Therapy for the elderly with melanoma may be affected by findings that aged tumor cells in melanoma behave differently than younger tumor cells. The microenvironment, particularly dermal fibroblast cells, were found to have age-related changes that could drive melanoma metastasis and its response to targeted therapy.1
“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 Ashani Weeraratna, PhD, associate professor in the Tumor Microenvironment and Metastasis Program at The Wistar Institute in Philadelphia, Pennsylvania, and lead author of the study.
Melanoma is the deadliest form of skin cancer, and patients with advanced disease have only a 20% chance for 5-year survival. Recent years have seen multiple targeted therapies for melanoma, but patients still eventually relapse and become resistant to these treatment options.
Age-related increases in cancer likely come from multiple factors; this study is the first to pinpoint changes in the microenvironment of tumor cells. The skin has cells known as dermal fibroblasts that help with recovery from injuries but can also contribute to the growth and invasion of melanoma cells.
This study compared dermal fibroblasts from healthy donors age 25 to 35 years with those from donors age 55 to 65 years. The aging cells had a secreted factor known as sFRP2, which regulates β-catenin, a protein that normally blocks the invasion of melanoma cells and reduces oxidative stress.
An aged microenvironment was shown to have fewer scavengers of free oxygen radicals, leading to more activity of reactive oxygen species (ROS). Meanwhile, age-related loss of β-catenin renders melanoma cells less capable of dealing with ROS, and thus the tumor becomes genetically unstable.
The scientists demonstrated that 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.
These findings highlight the significance of treating melanoma in an age-appropriate manner, reported Amanpreet Kaur, a graduate student in the Weeraratna laboratory, and first author of the study. “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.”
Wistar’s business development team is actively seeking meaningful collaborations with biotechnology and pharmaceutical partners to comprehensively interrogate the tumor microenvironment’s response to targeted therapies.
1. Kaur A, Webster MR, Marchbank K, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance [published online ahead of print April 4, 2016]. Nature. doi:10.1038/nature17392.