Details

Autor(en) / Beteiligte

• Mellone, Massimiliano
• Hanley, Christopher J
• Thirdborough, Steve
• Mellows, Toby
• Garcia, Edwin
• Woo, Jeongmin
• Tod, Joanne
• Frampton, Steve
• Jenei, Veronika
• Moutasim, Karwan A
• Kabir, Tasnuva D
• Brennan, Peter A
• Venturi, Giulia
• Ford, Kirsty
• Herranz, Nicolas
• Lim, Kue Peng
• Clarke, James
• Lambert, Daniel W
• Prime, Stephen S
• Underwood, Timothy J
• Vijayanand, Pandurangan
• Eliceiri, Kevin W
• Woelk, Christopher
• King, Emma V
• Gil, Jesus
• Ottensmeier, Christian H
• Thomas, Gareth J

Titel

Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis

Ist Teil von

• Aging (Albany, NY.), 2016-12, Vol.9 (1), p.114-132

Ort / Verlag

United States: Impact Journals LLC

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 , showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. , 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.