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

Biochimie. 2014 Feb;97:163-72. doi: 10.1016/j.biochi.2013.10.010. Epub 2013 Oct 19.

Abstract

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.

Keywords: ATP; BPV-1; Cell cycle; Equine; Genomic instability; SA-β-gal; Sarcoid-derived fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bovine papillomavirus 1
  • Cell Cycle
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence
  • DNA Breaks, Double-Stranded
  • DNA Breaks, Single-Stranded
  • DNA, Viral / genetics
  • Energy Metabolism*
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibroblasts / virology
  • Gene Expression
  • Genomic Instability*
  • Horse Diseases / metabolism
  • Horse Diseases / pathology*
  • Horse Diseases / virology
  • Horses
  • Oxidative Stress
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / veterinary*
  • Papillomavirus Infections / virology
  • Ploidies
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Skin Neoplasms / veterinary*
  • Skin Neoplasms / virology
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism

Substances

  • DNA, Viral
  • beta-Galactosidase