Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner.
Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin carcinogenesis, we found a proinflammatory gene signature in CAFs isolated from dysplastic skin. This signature was maintained in CAFs from subsequent skin carcinomas and was evident in mammary and pancreatic tumors in mice and in cognate human cancers. The inflammatory signature was already activated in CAFs isolated from the initial hyperplastic stage in multistep skin tumorigenesis. CAFs from this pathway promoted macrophage recruitment, neovascularization, and tumor growth, activities that are abolished when NF-kappaB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be "educated" by carcinoma cells to express proinflammatory genes.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 94143, USA.
Neta
N
Erez
Morgan
M
Truitt
Peter
P
Olson
Sarah Tuttleton
ST
Arron
Douglas
D
Hanahan
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic; D012878:Skin Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000473:pathology
D018836:Inflammation Mediators; D016328:NF-kappa B