title: Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner.
abstract: Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor alpha (ERalpha)-positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ERalpha-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3-dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics.
authors.affiliation: Center for Childhood Cancer, Children's Research Institute, WA 5015, USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Studebaker
authors.forename: Gianluca
authors.initials: G
authors.lastname: Storci
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Werbeck
authors.forename: Pasquale
authors.initials: P
authors.lastname: Sansone
authors.forename: A Kate
authors.initials: AK
authors.lastname: Sasser
authors.forename: Simona
authors.initials: S
authors.lastname: Tavolari
authors.forename: Tim
authors.initials: T
authors.lastname: Huang
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.forename: Frank C
authors.initials: FC
authors.lastname: Marini
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafé
authors.forename: Brett M
authors.initials: BM
authors.lastname: Hall
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D015850:Interleukin-6; D050796:STAT3 Transcription Factor