Study uncovers new pathway of melanoma metastasis

A new study suggests that in addition to potentially causing tumor-inducing DNA mutations, repetitive exposure to ultraviolet (UV) radiation can cause skin melanoma to metastasize.

The multicenter study, headed by a German research group from the University of Bonn, found that in a genetically engineered mouse model, repetitive exposure to UV radiation helped to cause metastatic progression independent of its tumor-initiating effects. The study noted that UV irradiation promoted expansion of tumor cells along the surfaces of abluminal blood vessels and increased lung metastases.

According to the study, the effect depended on the recruitment and activation of neutrophils from damaged epidermal keratinocytes. Neutrophilic inflammatory response, caused by UV damage, encouraged angiogenesis and enhanced melanoma cells’ ability to migrate toward endothelial cells and use select motility cues on their surfaces.

The study demonstrated how the innate immune system senses UV irradiation of epidermal keratinocytes, and how the resulting perivascular invasion - known as angiotropism - increases the chances of the melanoma spreading via intravasation or hematogenous dissemination. Angiotropism and a high risk of metastases are frequently found in ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis.

According to co-author Raymond L. Barnhill, M.D., of the University of California, Los Angeles Medical Center’s department of pathology and laboratory medicine, the study is based on the melanoma metastasis research field of angiotropism, pericytic mimicry and extravascular migratory metastasis (EVMM) in melanoma conducted by him and his UCLA colleague, co-author Claire Lugassy, M.D., some 15 years ago.

“During EVMM, tumor cells migrate in a crawling manner along the external surfaces of vascular channels, in a pericytic location, without intravasation, demonstrating angiotropism and pericytic mimicry,” Dr. Barnhill tells DermatologyTimes. “It is a revolutionary new paradigm about the mechanisms of melanoma metastasis, in addition to the extensively studied intravascular dissemination of tumor cells. Several (of our) former studies demonstrated that angiotropism is a prognostic factor in melanoma, and a marker of migration along the abluminal vascular surface. The new data are confirming (our earlier) works ... on angiotropic melanoma, pericytic mimicry and EVMM.

“This new study supports (our) research concerning an additional pathway of melanoma metastasis,” Dr. Barnhill adds. “The pathway is characterized by melanoma cell migration along the external surfaces of vascular channels distantly from the primary tumor site rather than the conventional routes of entry of melanoma cells into lymphatic or blood vascular channels.”

Dr. Lugassy notes that the study could pave the way to new oncology treatments.

“The significance of knowing about this new pathway of metastasis is that it provides additional information about how melanoma metastasizes and may lead to new forms of cancer therapy targeting such tumor-cell migration and the suppression or disruption of this type of metastatic spread, in addition to more conventional cancer therapies,” Dr. Lugassy tells Dermatology Times.

She says the next step in the team’s research will be to “identify new targets against this specific association between angiotropic melanoma cells and endothelial cells, representing a rational strategy to specifically interfere with EVMM and metastatic progression.

“We also hope that the exposure of this new area of melanoma research … will lead to a larger diffusion of knowledge about this subject in the scientific community,” Dr. Lugassy says, “and consequently will increase research devoted to potentially targeting this mechanism of metastasis.”

The study was published online Feb. 26 in Nature.