• 1 Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK
  • 2 Faculty of Medicine, University of Southampton, Southampton SO166YD, UK
  • 3 Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield S102TA, UK
  • 4 Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth PO63LY, UK
  • 5 MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12, UK
  • 6 Cancer Research Initiatives Foundation. Sime Darby Medical Centre, Subang Jaya, Selangor 47500, Malaysia
  • 7 Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E12AD, UK
  • 8 La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA
  • 9 Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin, WI 53706, USA
Aging (Albany NY), 2016 12 15;9(1):114-132.
PMID: 27992856 DOI: 10.18632/aging.101127


Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.