Advancing age is a risk factor for cancer, and there is no doubt that the accumulation of DNA damage over time contributes to the correlation of age with cancer risk: an increase in the number of oncogenic mutations in precancerous cells increases the odds of cellular transformation. In addition, age-related changes in the immune system can result in reduced adaptive immunity and a protumorigenic inflammatory microenvironment, which may fuel tumor progression and contribute to poor prognoses in older persons.
Approximately 50% of persons who receive a diagnosis of melanoma are older than 65 years of age, and although the activating mutations in oncogenes that confer susceptibility to melanoma (e.g., BRAF V600E) have been linked with old age,1 not much is known about the effects of an aging microenvironment. A study from the Weeraratna laboratory, reported by Kaur et al.,2 has shed some light on how fibroblasts in an aging microenvironment can contribute to melanoma growth and progression.
Normally, melanocytes occur at the basement membrane of the epidermal layer of the skin, and although they are usually not in direct contact with dermal fibroblasts, they are exposed to factors secreted by these cells. During aging, the architecture of the skin changes substantially (Figure 1FIGURE 1 Enhancement of Metastatic Potential of Melanoma Cells by Older Microenvironment.), and the DNA of fibroblasts, similar to that of melanocytes, accrues damage, the extent of which is correlated with an altered composition of secreted proteins. And, with age, fibroblasts have a higher tendency to enter senescence, a state of stable proliferative arrest induced by cellular stresses such as telomere erosion, DNA damage, or oncogenic signaling.
Kaur et al. addressed the role of the older microenvironment by injecting mouse melanoma cells that had the Braf V600E driver mutation into immunocompetent young or old mice. The tumors in the older mice grew much more slowly than those in young mice but with a more aggressive phenotype: the authors observed enhanced angiogenesis and a higher number of lung metastases in the older mice than in the young mice (Figure 1). Corroborating observations were made in three-dimensional models of human skin containing fibroblasts from either young persons (<35 years of age) or older persons (>55 years of age), in which the fibroblasts from older persons had a profound proinvasive effect on melanoma cells.
Detailed analysis of the fibroblasts from older persons revealed properties that not only contributed to the prometastatic activity but also interfered with the efficacy of BRAF V600E-targeted therapy. Older fibroblasts produced high amounts of secreted frizzled-related protein 2 (sFRP2), a secreted protein, which was detectable in the serum of the older mice and when administered to young mice, enhanced tumor angiogenesis and lung metastasis in the Braf V600E model. In addition, older fibroblasts secrete lower levels of scavengers of reactive oxygen species (ROS). Therefore, it seems that melanoma cells in the vicinity of older fibroblasts may have higher levels of oxidative stress than those in the vicinity of younger fibroblasts. Elevated levels of sFRP2 reduce the ability of melanoma cells to respond to oxidative stress. So together, the relative scarcity of scavengers of ROS and the relative abundance of sFRP2 represent a double whammy on the oxidative stress levels of melanoma cells. Indeed, fibroblasts from older mice induced a high level of oxidative stress in melanoma cells, which in turn led to DNA damage. Enhanced oxidative stress and DNA damage have been linked not only with a more aggressive tumor phenotype but also with resistance to BRAF-targeted drugs, such as vemurafenib. Kaur et al. found that allografts of melanoma with the Braf V600E mutation are less sensitive to vemurafenib in older mice than in younger mice.
The clinical relevance of this study is supported by data showing significantly higher serum levels of sFRP2 in patients with melanoma who are older than 55 years of age than in those who are younger than 40. Furthermore, melanoma samples from older patients showed lower expression of oxidative-stress regulators and higher expression of DNA-damage markers than samples from younger patients, a finding that should be evaluated for its correlation with disease stage (and hence progression). In the context of BRAF-targeted therapy, the authors tested whether age was associated with response to therapy in a small cohort of patients, with the idea that rate of response might be lower in older patients than in younger patients. A comparison of patients 65 years of age or younger with those older than 65 revealed a significant difference in the response to therapy.
In summary, Kaur et al. describe a novel molecular link, involving sFRP2, that connects the age of the patient with progression and therapy response in melanoma. Perhaps pharmacologic inhibition of sFRP2 would enhance tumor response to therapies, such as inhibitors of BRAF, in older patients. It is nevertheless uncertain whether sFRP2 is a candidate biomarker for response (or lack thereof) to BRAF inhibitors, because the cohort of patients was too small for investigators to observe a significant association between sFRP2 level and response to therapy. It is also unclear whether the cutoff ages in the different experiments were prespecified, and so tests of replication by other groups will be important. The authors proposed that antioxidants might be considered in the treatment of older patients with melanoma, but such an approach would require further investigation: in certain experimental contexts,4 antioxidants can promote experimental metastasis. That said, the exploration of age as an influence on clinical outcome in melanoma is stimulating and will no doubt play a role in future studies.
Article: Melanoma and the Microenvironment - Age Matters, Claudia Wellbrock, New England Journal of Medicine, doi: 10.1056/NEJMcibr1606907, published online 18 August.