Aged tumor cells in melanoma tend to be metastatic and more resistant to treatment compared with younger tumor cells, according to an international team led by researchers out of The Wistar Institute in Philadelphia.

The findings, which appear in the journal Nature, suggest that antioxidants may serve as a better treatment strategy for older patients with melanoma.

While multiple factors may contribute the age-related increases in cancer, Ashani Weeraratna, Ph.D., associate professor in the Tumor Microenvironment and Metastasis Program at Wistar (see image), and colleagues, pinpointed age-related changes that occur in the microenvironment of tumor cells. The researchers used dermal fibroblasts from healthy donors 25-35 years of age or from donors 55-65 years of age to understand what factors contribute to the difference in melanoma progression in aging cell populations.

A secreted factor sFRP2 was present in aging cells, the study found. SFRP2 regulates another protein called β-catenin that normally blocks the invasion of melanoma cells. In addition, b-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 was found with increased activity of ROS and decreased levels of β-catenin, both contribute to increased resistance to treatment with drugs that inhibit BRAF, which is mutated in approximately half of all cases of melanoma.

An antioxidant called N-acetylcysteine (NAC) killed melanoma cells in aged dermal fibroblasts, they report.

Wistar's business development team is actively seeking collaborations with biotechnology and pharmaceutical partners to comprehensively interrogate the tumor microenvironment's response to targeted therapies.