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  • 1
    Keywords: PATHWAY ; MICE ; MELANOMA ; p53 ; SURVEILLANCE ; MULTISTAGE CARCINOGENESIS ; CD4(+) T-CELLS ; REGRESSION ; ONCOGENE-INDUCED SENESCENCE ; TUMOR DORMANCY
    Abstract: Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-gamma (IFN-gamma) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-gamma and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-gamma and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-gamma- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-gamma and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
    Type of Publication: Journal article published
    PubMed ID: 23376950
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  • 2
    Abstract: BACKGROUND & AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) functions analogue to the receptor of advanced glycation end products, which has been implicated in the development of diabetic nephropathy (DN). We investigated the expression of ALCAM and its ligand S100B in patients with DN. METHODS: A total of 34 non-diabetic patients, 29 patients with type 2 diabetes and normal albuminuria and 107 patients with type 2 diabetes complicated with DN were assessed for serum concentration of soluble ALCAM (sALCAM) by ELISA. Expression of ALCAM and S100B in kidney histology from patients with DN was determined by immunohistochemistry. Cell expression of ALCAM and S100B was analyzed through confocal immunofluorescence microscopy. RESULTS: Serum concentration of sALCAM was increased in diabetic patients with DN compared to non-diabetic (59.85+/-14.99ng/ml vs. 126.88+/-66.45ng/ml, P〈0.0001). Moreover sALCAM correlated positively with HbA1c (R=0.31, P〈0.0001), as well as with the stages of chronic kidney disease and negatively correlated with eGFR (R=-0.20, P〈0.05). In diabetic patients with normal albuminuria sALCAM was increased compared to patients with DN (126.88+/-66.45ng/ml vs. 197.50+/-37.17ng/ml, P〈0.0001). In diabetic patients, ALCAM expression was significantly upregulated in both the glomeruli and tubules (P〈0.001). ALCAM expression in the glomeruli correlated with presence of sclerosis (R=0.25, P〈0.001) and localized mainly in the podocytes supporting the hypothesis that membrane bound ALCAM drives diabetic nephropathy and thus explaining sALCAM decrease in diabetic patients with DN. The expression of S100B was increased significantly in the glomeruli of diabetic patients (P〈0.001), but not in the tubules. S100B was as well localized in the podocytes. CONCLUSIONS: This study identifies for the first time ALCAM as a potential mediator in the late complications of diabetes in the kidney.
    Type of Publication: Journal article published
    PubMed ID: 28325697
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