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Cited by 114Telomeres, Telomerase, and SenescenceTGF-β signaling in diseasesCellular Mechanics and Interactions

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

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Mellone, Massimiliano, Hanley, Christopher J., Thirdborough, Steve, Mellows, Toby, Garcia, Edwin, Woo, Jeongmin, Tod, Joanne, Frampton, Steve +19 more·2016·Aging
DOI 10.18632/aging.101127PMC PMC5310659
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Abstract

, 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.

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  • There is clear overlap between the secretome of senescent fibroblasts and CAFs, with high levels of IL-6 production common to both, and senescent fibroblasts have been found in the microenvironment of some tumours.

    “There is clear overlap between the secretome of senescent fibroblasts and CAFs, with high levels of IL-6 production being common to both, and senescent fibroblasts have been found in the microenvironment of some tumours72.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [72]

    The Results describe senescent CAFs in head-and-neck tumour tissue, supporting their presence in some tumour microenvironments. The Discussion says both CAF types secrete factors that promote tumour-cell motility, but that those factors are mostly different; it does not establish high IL-6 production in both or clear overlap between their secretomes (searched: IL-6 and secretome overlap). Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Research works printed but not linked: 55

  1. [3]Sugimoto H Mundel TM Kieran MW Kalluri R Identification of fibroblast heterogeneity in the tumor microenvironment Cancer Biol Ther 2006 5 1640 46 10.4161/cbt.5.12.3354 17106243 · DOI
  2. [4]Eyden B The myofibroblast: a study of normal, reactive and neoplastic tissues, with an emphasis on ultrastructure. part 2 - tumours and tumour-like lesions J Submicrosc Cytol Pathol 2005 37 231 96 16612972
  3. [5]De Wever O Demetter P Mareel M Bracke M Stromal myofibroblasts are drivers of invasive cancer growth Int J Cancer 2008 123 2229 38 10.1002/ijc.23925 18777559 · DOI · Paper page
  4. [6]Hinz B Phan SH Thannickal VJ Prunotto M Desmoulière A Varga J De Wever O Mareel M Gabbiani G Recent developments in myofibroblast biology: paradigms for connective tissue remodeling Am J Pathol 2012 180 1340 55 10.1016/j.ajpath.2012.02.004 22387320 PMC3640252 · DOI · Paper page
  5. [7]Fujita H Ohuchida K Mizumoto K Nakata K Yu J Kayashima T Cui L Manabe T Ohtsuka T Tanaka M alpha-Smooth muscle actin expressing stroma promotes an aggressive tumor biology in pancreatic ductal adenocarcinoma Pancreas 2010 39 1254 62 10.1097/MPA.0b013e3181dbf647 20467342 · DOI
  6. [8]Marsh D Suchak K Moutasim KA Vallath S Hopper C Jerjes W Upile T Kalavrezos N Violette SM Weinreb PH Chester KA Chana JS Marshall JF Stromal features are predictive of disease mortality in oral cancer patients J Pathol 2011 223 470 81 10.1002/path.2830 21294121 · DOI
  7. [9]Yamashita M Ogawa T Zhang X Hanamura N Kashikura Y Takamura M Yoneda M Shiraishi T Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome Breast Cancer 2012 19 170 76 10.1007/s12282-010-0234-5 20978953 · DOI
  8. [10]Underwood TJ Hayden AL Derouet M Garcia E Noble F White MJ Thirdborough S Mead A Clemons N Mellone M Uzoho C Primrose JN Blaydes JP Thomas GJ Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in oesophageal adenocarcinoma J Pathol 2015 235 466 77 10.1002/path.4467 25345775 PMC4312957 · DOI
