Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure

Kajiwara, Shinya; Ishii, Kenichiro; Sasaki, Takeshi; Kato, Manabu; Nishikawa, Kohei; Kanda, Hideki; Arima, Kiminobu; Watanabe, Masatoshi; Sugimura, Yoshiki

doi:10.1038/s41374-019-0352-4

Cited by 10 publications

(11 citation statements)

References 38 publications

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“…Although this grading system is based on quantification of reactive stromal elements to predict disease progression, the biochemical characteristics of CAFs and/or ECM deposition in the reactive stroma have not been well investigated. Using original CAFs including human PCa‐derived stromal cells (PCaSCs) and primary cultures of prostate fibroblasts (pcPrFs), we reported in several of our previous studies the highly diverse biochemical characteristics of CAFs (e.g., the clinicopathological characteristics of PCa patients and the levels of growth factors and cytokines secreted from CAFs) 7‐11 In addition, we demonstrated that normal fibroblasts cocultured with PCa cells become activated and exhibit the biochemical characteristics of CAFs in a PCa cell‐specific manner 8 . These findings suggest that PCa cells may determine the biochemical characteristics of adjacent CAFs within individual focal lesions, leading to heterogeneous formation of structural atypia.…”

Section: Introductionmentioning

confidence: 88%

Heterogeneous induction of an invasive phenotype in prostate cancer cells by coculturing with patient‐derived fibroblasts

Ishii

Nakagawa

Matsuda

et al. 2021

J of Cellular Biochemistry

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Prostate cancer (PCa) cells frequently invade the surrounding stroma, leading to heterogeneous formation of structural atypia. The surrounding stroma contains multiple functionally diverse populations of fibroblasts that trigger numerous changes in PCa cells including motility. Thus, we hypothesized that direct or indirect contact of PCa cells with fibroblasts determines an invasive phenotype in PCa cells. We investigated the effects of 10 different patient‐derived fibroblast lines on the three‐dimensional (3D) morphogenesis of PCa cells growing on a viscous substrate in vitro. When grown alone, all 10 patient‐derived fibroblast lines clumped on the viscous substrate, whereas the human androgen‐sensitive PCa cell line LNCaP did not. Cocultures of LNCaP cells with seven of the patient‐derived fibroblast lines (PrSC, pcPrF‐M5, pcPrF‐M7, pcPrF‐M23, pcPrF‐M24, pcPrF‐M28, and pcPrF‐M31) formed a thick fibroblast layer that resembled human prostate stromal structures. In contrast, cocultures of LNCaP cells with the remaining three fibroblast lines (NPF‐M13, pcPrF‐M10, and pcPrF‐M26) did not form a thick fibroblast layer. Of the seven fibroblast lines that caused thick layer formation, four patient‐derived fibroblast lines (PrSC, pcPrF‐M5, pcPrF‐M28, and pcPrF‐M31) induced an invasive phenotype in LNCaP cells with a cord‐like infiltrating growth pattern, whereas the other three fibroblast lines (pcPrF‐M7, pcPrF‐M23, and pcPrF‐M24) induced no or a very weak invasive phenotype. Using cell culture inserts, none of the four patient‐derived fibroblast lines that induced an invasive phenotype (PrSC, pcPrF‐M5, pcPrF‐M28, and pcPrF‐M31) affected CDH1 mRNA expression in LNCaP cells; yet, two patient‐derived fibroblast lines (pcPrF‐M5 and pcPrF‐M28) increased CDH2 mRNA expression in LNCaP cells, whereas the other two fibroblast lines (PrSC and pcPrF‐M31) did not. These results suggest that the existence of multiple functionally diverse populations of fibroblasts in PCa tissue may be responsible for the diversity in PCa cell invasion, leading to heterogeneous formation of structural atypia.

