Aging Influences Melanoma Response to Therapies, but Antioxidants Could Provide Answer

May 2, 2016
Sharon Marston

Aging and melanoma

April 2016: The risk of developing cancer increases with age as accumulated damage to the cells and chronic inflammation arise over time. In a new study published in Nature, an international team of researchers led by The Wistar Institute demonstrated that aged melanoma cells behave in a different manner than younger cells, and that antioxidants could be a potential treatment strategy for older melanoma patients. The study is titled “sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.”

Alterations in the tumor microenvironment make older melanoma cells more metastatic and more resistant to targeted therapies.

“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,” lead author Ashani Weeraratna, Ph.D., associate professor in the Tumor Microenvironment and Metastasis Program at Wistar, said in a news release.

Melanoma, also known as malignant melanoma, is a type of cancer that develops from the pigment-containing cells known as melanocytes, and is the most lethal form of skin cancer. After five years of diagnosis, patients with advanced melanoma have only a 20 percent chance of survival. In the last years, many targeted therapies have been approved for melanoma patients, many of whom eventually relapse and become resistant to such therapies.

The effects of the aged microenvironment in tumor progression have been largely unexplored, and now Weeraratna Lab researchers have found that age-related alterations occur in the tumor cells’ microenvironment. Dermal fibroblasts, a type of skin cells, help the skin recover from injuries and can contribute to the development and invasion of melanoma cells. Researchers used dermal fibroblasts from healthy individuals ages 25 to 35 or from individuals ages 55 to 65 to examine whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy.

They found that secreted frizzled-related protein 2a (sFRP2), a secreted factor, was present in aging cells. sFRP2  is a protein that in humans is encoded by the SFRP2 gene, a regulator of the β-catenin protein that usually blocks the invasion of melanoma cells. Evidence has also shown that loss of β-catenin promotes oxidative stress in some cells.

In an aged microenvironment, there are fewer scavengers of free radicals, leading to an increased activity of reactive oxygen species (ROS). Moreover, age-induced loss of beta-catenin reduces the number of melanoma cells capable to deal with ROS, leading to a genetically volatile tumor.

The researchers found that resistance to targeted therapies in older melanoma patients increased the activity of ROS and decreased the levels of β-catenin. This led to an increase in the resistance to drugs that inhibit the BRAF gene, which is mutated in about 50 percent of all melanomas.

The team also demonstrates how antioxidants might be a potential treatment strategy for older patients with melanoma, since an antioxidant known as N-acetylcysteine (NAC) eradicated 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 lab and first author of the study. “With other studies confirming the effectiveness of anti-oxidants in treating BRAF-mutated cancers, we have more evidence of how an older population may benefit from new therapeutic strategies.”

The corporate team at Wistar is seeking collaborations with pharmaceutical and biotechnology companies to cross-examine the response of the tumor microenvironment to targeted therapies.