  9. [11]Goetz JG Minguet S Navarro-Lérida I Lazcano JJ Samaniego R Calvo E Tello M Osteso-Ibáñez T Pellinen T Echarri A Cerezo A Klein-Szanto AJ Garcia R Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis Cell 2011 146 148 63 10.1016/j.cell.2011.05.040 21729786 PMC3244213 · DOI · Paper page
  10. [13]Calvo F Ege N Grande-Garcia A Hooper S Jenkins RP Chaudhry SI Harrington K Williamson P Moeendarbary E Charras G Sahai E Mechanotrans-duction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts Nat Cell Biol 2013 15 637 46 10.1038/ncb2756 23708000 PMC3836234 · DOI · Paper page
  11. [14]Hanley CJ Noble F Ward M Bullock M Drifka C Mellone M Manousopoulou A Johnston HE Hayden A Thirdborough S Liu Y Smith DM Mellows T A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers Oncotarget 2016 7 6159 74 10.18632/oncotarget.6740 26716418 PMC4868747 · DOI
  12. [15]Neri S Hashimoto H Kii H Watanabe H Masutomi K Kuwata T Date H Tsuboi M Goto K Ochiai A Ishii G Cancer cell invasion driven by extracellular matrix remodeling is dependent on the properties of cancer-associated fibroblasts J Cancer Res Clin Oncol 2016 142 437 46 10.1007/s00432-015-2046-7 26374424 PMC11819212 · DOI
  13. [16]Costea DE Hills A Osman AH Thurlow J Kalna G Huang X Pena Murillo C Parajuli H Suliman S Kulasekara KK Johannessen AC Partridge M Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma Cancer Res 2013 73 3888 901 10.1158/0008-5472.CAN-12-4150 23598279 · DOI
  14. [17]Pavlides S Whitaker-Menezes D Castello-Cros R Flomenberg N Witkiewicz AK Frank PG Casimiro MC Wang C Fortina P Addya S Pestell RG Martinez-Outschoorn UE Sotgia F Lisanti MP The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma Cell Cycle 2009 8 3984 4001 10.4161/cc.8.23.10238 19923890 · DOI · Paper page
  15. [18]Erez N Truitt M Olson P Arron ST Hanahan D Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner Cancer Cell 2010 17 135 47 10.1016/j.ccr.2009.12.041 20138012 · DOI · Paper page
  16. [19]Krtolica A Parrinello S Lockett S Desprez PY Campisi J Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging Proc Natl Acad Sci USA 2001 98 12072 77 10.1073/pnas.211053698 11593017 PMC59769 · DOI · Paper page
  17. [20]Coppé JP Desprez PY Krtolica A Campisi J The senescence-associated secretory phenotype: the dark side of tumor suppression Annu Rev Pathol 2010 5 99 118 10.1146/annurev-pathol-121808-102144 20078217 PMC4166495 · DOI · Paper page
  18. [21]Goruppi S Dotto GP Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer Trends Cell Biol 2013 23 593 602 10.1016/j.tcb.2013.08.006 24074947 PMC3864622 · DOI
  19. [22]Campisi J d'Adda di Fagagna F Cellular senescence: when bad things happen to good cells Nat Rev Mol Cell Biol 2007 8 729 40 10.1038/nrm2233 17667954 · DOI · Paper page
  20. [23]Bavik C Coleman I Dean JP Knudsen B Plymate S Nelson PS The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms Cancer Res 2006 66 794 802 10.1158/0008-5472.CAN-05-1716 16424011 · DOI · Paper page
  21. [25]Jun JI Lau LF The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing Nat Cell Biol 2010 12 676 85 10.1038/ncb2070 20526329 PMC2919364 · DOI · Paper page
  22. [27]Klungland A Rosewell I Hollenbach S Larsen E Daly G Epe B Seeberg E Lindahl T Barnes DE Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage Proc Natl Acad Sci USA 1999 96 13300 05 10.1073/pnas.96.23.13300 10557315 PMC23942 · DOI · Paper page
  23. [29]Verrecchia F Chu ML Mauviel A Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach J Biol Chem 2001 276 17058 62 10.1074/jbc.M100754200 11279127 · DOI
  24. [30]Fridman AL Tainsky MA Critical pathways in cellular senescence and immortalization revealed by gene expression profiling Oncogene 2008 27 5975 87 10.1038/onc.2008.213 18711403 PMC3843241 · DOI · Paper page
