When the Secretome Is Out

Cellular senescence can be an ally against cancer by preventing cells with worn-down telomeres or damaged DNA from dividing. But researchers have also shown that senescent cells can help tumors.

New research (Ohanna et al. Genes Dev 2011;25:1245–61) reveals another possible drawback of senescence: it might induce metastasis by melanoma cells.

But the study also suggests that blocking secretion by senescent cells could make chemotherapy for melanoma more potent.

Cellular senescence might have evolved as a way to prevent tumors by switching off cancer-prone cells. Some agents, such as temozolomide (Temodar; Merck), a treatment for glioblastoma and other cancers, work in part by exploiting this process.

However, problems can arise because senescent cells don't shut down metabolically. Instead, they begin leaking a cocktail of growth factors, cytokines, and enzymes—the secretome—that might promote cancer. For example, injecting senescent cells and premalignant cells into mice, one study found, speeds the transformation of the premalignant cells into cancerous ones. And other work has revealed that injecting senescent cells and cancer cells into mice hastens the formation of tumors.

Ohanna and colleagues tackled the questions of whether senescent melanoma cells secrete and what effects they have on neighboring cells.

The researchers found that 2 drugs used for treating late-stage melanoma, temozolomide and fotemustine, triggered melanoma cells to senesce and morph into secretory powerhouses. The cells' most important product, the chemokine CCL2, caused other melanoma cells to migrate in vitro. The same effect occurred in vivo. When the researchers implanted mice with noninvasive melanoma cells soaked in medium from cultures of senescent melanoma cells, the cancer cells metastasized to the animals' lungs. Melanoma cells exposed to the medium from nonsenescent cultures did not form tumors.

“What we've shown is that the secretome that contains CCL2 promotes survival and migration of melanoma cells,” says the study's senior author, Corine Bertolotto of the French National Institute of Health and Medical Research in Nice, France.

The findings might explain why temozolomide, fotemustine, and another late-stage melanoma treatment, dacarbazine, fail in about 85% to 90% of patients.