Sarcoid-derived fibroblasts: links between genomic instability, energy metabolism and senescence.

Potocki, Leszek; Lewinska, Anna; Klukowska-Rötzler, Jolanta; Bielak-Zmijewska, Anna; Grabowska, Wioleta; Rzeszutek, Iwona; Kaminska, Patrycja; Roga, Elzbieta; Bugno-Poniewierska, Monika; Slota, Ewa; Mählmann, Kathrin; Koch, Christoph; Wnuk, Maciej (2014). Sarcoid-derived fibroblasts: links between genomic instability, energy metabolism and senescence. Biochimie, 97, pp. 163-172. Elsevier Masson SAS 10.1016/j.biochi.2013.10.010

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Bovine papillomavirus 1 (BPV-1) is a well recognized etiopathogenetic factor in a cancer-like state in horses, namely equine sarcoid disease. Nevertheless, little is known about BPV-1-mediated cell transforming effects. It was shown that BPV-1 triggers genomic instability through DNA hypomethylation and oxidative stress. In the present study, we further characterized BPV-1-positive fibroblasts derived from sarcoid tumors. The focus was on cancer-like features of sarcoid-derived fibroblasts, including cell cycle perturbation, comprehensive DNA damage analysis, end-replication problem, energy metabolism and oncogene-induced premature senescence. The S phase of the cell cycle, polyploidy events, DNA double strand breaks (DSBs) and DNA single strand breaks (SSBs) were increased in BPV-1-positive cells compared to control fibroblasts. BPV-1-mediated oxidative stress may contribute to telomere dysfunction in sarcoid-derived fibroblasts. Loss of mitochondrial membrane potential and concurrent elevation in intracellular ATP production may be a consequence of changes in energy-supplying pathways in BPV-1-positive cells which is also typical for cancer cells. Shifts in energy metabolism may support rapid proliferation in cells infected by BPV-1. Nevertheless, sarcoid-derived fibroblasts representing a heterogeneous cell fraction vary in some aspects of metabolic phenotype due to a dual role of BPV-1 in cell transformation and oncogene-induced premature senescence. This was shown with increased senescence-associated β-galactosidase (SA-β-gal) activity. Taken together, metabolic phenotypes in sarcoid-derived fibroblasts are plastic, which are similar to greater plasticity of cancer tissues than normal tissues.

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