  25. [31]Klingberg F Hinz B White ES The myofibroblast matrix: implications for tissue repair and fibrosis J Pathol 2013 229 298 309 10.1002/path.4104 22996908 PMC4005341 · DOI · Paper page
  26. [33]Naba A Clauser KR Hoersch S Liu H Carr SA Hynes RO The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices Mol Cell Proteomics 2012 11 M111.014647 10.1074/mcp.M111.014647 PMC3322572 22159717 · DOI · Paper page
  27. [34]Bauer JA Trask DK Kumar B Los G Castro J Lee JS Chen J Wang S Bradford CR Carey TE Reversal of cisplatin resistance with a BH3 mimetic, (−)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL Mol Cancer Ther 2005 4 1096 104 10.1158/1535-7163.MCT-05-0081 16020667 · DOI
  28. [35]Cancer Genome Atlas Network Comprehensive genomic characterization of head and neck squamous cell carcinomas Nature 2015 517 576 82 10.1038/nature14129 25631445 PMC4311405 · DOI
  29. [36]Ottensmeier CH Perry KL Harden EL Stasakova J Jenei V Fleming J Wood O Woo J Woelk CH Thomas GJ Thirdborough SM Upregulated glucose metabolism correlates inversely with cd8+ t-cell infiltration and survival in squamous cell carcinoma Cancer Res 2016 76 4136 48 10.1158/0008-5472.CAN-15-3121 27206847 · DOI
  30. [37]Togo S Polanska UM Horimoto Y Orimo A Carcinoma-associated fibroblasts are a promising therapeutic target Cancers (Basel) 2013 5 149 69 10.3390/cancers5010149 24216702 PMC3730310 · DOI
  31. [38]Levental KR Yu H Kass L Lakins JN Egeblad M Erler JT Fong SF Csiszar K Giaccia A Weninger W Yamauchi M Gasser DL Weaver VM Matrix crosslinking forces tumor progression by enhancing integrin signaling Cell 2009 139 891 906 10.1016/j.cell.2009.10.027 19931152 PMC2788004 · DOI · Paper page
  32. [40]Witkiewicz AK Rivadeneira DB Ertel A Kline J Hyslop T Schwartz GF Fortina P Knudsen ES Association of RB/p16-pathway perturbations with DCIS recurrence: dependence on tumor versus tissue microenvironment Am J Pathol 2011 179 1171 78 10.1016/j.ajpath.2011.05.043 21756866 PMC3157259 · DOI
  33. [41]Hassona Y Cirillo N Lim KP Herman A Mellone M Thomas GJ Pitiyage GN Parkinson EK Prime SS Progression of genotype-specific oral cancer leads to senescence of cancer-associated fibroblasts and is mediated by oxidative stress and TGF-β Carcinogenesis 2013 34 1286 95 10.1093/carcin/bgt035 23358854 · DOI
  34. [43]Barcellos-Hoff MH Nguyen DH Radiation carcinogenesis in context: how do irradiated tissues become tumors? Health Phys 2009 97 446 57 10.1097/HP.0b013e3181b08a10 19820454 PMC2761885 · DOI
  35. [44]Vijayachandra K Lee J Glick AB Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model Cancer Res 2003 63 3447 52 12839923
  36. [45]Tremain R Marko M Kinnimulki V Ueno H Bottinger E Glick A Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras Oncogene 2000 19 1698 709 10.1038/sj.onc.1203471 10763827 · DOI
  37. [46]Yang N Mosher R Seo S Beebe D Friedl A Syndecan-1 in breast cancer stroma fibroblasts regulates extracellular matrix fiber organization and carcinoma cell motility Am J Pathol 2011 178 325 35 10.1016/j.ajpath.2010.11.039 21224069 PMC3069862 · DOI
  38. [47]Conklin MW Eickhoff JC Riching KM Pehlke CA Eliceiri KW Provenzano PP Friedl A Keely PJ Aligned collagen is a prognostic signature for survival in human breast carcinoma Am J Pathol 2011 178 1221 32 10.1016/j.ajpath.2010.11.076 21356373 PMC3070581 · DOI
  39. [48]Bredfeldt JS Liu Y Pehlke CA Conklin MW Szulczewski JM Inman DR Keely PJ Nowak RD Mackie TR Eliceiri KW Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer J Biomed Opt 2014 19 16007 10.1117/1.JBO.19.1.016007 24407500 PMC3886580 · DOI
  40. [49]Ramaswamy S Ross KN Lander ES Golub TR A molecular signature of metastasis in primary solid tumors Nat Genet 2003 33 49 54 10.1038/ng1060 12469122 · DOI
