Metastatic melanoma is a highly aggressive disease; with a 5-year survival rate of 15- 20% for late metastatic patients. The survival rates are even lower among the middle aged and elderly patients. The role of the tumor microenvironment in modulating disease outcome is widely recognized and has been known to affect characteristics of the tumor. Due to this, we asked whether changes in tumor microenvironment due to aging could affect the progression of melanoma. We obtained skin fibroblasts from healthy donors aged 25-35, as well as skin fibroblasts from healthy donors aged 55-65. We treated melanoma cells with conditioned media from young or aged fibroblasts and observed increased invasion of melanoma cells in aged microenvironment. We analyzed the differences in secretome of young and aged fibroblasts and identified multiple pathways to be differentially regulated in aged microenvironment. First, we assessed changes in Wnt pathway protein, sFRP2 in the aged microenvironment. We observed that melanoma cells treated with sFRP2 show increased invasion and therapy resistance to PLX4720 both in vitro and in vivo. Further, upregulation of sFRP2 leads to loss of Ape1 that promotes DNA damage and genetic instability in melanomas. Next, we assessed changes in the extracellular matrix proteins LAMB2 and HAPLN1 in modulating ECM to promote invasion in the elderly. We observed that decrease in HAPLN1 as well as increase in LAMB2 during aging increases migratory potential of the melanoma cells in the microenvironment. From these results, we demonstrate that alternations in protein secretion by aging fibroblasts could alter tumor microenvironment thus resulting in increased DNA damage, metastasis and therapy resistance in the elderly. It is important that studies of cancer therapies take into account the age of the patient to achieve better response in patients.
|Commitee:||Chen, Bin, Herlyn, Meenhard, Murphy, Maureen, Pape-Zambito, Dana|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Biology, Cellular biology|
|Keywords:||Aging, DNA damage, Melanoma, SFRP2, Tumor microenvironment, Wnt signaling|
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