Discovery of signaling mechanism may help prevent metastatic melanoma

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Researchers at Northwestern University have discovered a key signaling mechanism that may promote the ability of highly aggressive malignant melanoma cells to metastasize, or spread from a primary tumor to distant sites within the body.

Results of their study, published in the November issue of Cancer Research, suggest that the signaling mechanism may be a potential target for prevention of metastatic melanoma.

The study was led by Angela R. Hess, a research scientist at the Children's Memorial Research Center, and was conducted in the laboratory of Mary Hendrix, president and scientific director of the Children's Memorial Research Center and professor of pediatrics at Northwestern University Feinberg School of Medicine.

Metastatic cancer cells are characterized by increased tumor cell invasion and migration, as well as tumor cell plasticity, manifested as vasculogenic mimicry – the ability of aggressive melanoma cells to masquerade as endothelial-like cells by forming their own vascular networks. Hess and co-investigators found that an enzyme known as focal adhesion kinase (FAK), which is important for many cellular processes, including cell survival, invasion and migration, is activated in malignant uveal (eye) and skin melanoma.

They hypothesized that FAK could play a major role in promoting aggressive melanoma because its increased production has been linked to tumor cell aggressiveness in other cancers, including prostate, thyroid, colorectal, ovarian and oral tumors.

Hess and colleagues found that elevated activity of FAK in aggressive melanoma cells correlated with the cells' increased invasion, migration and vasculogenic mimicry behaviors.

As proof of principle, the researchers then blocked FAK signaling in aggressive melanoma cells, which resulted in a decrease in melanoma cell invasion, migration and vasculogenic mimicry.

"Collectively, our data suggest a new mechanism involved in promoting aggressive melanoma though FAK-mediated signal transduction pathways, thus providing new insights into possible therapeutic intervention strategies," Hess said. "Understanding the molecular mechanisms that promote aggressive melanoma is essential to predicting the likelihood of metastasis at a stage when intervention is possible," Hess said.

The Hendrix laboratory has identified several signal transduction components that seem to play significant roles in mediating the aggressive properties of melanoma cells.

"Although we are beginning to understand the involvement of some of the signaling pathways that regulate cell invasion, migration and vasculogenic mimicry, the complexity of the coordinated molecular interactions underlying these processes remains to be elucidated," Hendrix said.

Malignant melanoma is curable when detected early. However, left untreated and allowed to metastasize, malignant melanoma often is fatal. In the United States, the incidence of melanoma has tripled in the past 50 years and has almost doubled in the last decade. It is estimated that approximately 48,000 new cases of melanoma will be diagnosed this year, with an expected 7,700 deaths, according to data from the American Cancer Society.

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