Abstract ED04-03: Interleukins at the crossroad of inflammation, senescence, and cancer
Authors: Peeper Daniel 
Published: May 2012

Abstract
ED04-03
Benign lesions commonly contain one or more ‘driver’ mutations that may cause an initial phase of proliferation. Several mechanisms including apoptosis and lack of vessel formation, account for their failure to continue growing and to undergo full malignant transformation. As is illustrated by the absence of mitotic figures often seen in longstanding benign tumors, proliferative arrest represents an effective mechanism suppressing continued outgrowth and transformation to overt cancer.
The proliferative arrest of long-term benign lesions, such as melanocytic nevi, shares a number of characteristics with cellular senescence, originally defined as a mechanism accounting for the cellular response to telomere attrition-dependent DNA damage in vitro. Recent evidence has implicated Oncogene-Induced cellular Senescence (OIS), which is induced prematurely (that is, before telomeric shortening can account for it), as a critical cause of arrest of benign neoplasms. It can be triggered by an activated oncogene like BRAFE600 or RASV12, or by the loss of a tumor suppressor gene, like PTEN or NF1, and occurs in a variety of cell types. OIS is associated with a largely irreversible loss of proliferative activity that is often accompanied by the upregulation of tumor suppressors like p16INK4A (a CDK4/6 inhibitor) and p21CIP1, an increase in Senescence-Associated β-Galactosidase (SA-β-Gal) activity, and elevated levels of PAI-1. A further hallmark of OIS is the formation of Senescence-Associated Heterochromatic Foci (SAHF), corresponding to subnuclear structures that contain heterochromatin proteins such as HP1. SAHF are associated with methylation of lysine 9 of histone H3 (K9M-H3) and are thought to contribute to the irreversible cell cycle exit of senescent cells by repressing the promoters of proliferation-associated genes. In addition to telomere dysfunction and oncogenic genetic events, senescence can be triggered by oxidative stress and by exposure to DNA-damaging agents. In vivo, OIS has been correlated with DNA replication stress and DNA hyper-replication.
Convincing evidence of the importance of OIS as a physiologically relevant mechanism limiting tumorigenesis is rapidly emerging. Senescence markers have been identified in various in vivo lesions, including human melanocytic nevi, murine lung adenomas, human dermal neurofibromas, human and murine prostatic adenomas, pancreatic intraductal neoplasias, murine lymphomas and early murine melanomas. In aggregate, indications are that the role of OIS in the prevention of cancer is substantial.
In recent years, unbiased experimental approaches including function-based genome-wide screens have unraveled unanticipated tumorigenic mechanisms. Despite such recent progress, we are only beginning to unveil the molecular mechanism of OIS and to identify the key players involved. By using a combination of gene expression microarrays and RNA interference, we asked whether we could uncover novel pathways that relay OIS.
Combined microarray expression and Gene Ontology analysis revealed that OIS is specifically linked to an inflammatory transcriptome. Induced genes included interleukin 6 (IL-6), a pleiotropic cytokine often associated with cancer-promoting paracrine effects. Indeed, upon secretion by senescent cells IL-6 acted mitogenically in a paracrine fashion. Unexpectedly, in OIS IL-6 had a cell-autonomous role, being required in an autocrine fashion both for the induction and maintenance of cell cycle arrest of cells exposed to oncogenic stress. Upon IL-6 depletion, the inflammatory network collapsed and cells bypassed senescence. The transcription factor C/EBPβ was identified as an OIS integrator, acting with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically co-localized with arrested, p16INK4A-positive epithelium. On the basis of these results we propose a model in which the antagonistic functions of interleukins contribute to connect senescence with an inflammatory phenotype and cancer.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED04-03.