Elsevier

Neoplasia

Volume 15, Issue 4, April 2013, Pages 409-420, IN14-IN18
Neoplasia

Interleukin-1β Promotes Ovarian Tumorigenesis through a p53/NF-κB-Mediated Inflammatory Response in Stromal Fibroblasts1,2

https://doi.org/10.1593/neo.121228Get rights and content
Under a Creative Commons license
open access

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.

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1

This work was supported by the National Institutes of Health National Cancer Institute (5R01 CA131183) and the Ovarian Cancer Research Fund (to J.L.). We also acknowledge the support of the Ovarian Cancer Specialized Program of Research Excellence (5P50 CA83639), as well as shared resources funded in part by the Cancer Center Support Grant (5P30 CA016672) at The University of Texas MD Anderson Cancer Center.

2

This article refers to supplementary materials, which are designated by Tables W1 to W5 and Figures W1 to W6 and are available online at www.neoplasia.com.

3

These authors contributed equally to this work.

4

Present address: Department of Pathology, Fourth Military Medical University, Xi'an, Shaanxi, China.