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Section: Introductionmentioning

confidence: 88%

Heterogeneous induction of an invasive phenotype in prostate cancer cells by coculturing with patient‐derived fibroblasts

Ishii

Nakagawa

Matsuda

et al. 2021

J of Cellular Biochemistry

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“…The crosstalk between epithelial cells and the surrounding stromal components is fundamental in the context of normal prostate tissue to maintain its homeostasis [1,64]. The epithelium is well-organized and contains polarized epithelial cells with their apical side facing the lumen of the duct and their basal side facing the basement membrane [65], a fibrous, thin ECM layer rich in laminin and collagen type-IV that separates the epithelial cells from the stroma [66]. There are three main types of epithelial cells: luminal cells, basal cells, and rare neuroendocrine cells [67].…”

Section: The Stroma In Prostate Homeostasismentioning

confidence: 99%

“…Luminal cells are secretory cells that are exposed to the lumen of the duct and that express cytokeratins 8 and 18 (CYK8, CYK18), AR (androgen receptor), NK3 Homeobox 1 (NKX3.1), and prostate specific antigen (PSA) [67,68]. In the absence of androgens these cells undergo apoptosis, leading to the regression of the prostate tissue [65]. Basal cells adhere to the basement membrane and are characterized by the expression of p63 and cytokeratins 5 and 14 (CYK5, CYK14), while neuroendocrine cells express chromogranin A, synaptophysin, enolase 2, and CD56 [67,68].…”

Section: The Stroma In Prostate Homeostasismentioning

confidence: 99%

“…PCa cells release TGFβ to induce normal fibroblasts-to-MFBs transition and stimulate TNC deposition (Figure 1) [42]. This TGFβ-mediated effect on CAFs is further increased after castration, suggesting that stromal remodeling underlies the development of CRPC [65]. TGFβ released from PCa cells also determines NADPH-oxidase 4 (Nox4) expression in CAFs (Figure 1), which induces metabolic changes characterized by high ROS production [124].…”

Section: Caf-tumor Signaling: Paracrine Systemic Cell-cell Direct mentioning

confidence: 99%

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The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Bonollo

Thalmann

Julio

et al. 2020

Cancers

104

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Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

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“…The secondary lower urinary tract symptoms (LUTS) impair the quality of their life [ 4 ]. Histopathologically, it results from a loss of homeostasis between cell proliferation and cell death with cell proliferation being dominant [ 5 ]. In addition to androgen and age dependence, androgen-estrogen ratio, the interaction between stromal and epithelial cells, and inflammation, as well as growth factors, are the other accepted predisposing BPH factors [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

The Prostate-Associated Gene 4 (PAGE4) Could Play a Role in the Development of Benign Prostatic Hyperplasia under Oxidative Stress

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Benign prostatic hyperplasia (BPH) is a common disease in elderly men with uncertain molecular mechanism, and oxidative stress (OS) has also been found associated with BPH development. Recently, we found that prostate-associated gene 4 (PAGE4) was one of the most significantly changed differentially expressed genes (DEGs) in BPH, which can protect cells against stress stimulation. However, the exact role of PAGE4 in BPH remains unclear. This study is aimed at exploring the effect of PAGE4 in BPH under OS. Human prostate tissues and cultured WPMY-1 and PrPF cells were utilized. The expression and localization of PAGE4 were determined with qRT-PCR, Western blotting, and immunofluorescence staining. OS cell models induced with H2O2 were treated with PAGE4 silencing or PAGE4 overexpression or inhibitor (N-acetyl-L-cysteine (NAC)) of OS. The proliferation activity, apoptosis, OS markers, and MAPK signaling pathways were detected by CCK-8 assay, flow cytometry analysis, and Western blotting. PAGE4 was shown to be upregulated in human hyperplastic prostate and mainly located in the stroma. Acute OS induced with H2O2 increased PAGE4 expression (which was prevented by OS inhibitor), apoptosis, cell cycle arrest, and reactive oxygen species (ROS) accumulation in WPMY-1 and PrPF cells. siPAGE4 plus H2O2 potentiated H2O2 effect via reducing the p-ERK1/2 level and increasing p-JNK1/2 level. Consistently, overexpression of PAGE4 offset the effect of H2O2 and partially reversed the PAGE4 silencing effect. However, knocking down and overexpression of PAGE4 alone determined no significant effects. Our novel data demonstrated that augmented PAGE4 promotes cell survival by activating p-ERK1/2 and decreases cell apoptosis by inhibiting p-JNK1/2 under the OS, which could contribute to the development of BPH.

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Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure

Cited by 10 publications

References 38 publications

Heterogeneous induction of an invasive phenotype in prostate cancer cells by coculturing with patient‐derived fibroblasts

Heterogeneous induction of an invasive phenotype in prostate cancer cells by coculturing with patient‐derived fibroblasts

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

The Prostate-Associated Gene 4 (PAGE4) Could Play a Role in the Development of Benign Prostatic Hyperplasia under Oxidative Stress

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