Hypoxia-induced senescence contributes to the regulation of microenvironment in melanomas.

Abstract Senescence, an irreversible state of cell cycle arrest, maintains metabolic activity. Although being a barrier against tumor development, senescence could also promote tumor progression by influencing the microenvironment. Necrosis is a common feature of various malignant tumors, which also has two opposing effects: pro-tumor by chronic inflammation and anti-tumor by effective cell clearance. However, the role of senescence in melanoma and whether it is associated with necrosis remain unclear. By detecting senescence-associated β-galactosidase activity and pimonidazole (hypoxia probe), we found that senescent cells (SA-β-gal positive) are mainly located around the necrotic/hypoxic areas of melanoma from C57BL/6J mice. Moreover, treatment of hypoxia induced irreversibly cellular senescence in vitro . In addition, the senescent cells may facilitate microenvironment modulation and promote the invasion of melanoma cells by secreting matrix metalloproteinase-2(MMP-2). Moreover, Kaplan–Meier analysis showed that the presence of necrosis in melanomas had an inverse correlation with patient survival and may serve as an independent prognostic marker. Therefore, hypoxic stress imposed on melanomas may lead to cellular senescence surrounding necrotic areas, and the adverse effects of necrosis in tumor may be attributed to the adjacent senescent cells with senescence-associated secretion phenotype (SASP), including secretion of MMP-2.