Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner.
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.
Studebaker
Adam W
AW
Center for Childhood Cancer, Children's Research Institute, WA 5015, USA.
Storci
Gianluca
G
Werbeck
Jillian L
JL
Sansone
Pasquale
P
Sasser
A Kate
AK
Tavolari
Simona
S
Huang
Tim
T
Chan
Michael W Y
MW
Marini
Frank C
FC
Rosol
Thomas J
TJ
Bonafé
Massimiliano
M
Hall
Brett M
BM
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
D017077:Culture Media, Conditioned; D015850:Interleukin-6; D050796:STAT3 Transcription Factor