Melanoma: Causes and Prevention
Melanoma is a type of skin cancer that arises from melanocytes, the pigmented cell type of the skin found in the outer layer of the skin (the epidermis). Although melanoma makes up only a small percentage of skin cancers (about 1%), it is responsible for the majority of skin cancer-related deaths. According to the American Cancer Society, just over 7,000 people will die of melanoma in 2019 in the US.
One of the major causes of melanoma is exposure to ultraviolet light, which causes mutations in the DNA of melanocytes. Over time, an accumulation of cancer-causing mutations can lead to melanoma. Melanoma causes death in large part due to its ability to metastasize, or spread to other parts of the body. Once this occurs, secondary tumors may form in other organs like the brain, liver, or lung, and the disease becomes much more complicated to treat. Given the significant role of exposure to ultraviolet light as a cause of melanoma, prevention methods include using protective sunscreen and regular screenings.
Lifeline® Melanocytes in Melanoma Metastasis Research
Given the significant role of metastasis in melanoma-related death, understanding the metastatic process that drives the spread of melanoma cells may help inform treatment and prevention strategies. In a 2019 study in Cancer Letters, Chen and colleagues investigated the role of the melanoma cell adhesion molecule (MCAM) and the heterodimeric protein S100A8/A9 in melanoma cell metastasis to the lung. The researchers first examined MCAM expression in melanoma cell lines and found that its expression was higher in the WM-266-4 metastatic cell line than in the WM-115 non-metastatic cell line. When non-metastatic WM-115 cells were exposed to S100A8/A9 and MCAM was overexpressed, migration increased in an MCAM-specific manner. The authors then screened for transcription factors that might mediate MCAM-S100A8/A9 signaling to induce cell migration. They found that the candidate transcription factor ETV4 was activated in response to MCAM-S100A8/A9 and confirmed that ETV4 expression was also upregulated in melanoma samples from human patients.
Mutations in the BRAF MAP kinase (MAPK) oncogene occur in the majority of melanomas. The authors next wanted to determine whether other MAPKs were involved in S100A8/A9/MCAM-ETV4 signaling, and identified TLP2 as a candidate. Using a TLP2 kinase-dead mutant and an ERK1/2 inhibitor, the authors showed that TLP2 activates ETV4 through ERK1/2 to induce cell migration following S100A8/A9 stimulation. To determine whether this pathway contributes to melanoma metastasis in vivo, the authors performed tail vein injections with mouse melanoma B16 cells and evaluated metastasis to the lung. They found that cells overexpressing MCAM and ETV4 formed significantly larger lung nodules than B16 cells expressing MCAM and a dominant negative form of ETV4, suggesting that ETV4 is a key regulator of melanoma metastasis to the lung in response to S100A8/A9.
To further determine which genes are activated by ETV4 to enhance melanoma cell migration, the authors examined gene expression of matrix metalloproteases (MMPs), enzymes that degrade extracellular matrix proteins. Of the MMPs examined the group identified MMP25 as an ETV4 target. Additionally, they found that MMP25 protein expression was upregulated in melanoma patient tissue samples. Consistent with their previous results, the authors used migration and invasion assays to determine that MPP25 regulates melanoma cell migration and invasion. Finally, the authors demonstrated that compared with Lifeline® normal melanocytes, melanoma cell lines overexpressed MMP25.
Together, the researchers concluded that their results suggest S100A8/A9, released by keratinocytes, binds MCAM on the surface of melanocytes and induces TPL2 and ETV4, which induce migratory and invasion behavior through MMP25.
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Melanoma statistics from www.cancer.org.