Abstractp16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.
ObjectiveCellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development.DesignTo uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment.ResultsWe found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma.ConclusionsThese findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.
Transforming growth factor alpha (TGF-α) is a mitogenic factor for hepatocyte and a ligand of the epithelial growth factor receptor (EGFR). TGF-α promotes liver carcinogenesis. TGF-α is also overexpressed in regenerative nodules of the cirrhotic liver but the mechanism of this expression is poorly known. Because hypoxia is a feature of cirrhotic livers and hypoxia may induce TGF-α and EGFR expressions, the aim of this study was to determine whether the TGF-α/EGFR pathway is affected by hypoxia in liver cells. Cell isolates were prepared from normal Wistar rats. Liver myofibroblasts were obtained in culture by activation of hepatic stellate cells (HSC), and by outgrowth of portal myofibroblasts from bile duct segments. Hepatocytes, Kupffer cells and liver myofibroblasts in culture were submitted to hypoxia for 4-24 hours. Hypoxia was achieved using a catalytic system, which reduces oxygen concentration to less than 1% within 30 minutes. The absence of toxicity was verified by lactate dehydrogenase dosing in cell supernatant. Vascular endothelial growth factor (VEGF) served as a hypoxia-inducible control gene. Gene expression was assessed by real-time reverse transcription polymerase chain reaction (RT-PCR). Under normoxia, the expression of TGF-α was significantly higher in hepatocytes than in non-parenchymal liver cells (~1.7-fold). EGFR transcripts were also more abundant in Hepatocytes than in myofibroblasts (~3-fold) or in Kupffer cells (~22-fold). Hypoxia induced an increase in VEGF mRNA to a similar extent in all cell types. By contrast, hypoxia caused an increase in TGF-α transcripts mainly in Hepatocytes (112 ± 7 vs 32 ± 2 under normoxia), also but to a lesser extent in portal myofibroblasts (35 ± 5 vs 17 ± 4), but not in HSC-derived myofibroblasts nor in Kupffer cells. An increase in EGFR expression was induced by hypoxia also predominantly in Hepatocytes (125 ± 12 vs 44 ± 6), and to a much lesser extent in other cell types. These results demonstrate that hypoxia induces TGF-and EGFR overexpression in hepatocytes and, thereby, might act as a promoting event in liver carcinogenesis upon cirrhotic liver.
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