Melanomagenesis: overcoming the barrier of melanocyte senescence

Abstract

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.

Fig. 1

Growing and senescent melanocytes. Growing Arf-deficient (A) and senescent wild-type (B) melanocytes by bright field microscopy after staining for SA-β–gal. Blue indicates senescent cells. C, D. Heterochromatin protein 1-γ-positive senescence-associated heterochromatin foci. Tp53-deficient melanocytes were infected with pBabe retrovirus containing Arf cDNA (D) or an empty vector control (C). Cells were fixed 48 h after infection and incubated with anti-HP1γ antibody, followed by a secondary antibody conjugated with FITC, and then viewed with a fluorescent microscope. Shown are green nuclei with more intensely stained green foci, marking senescence. All images are at the same magnification. E. p16-deficient melanocytes at the same passage level as in A and B by bright field microscopy (no SA-β–gal staining). Portions of this figure are reproduced from Ref. , with permission.

Fig. 2

p53-independent action of Arf on melanocyte senescence. Shown are Ink4a/Rb and Arf/p53 pathways implicated in senescence, mostly derived from work with fibroblasts. In mouse melanocytes Arf can promote the p53-independent degradation of E2F1. This, and perhaps other mechanisms (indicated by question mark), could trigger senescence.