The likelihood of developing an aggressive type of tumor that is more resistant to drugs increases directly with age. This is, at least in part, due to the accumulating damage and chronic inflammation of aging cells. Now an international collaboration led by The Wistar Institute has shown in skin cells that it is the aging microenvironment that may give rise to the oncogenic potential of these cells. And their insights highlight new treatment strategies for cancer.
The international effort headed up by The Wistar Institute published their work earlier this week in the scientific journal Nature.
"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," said Ashani Weeraratna, lead author of the study, in a news release. "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."
Melanoma is a type of skin cancer that is classically associated with resistance to drug treatment. In the study, the researchers use this as a model of cancer to study the microenvironment and the contribution of surrounding cells to the progression of skin cancer.
They obtained skin biopsies from healthy donors from the ages of 25-35 and 55-65 to represent the "young" and "old" groups, respectively. From these tiny portions of tissue they extract dermal fibroblasts--cells known to help the recovery of skin after injury.
From these fibroblast cells they found a protein called sFRP2 that is secreted by the older cells but not the young cells, sFRP2 is known to negatively regulate beta-catenin, which normally functions to block melanoma cells from growing. Reduced beta-catenin protein also helps to create oxidative stress through the generation of reactive oxygen species (ROS) in some cell types--thought to be a trigger for drug resistance in patients with melanoma.
"Our findings highlight how vital it is to treat that melanoma in an age-appropriate manner," said Amanpreet Kaur, who is a graduate student in the lab and first author of the study, in the release. "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."
In this study, the researchers suggest that higher ROS and lower beta-catenin, together, will increase the likelihood that older patients with melanoma will suffer from drug resistance. This fits nicely with their proposed mechanism of how antioxidant treatment may also render melanoma drugs more effective in older patients with the cancer.