title: Heterogenous induction of carcinoma-associated fibroblast-like differentiation in normal human prostatic fibroblasts by co-culturing with prostate cancer cells.
abstract: In the tumor microenvironment, carcinoma-associated fibroblasts (CAFs) are considered to play a critical role in the promotion of tumorigenesis. However, the mechanisms that generate CAFs are not well elucidated. To understand how CAFs are generated during primary cancer progression, we investigated the biochemical characteristics of normal human prostate stromal cells (PrSC) co-cultured with human prostate cancer (PCa) cells in vitro. In primary cultures of human PCa-derived stromal cells (PCaSC-8 and PCaSC-9), expression of TNC, ACTA2, EGF, FGF7, and IGF1 mRNA was generally higher than PrSC but gene expression patterns were not uniform between PCaSC-8 and PCaSC-9 cells. Transforming growth factor β (TGFβ) and vascular endothelial growth factor (VEGF) protein levels in both PCaSC-8 and PCaSC-9 cells were generally higher than PrSC but levels of both secreted proteins were not same. When PrSCs were co-cultured with androgen-sensitive LNCaP cells or its sublines, androgen-low-sensitive E9 cells and androgen-insensitive AIDL cells, mRNA expression of IGF1 was significantly increased in all combinations. In contrast, expression of COL1A1, TNC, and ACTA2 mRNA was significantly increased only in LNCaP + PrSC and E9 + PrSC co-cultures. Protein production of VEGF was significantly increased only in LNCaP + PrSC and E9 + PrSC co-cultures. Increase of TGFβ protein was observed only in E9 + PrSC co-cultures. These biochemical characteristics of PrSC were partially recapitulated in TGFβ-treated PrSC. We have demonstrated that normal fibroblasts co-cultured with cancer cells become activated and exhibit biochemical characteristics of CAFs in a heterogenous manner. Our results suggest that heterogenous induction of CAF-like differentiation might be strongly dependent on biochemical characteristics of adjacent cancer cells.
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie, Japan. kenishii@clin.medic.mie-u.ac.jp
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizokami
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Kato
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hori
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Arima
authors.forename: Mikio
authors.initials: M
authors.lastname: Namiki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugimura
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005347:Fibroblasts / Q000166:cytology; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D011467:Prostate / Q000166:cytology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger