title: Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer.
abstract: In patients with prostate cancer (PCa), serum prostate-specific antigen (PSA) is a useful marker for evaluating the effects of androgen deprivation therapy (ADT). Intuitively, most urologists expect that a more rapid PSA decline in response to ADT would be positively associated with extended survival. Recently, we have reported that prolonged gradual serum PSA decline after ADT is strongly associated with favorable prognosis in PCa patients, however, the mechanism remains unknown. We investigated the role of fibroblasts in serum PSA decline after ADT. We performed in vitro experiments using androgen-sensitive, androgen receptor (AR)-positive prostate epithelial cell lines (LNCaP, 22Rv1, and RWPE-1 cells), commercially available prostate stromal cells (PrSC), and primary cultures of prostate fibroblasts (pcPrFs). In LNCaP and 22Rv1 cells, PSA production was increased by co-culture with fibroblasts under androgen-deprived conditions. In an in vivo model using LNCaP cells, serum PSA declined rapidly after ADT becoming undetectable within 14 days in mice inoculated with LNCaP cells alone. In contrast, when LNCaP cells were co-inoculated with fibroblasts, serum PSA levels were still high on 14 days post ADT and did not drop to undetectable levels until 21 days post ADT. Tumor volumes and Ki67 labeling indices were not altered between days 14 and 21 post ADT in mice inoculated with LNCaP cells; however, those in mice inoculated with LNCaP cells plus fibroblasts decreased gradually. PSA protein was detected in all tumors on 21 days post ADT by immunohistochemical staining. Microvessel densities were higher on 14 days post ADT for tumors from mice inoculated with LNCaP cells plus fibroblasts as compared with LNCaP cells alone. In summary, co-inoculation of fibroblasts with LNCaP cells prolonged serum PSA decline after ADT and enhanced the efficacy of ADT. Prolonged serum PSA decline may indicate the presence of protective fibroblasts that preserve the AR dependence of PCa cells, improving treatment efficacy.
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Miki
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Arima
authors.affiliation: Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugimura
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000209:etiology; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000726:Androgen Antagonists; D017430:Prostate-Specific Antigen