Age-related changes in how fibroblasts behave appear to both contribute to angiogenesis and metastasis of skin cancer tumours, and to resistance to certain types of targeted therapy, suggesting that patient age needs to be taken into account when developing a program of melanoma therapy, researchers report in a paper published online ahead of print in Nature (Apr. 4, 2016).
The authors report that older fibroblasts secrete a protein known as sFRP2, an antagonist to the wnt signalling pathway. This triggers a cascade of processes in melanoma cells which leads to a decreases in β-catenin and microphthalmia-associated transcription factor (MITF). As a result, older cells have fewer scavengers of free oxygen radicals, leading to more activity of reactive oxygen species (ROS). The reduction of β-catenin also renders melanoma cells less capable of dealing with ROS, making tumours more genetically unstable, according to the paper. Lack of β-catenin and excess ROS also makes older patients more resistant to treatment with BRAF
inhibitor drugs, the authors note.
“It is 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 tumour is an island, and even therapies targeted against these driver mutations
are affected by the way the tumour cell communicates with its microenvironment,” said lead
author Ashani Weeraratna, PhD, in a press release. Dr. Weeraratna is an associate professor in
the Tumor Microenvironment and Metastasis Program at The Wistar Institute, a U.S. National
Cancer Institute cancer research center in Philadelphia.
The study findings also suggest that treatment with antioxidants may help overcome the observed rise in treatment resistance with age.
“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, in the release. “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.”