title: NPPB is a novel candidate biomarker expressed by cancer-associated fibroblasts in epithelial ovarian cancer.
abstract: Most solid tumors contain cancer-associated fibroblasts (CAFs) that support tumorigenesis and malignant progression. However, the cellular origins of CAFs in epithelial ovarian cancers (EOCs) remain poorly understood, and their utility as a source of clinical biomarkers for cancer diagnosis has not been explored in great depth. Here, we report establishing in vitro and in vivo models of CAFs in ovarian cancer development. Normal ovarian fibroblasts and mesenchymal stem cells cultured in the presence of EOC cells acquired a CAF-like phenotype, and promoted EOC cell migration in vitro. CAFs also promoted ovarian cancer growth in vivo in both subcutaneous and intraperitoneal murine xenograft assays. Molecular profiling of CAFs identified gene expression signatures that were highly enriched for extracellular and secreted proteins. We identified novel candidate CAF-specific biomarkers for ovarian cancer including NPPB, which was expressed in the stroma of 60% primary ovarian cancer tissues (n = 145) but not in the stroma of normal ovaries (n = 4). NPPB is a secreted protein that was also elevated in the blood of 50% of women with ovarian cancer (n = 8). Taken together, these data suggest that the tumor stroma is a novel source of biomarkers, including NPPB, that may be of clinical utility for detection of EOC.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrenson
authors.forename: Barbara
authors.initials: B
authors.lastname: Grun
authors.forename: Nathan
authors.initials: N
authors.lastname: Lee
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.forename: Jenny
authors.initials: J
authors.lastname: Kan
authors.forename: Steve
authors.initials: S
authors.lastname: Swenson
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
authors.forename: Joshua
authors.initials: J
authors.lastname: Millstein
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000737:chemistry*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000737:chemistry / Q000502:physiology; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000737:chemistry / Q000473:pathology*; D009579:Nitrobenzoates / Q000032:analysis*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D009579:Nitrobenzoates; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid
keywords: BNP; NPPB; cancer-associated fibroblast; fibroblast; microarray; microenvironment; ovarian cancer; stroma; xenograft