  41. [50]Lewis MP Lygoe KA Nystrom ML Anderson WP Speight PM Marshall JF Thomas GJ Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells Br J Cancer 2004 90 822 32 10.1038/sj.bjc.6601611 14970860 PMC2410183 · DOI
  42. [51]Yap LF Jenei V Robinson CM Moutasim K Benn TM Threadgold SP Lopes V Wei W Thomas GJ Paterson IC Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation Oncogene 2009 28 2524 34 10.1038/onc.2009.105 19448673 · DOI
  43. [52]Thomas GJ Lewis MP Whawell SA Russell A Sheppard D Hart IR Speight PM Marshall JF Expression of the alphavbeta6 integrin promotes migration and invasion in squamous carcinoma cells J Invest Dermatol 2001 117 67 73 10.1046/j.0022-202x.2001.01379.x 11442751 · DOI
  44. [53]James EL Michalek RD Pitiyage GN de Castro AM Vignola KS Jones J Mohney RP Karoly ED Prime SS Parkinson EK Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease J Proteome Res 2015 14 1854 71 10.1021/pr501221g 25690941 · DOI · Paper page
  45. [54]Dimri GP Lee X Basile G Acosta M Scott G Roskelley C Medrano EE Linskens M Rubelj I Pereira-Smith O A biomarker that identifies senes-cent human cells in culture and in aging skin in vivo Proc Natl Acad Sci USA 1995 92 9363 67 10.1073/pnas.92.20.9363 7568133 PMC40985 · DOI · Paper page
  46. [55]Drifka CR Tod J Loeffler AG Liu Y Thomas GJ Eliceiri KW Kao WJ Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis Mod Pathol 2015 28 1470 80 10.1038/modpathol.2015.97 26336888 · DOI
  47. [56]Law CW Chen Y Shi W Smyth GK voom: precision weights unlock linear model analysis tools for RNA-seq read counts Genome Biol 2014 15 R29 10.1186/gb-2014-15-2-r29 24485249 PMC4053721 · DOI · Paper page
  48. [57]Ritchie ME Phipson B Wu D Hu Y Law CW Shi W Smyth GK limma powers differential expression analyses for RNA-sequencing and microarray studies Nucleic Acids Res 2015 43 e47 10.1093/nar/gkv007 25605792 PMC4402510 · DOI · Paper page
  49. [59]Chen J Bardes EE Aronow BJ Jegga AG ToppGene Suite for gene list enrichment analysis and candidate gene prioritization Nucleic Acids Res 2009 37 W305 11 10.1093/nar/gkp427 19465376 PMC2703978 · DOI · Paper page
  50. [60]Thurlow JK Peña Murillo CL Hunter KD Buffa FM Patiar S Betts G West CM Harris AL Parkinson EK Harrison PR Ozanne BW Partridge M Kalna G Spectral clustering of microarray data elucidates the roles of microenvironment remodeling and immune responses in survival of head and neck squamous cell carcinoma J Clin Oncol 2010 28 2881 88 10.1200/JCO.2009.24.8724 20458058 · DOI
  51. [61]Rickman DS Millon R De Reynies A Thomas E Wasylyk C Muller D Abecassis J Wasylyk B Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays Oncogene 2008 27 6607 22 10.1038/onc.2008.251 18679425 · DOI
  52. [62]Theocharidis A van Dongen S Enright AJ Freeman TC Network visualization and analysis of gene expression data using BioLayout Express(3D) Nat Protoc 2009 4 1535 50 10.1038/nprot.2009.177 19798086 · DOI
  53. [63]Schindelin J Arganda-Carreras I Frise E Kaynig V Longair M Pietzsch T Preibisch S Rueden C Saalfeld S Schmid B Tinevez JY White DJ Hartenstein V Fiji: an open-source platform for biological-image analysis Nat Methods 2012 9 676 82 10.1038/nmeth.2019 22743772 PMC3855844 · DOI · Paper page
  54. [64]Beacham DA Amatangelo MD Cukierman E Preparation of extracellular matrices produced by cultured and primary fibroblasts Current protocols in cell biology 2007 Chapter 10:Unit 10 19 18228495
  55. [65]Robinson MD McCarthy DJ Smyth GK edgeR: a Bioconductor package for differential expression analysis of digital gene expression data Bioinformatics 2010 26 139 40 10.1093/bioinformatics/btp616 19910308 PMC2796818 · DOI · Paper page

