Various mutations can make normal mammalian cells cancerous. Luckily, several built-in mechanisms that inhibit tumour formation are in place. For example, a host of molecular factors, including tumour-suppressor proteins, blunt the accumulation of potentially dangerous cells by promoting either cellular senescence or apoptosis (programmed cell death) (1). But tumour suppressors are neither infallible nor work in isolation. So the quest is on for other natural anticancer agents. In papers published in Cell, Kuilman et al. (2) and Acosta et al. (3) describe the role of several secreted immune mediators in promoting cellular senescence in response to oncogene activation.
Senescent cells are metabolically active and can secrete various proteins, including growth factors, matrix metalloproteinases, protease inhibitors and cytokines, each of which can have multiple effects on the tumour microenvironment and, ultimately, on tumour development (4,5). The two teams (2,3) also independently arrive at the secretome (a collection of secretory cellular molecules) as a central switch in oncogene-induced cellular senescence.
Kuilman et al. wanted to identify genes that respond differentially to the [BRAF.sup.V600E] oncogene, and came upon a footprint of immune mediators (cytokines and chemokines) that are induced only in senescent cells. For example, they find that, in fibroblasts expressing [BRAF.sup.V600E], signals from this oncogene induce secretion of the cytokine IL-6, which is essential--although insufficient--for the induction and maintenance of senescence in the very cells that secrete them (Fig. 1).
The authors also find that the gene transcription factor C/EBP[beta] regulates IL-6 expression, and that it is crucial for mediating oncogene-induced senescence. Depletion of IL-6 reduced C/EBP[beta] expression and vice versa, suggesting that an interconnected feedforward loop operates between the genes encoding these proteins. The precise sequence of events downstream of IL-6 activity is undefined, but Kuilman and colleagues...