BACKGROUND: Stromal-epithelial interactions are important in both development and prostate cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. We investigated whether stromal cathepsin D (CathD) overexpression affects prostate tumorigenesis through a paracrine mechanism. METHODS: Normal prostate fibroblasts (NPF) were retrovirally transduced to overexpress cyclin D1 (CD1) and were designated NPF(CD1) . Cathepsin D expression was knocked down using shRNA in cancer associated fibroblasts (CAF) and NPF(CD1) . We analyzed these stromal cell lines using immunohistochemistry, Western blot, and tissue recombination. RESULTS: An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue. Overexpression of CD1 in normal prostate fibroblasts (NPF(CD1) ) produced a phenotype similar to, but more moderate than, CAF in a tissue recombination model. Knockdown studies revealed that CathD is required for NPF(CD1) motility and invasive growth in vitro. BPH-1 cell proliferation was found to be induced when cultured with NPF(CD1) conditioned medium, this effect was inhibited when CathD was knocked down in NPF(CD1) cells. Overexpression of CathD in prostate stromal cells induced malignancy in adjacent epithelium, and this transformation was inhibited when stromal CathD expression was knocked down in CAF. CONCLUSIONS: The study presented here demonstrates increased CathD expression is seen in human CAF. The upregulation of CD1 results in concomitant increases in CathD expression. Elevated CathD expression in the stroma contributes to tumor promotion.
BACKGROUND: Stromal-epithelial interactions are important in both development and prostate cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. We investigated whether stromal cathepsin D (CathD) overexpression affects prostate tumorigenesis through a paracrine mechanism. METHODS: Normal prostate fibroblasts (NPF) were retrovirally transduced to overexpress cyclin D1 (CD1) and were designated NPF(CD1) . Cathepsin D expression was knocked down using shRNA in cancer associated fibroblasts (CAF) and NPF(CD1) . We analyzed these stromal cell lines using immunohistochemistry, Western blot, and tissue recombination. RESULTS: An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue. Overexpression of CD1 in normal prostate fibroblasts (NPF(CD1) ) produced a phenotype similar to, but more moderate than, CAF in a tissue recombination model. Knockdown studies revealed that CathD is required for NPF(CD1) motility and invasive growth in vitro. BPH-1 cell proliferation was found to be induced when cultured with NPF(CD1) conditioned medium, this effect was inhibited when CathD was knocked down in NPF(CD1) cells. Overexpression of CathD in prostate stromal cells induced malignancy in adjacent epithelium, and this transformation was inhibited when stromal CathD expression was knocked down in CAF. CONCLUSIONS: The study presented here demonstrates increased CathD expression is seen in humanCAF. The upregulation of CD1 results in concomitant increases in CathD expression. Elevated CathD expression in the stroma contributes to tumor promotion.
Authors: J L Phillips; S W Hayward; Y Wang; J Vasselli; C Pavlovich; H Padilla-Nash; J R Pezullo; B M Ghadimi; G D Grossfeld; A Rivera; W M Linehan; G R Cunha; T Ried Journal: Cancer Res Date: 2001-11-15 Impact factor: 12.701
Authors: S W Hayward; Y Wang; M Cao; Y K Hom; B Zhang; G D Grossfeld; D Sudilovsky; G R Cunha Journal: Cancer Res Date: 2001-11-15 Impact factor: 12.701
Authors: A Reles; W H Wen; A Schmider; C Gee; I B Runnebaum; U Kilian; L A Jones; A El-Naggar; C Minguillon; I Schönborn; O Reich; R Kreienberg; W Lichtenegger; M F Press Journal: Clin Cancer Res Date: 2001-10 Impact factor: 12.531
Authors: W Morikawa; K Yamamoto; S Ishikawa; S Takemoto; M Ono; J i Fukushi; S Naito; C Nozaki; S Iwanaga; M Kuwano Journal: J Biol Chem Date: 2000-12-08 Impact factor: 5.157
Authors: Gaelle Fiard; Vasilis Stavrinides; Emma S Chambers; Susan Heavey; Alex Freeman; Rhys Ball; Arne N Akbar; Mark Emberton Journal: Nat Rev Urol Date: 2021-07-22 Impact factor: 14.432
Authors: Laia Querol Cano; Derek N Lavery; Soraya Sin; Emma Spanjaard; Greg N Brooke; Jessica D Tilman; Ahmed Abroaf; Luke Gaughan; Craig N Robson; Rakesh Heer; Francesco Mauri; Johan de Rooij; Keltouma Driouch; Charlotte L Bevan Journal: Mol Oncol Date: 2014-09-06 Impact factor: 6.603