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Authors
Mellone, M., Hanley, C. J., Thirdborough, S., Mellows, T., Garcia, E., Woo, J., Tod, J., Frampton, S., Jenei, V., Moutasim, K. A., Kabir, T. D., Brennan, P. A., Venturi, G., Ford, K., Herranz, N., Lim, K. P., Clarke, J., Lambert, D. W., Prime, S. S., Underwood, T. J., Vijayanand, P., Eliceiri, K. W., Woelk, C., King, E. V., Gil, J., Ottensmeier, C. H., & Thomas, G. J.
Affiliations
  • University of Southampton (GB)
  • University of Sheffield (GB)
  • Queen Alexandra Hospital (GB)
  • MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12, UK
  • Cancer Research Malaysia (MY)
  • Queen Mary University of London (GB)
  • Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK
  • La Jolla Institute for Immunology (US)
  • University of Wisconsin–Madison (US)
Corresponding author
Thomas, Gareth J.
ORCID
Venue
Aging
Publisher
Impact Journals, LLC
Published
2016-12-15
Volume
9
Issue
1
Pages
114-132
ISSN
1945-4589 (ISSN-L)
DOI
10.18632/aging.101127
PMC
PMC5310659
OpenAlex
W2561691830
Cited by
114
References
12
Citations by year
2026: 6 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 20 · 2021: 11 · 2020: 20 · 2019: 10 · 2018: 8 · 2017: 9
FWCI
7.25
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • GlaxoSmithKline
  • Cancer Research UK (C21825/A13315, S_1716, 18892, 15951, 20613, 22795)
  • National Institute for Health and Care Research (CL-2011-26-003)
  • Academy of Medical Sciences (AMS-SGCL12-Moutasim)
  • University of Southampton
  • National Institutes of Health (1s10od016262-01)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
fibroblast senescence, myofibroblasts, cancer-associated fibroblasts, TGF-beta signaling, smooth muscle actin, tumor cell motility, tumor invasion, extracellular matrix deposition, collagen fiber organization, head and neck squamous cell carcinoma, esophageal adenocarcinoma, cancer prognosis, second harmonic generation microscopy
MeSH terms
Animals, Cell Differentiation, Extracellular Matrix, Fibroblasts, Humans, Neoplasms, Phenotype, Prognosis, Signal Transduction, Cellular Senescence, Cell Line, Tumor, Mice, Transforming Growth Factor beta1, Myofibroblasts

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