Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes.
Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and -restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicates the IL8 pathway as a mediator of the proinvasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry correlated with decreased survival in patients with early-stage disease. These data support senescent fibroblasts as a pathologically and clinically relevant feature of pancreatic cancer. The inhibition of senescent stroma-cancer signaling pathways has the potential to restrain pancreatic cancer progression.



Findings show that senescent cancer-associated fibroblasts secret excess IL8 to promote pancreatic cancer invasion and metastasis; thus, senescent CAFs represent a phenotypic subtype, challenging conventional assumptions that CAFs are a homogeneous population. Mol Cancer Res; 15(1); 3-14. ©2016 AACR.
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Department of Pathology, University Health Network, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Tao
T
Wang
Ontario Institute for Cancer Research, Toronto, Canada.
Faiyaz
F
Notta
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Roya
R
Navab
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Joella
J
Joseph
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Ontario Institute for Cancer Research, Toronto, Canada.
Emin
E
Ibrahimov
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Jing
J
Xu
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Chang-Qi
CQ
Zhu
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada.
Ayelet
A
Borgida
Department of General Surgery, University Health Network, Toronto, Canada.|Department of Surgery, University of Toronto, Toronto, Canada.
Steven
S
Gallinger
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. ming.tsao@uhn.ca.|Department of Pathology, University Health Network, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Ming-Sound
MS
Tsao
D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010641:Phenotype; D017154:Stromal Cells / Q000473:pathology; D015854:Up-Regulation
D016209:Interleukin-8