title: Interleukin-1β promotes ovarian tumorigenesis through a p53/NF-κB-mediated inflammatory response in stromal fibroblasts.
abstract: Cancer has long been considered a disease that mimics an "unhealed wound," with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1β (IL-1β) as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs). Elevated expression of IL-1β and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-α), IL-6, IL-1β, and vascular endothelial growth factor (VEGF), significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-κB) p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1β as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4095, USA.
authors.forename: Isaiah Gregory
authors.initials: IG
authors.lastname: Schauer
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xing
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guo
authors.forename: Imelda
authors.initials: I
authors.lastname: Mercado-Uribe
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019899:Paracrine Communication; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism*; D046888:Tissue Array Analysis; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D018925:Chemokines; D053583:Interleukin-1beta; C498143:RELA protein, human; D017472:Receptors, Interleukin-1; C495901:TP53 protein, human; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53
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