UV Light Accelerates Melanoma Metastasis

Scientists have confirmed that melanoma cells can spread along the outside of blood vessels, and, for the first time, have found this alternative metastatic process speeds up when the cells are exposed to UV light.

The findings, published recently in Nature, confirm a discovery made 15 years ago by two scientists in the pathology department of the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Claire Lugassy, MD, and Raymond Barnhill, MD: Melanoma cells can crawl along the outer surface of blood vessels (Nature 2014;507:109–13).

The feat is accomplished through angiotropism, by which melanoma cells mimic pericytes located outside blood vessels. These creeping melanoma cells are thus able to spread to nearby or distant sites without ever entering the bloodstream or lymphatic system. Lugassy and Barnhill named the metastatic process extravascular migratory metastasis, or EVMM.

Lugassy and Barnhill collaborated with German researchers at the University of Bonn on the new study, led by Thomas Tüting, MD. In a genetically engineered mouse model of melanoma, they found that repetitive exposure to UV light caused inflammation at the primary tumor site. Inflammation triggered the mouse immune response to recruit and activate neutrophils, which in turn stimulated new blood vessel formation and the migration of melanoma cells toward endothelial cells. The result was accelerated angiotropism, increased EVMM, and more lung metastases in UV-irradiated mice than in mice not exposed to UV light.

It is well established that UV sun exposure plays a key role in causing melanoma through DNA mutations in melanocytes. However, these new findings indicate that UV light inflicts damage independent of its tumor-inducing effect, Barnhill says.

“Here we have ultraviolet light inducing inflammation, and the inflammation is inducing a mechanism of cancer spread. These very important aspects of cancer development and cancer spread are now linked,” says Barnhill.

Although scientists don't know how frequently EVMM occurs in melanoma, Barnhill says its incidence is likely “significant and may mark a certain point in the evolution of melanomas.”

The new findings could lead to the development of novel drugs to disrupt the EVMM process, says Lugassy.

“This work led by Tüting has shown for the first time that in addition to the specific association between angiotropic tumor cells and vessels, the inflammatory response due to ultraviolet light could also be a drug target,” she says. “Targeting UV-activated neutrophils represents a potential therapeutic opportunity to interfere with metastatic melanoma, and potentially with other cancer types.” Other studies have found angiotropism and EVMM also occur in glioblastoma and pancreatic cancer.

Of the 76,100 Americans expected to be diagnosed with melanoma in 2014, nearly 10,000 will die—most of them from metastatic disease. “We need more research teams working on this new field of angiotropism and EVMM,” Lugassy says. “There's still a lot of work left to find the right target to hopefully control melanoma metastasis.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.