scientific community can now begin looking for a drug target that will interfere with this EVMM process.

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma,” Nature, March 6, 2014

 





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