Melanomagenesis: overcoming the barrier of melanocyte senescence.
Although melanoma ultimately progresses to a highly aggressive and metastatic disease that is typically resistant to currently available therapy, it often begins as a benign nevus consisting of a clonal population of hyperplastic melanocytes that cannot progress because they are locked in a state of cellular senescence. Once senescence is overcome, the nevus can exhibit dysplastic features and readily progress to more lethal stages. Recent advances have convincingly demonstrated that senescence represents a true barrier to the progression of many types of cancer, including melanoma. Thus, understanding the mechanism(s) by which melanoma evades senescence has become a priority in the melanoma research community. Senescence in most cells is regulated through some combination of activities within the RB and p53 pathways. However, differences discovered among various tumor types, some subtle and others quite profound, have revealed that senescence frequently operates in a context-dependent manner. Here we review what is known about melanocyte senescence, and how such knowledge may provide a much-needed edge in our struggles to contain or perhaps vanquish this often-fatal malignancy.
Ha
Linan
L
Division of Monoclonal Antibody, Center of Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
Merlino
Glenn
G
Sviderskaya
Elena V
EV
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D016922:Cellular Senescence; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D019098:Telomerase; D020727:ADP-Ribosylation Factors