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sFRP2 in Aged Melanoma Tumor Cells Drives Metastasis and Therapy Resistance

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Key Points

  • A secreted factor, sFRP2, was present in aging cells. sFRP2 regulates another protein called β-catenin that normally blocks the invasion of melanoma cells.
  • In an aged microenvironment, there are fewer scavengers of free oxygen radicals, leading to more activity of reactive oxygen species (ROS). At the same time, the age-induced loss of beta-catenin renders melanoma cells less capable of dealing with ROS, resulting in a genetically unstable tumor.
  • Scientists also showed how antioxidants might be a more effective strategy for treating older melanoma patients. An antioxidant called N-acetylcysteine (NAC) killed melanoma cells in aged dermal fibroblasts.

Cancer risk increases with one's age as accumulated damage to our cells and chronic inflammation occur over time. Now, an international team of scientists led by The Wistar Institute has shown that aged tumor cells in melanoma behave differently from younger tumor cells, according to study results published by Kaur et al in Nature.

Changes in the microenvironment make these older tumor cells more metastatic and more resistant to treatment with targeted therapies. In light of these findings, the scientists demonstrated how antioxidants could serve as a better treatment strategy for older patients with melanoma.

“It's fascinating to see that the microenvironment can have such a profound effect on both metastasis and response to a therapy that is specifically targeted to a mutation in a gene. This tells us that no tumor is an island, and even therapies targeted against these driver mutations are affected by the way the tumor cell communicates with its microenvironment,” said lead author Ashani Weeraratna, PhD, Associate Professor in the Tumor Microenvironment and Metastasis Program at Wistar.

While multiple factors may contribute the age-related increases in cancer, for the first time, the Weeraratna Laboratory has pinpointed age-related changes that occur in the microenvironment of tumor cells. Dermal fibroblasts help the skin recover from injuries and can contribute to the growth and invasion of melanoma cells. The researchers used dermal fibroblasts from healthy donors aged 25 to 35 years or from donors aged 55 to 65 years to understand what factors contribute to the difference in melanoma progression in aging cell populations.

Study Findings

Dr. Weeraratna and colleagues determined that a secreted factor, sFRP2, was present in aging cells. sFRP2 regulates another protein called beta-catenin that normally blocks the invasion of melanoma cells. In addition, beta-catenin loss has been shown to promote oxidative stress in some cell types.

The researchers showed that in an aged microenvironment, there are fewer scavengers of free oxygen radicals, leading to more activity of reactive oxygen species (ROS). At the same time, the age-induced loss of beta-catenin renders melanoma cells less capable of dealing with ROS, resulting in a genetically unstable tumor.

Treatment resistance experienced by older melanoma patients with increased activity of ROS and decreased levels of beta-catenin all contribute to increased resistance to treatment with drugs that inhibit the BRAF gene, which is mutated in approximately half of all cases of melanoma. Wistar scientists also showed how antioxidants might be a more effective strategy for treating older melanoma patients. An antioxidant called N-acetylcysteine (NAC) killed melanoma cells in aged dermal fibroblasts.

“Our findings highlight how vital it is to treat that melanoma in an age-appropriate manner,” said Amanpreet Kaur, a graduate student in the Weeraratna Laboratory. “With other studies confirming the effectiveness of antioxidants in treating BRAF-mutated cancers, we have more evidence of how an older population may benefit from new therapeutic strategies.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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