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Special Issue "Cytobiology of Human Prostate Cancer Cells and Its Clinical Applications"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (30 April 2019)

Special Issue Editor

Guest Editor
Dr. Kenichiro Ishii

Department of Oncologic Pathology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu Mie 514-8507, Japan
Website | E-Mail
Interests: tumor microenvironment; prostate cancer; pancreatic cancer; stromal paracrine signals; carcinoma-associated fibroblasts (CAFs); drug repositioning

Special Issue Information

Dear Colleagues,

The number of males diagnosed with prostate cancer is increasing all over the world. Most patients with early-stage prostate cancer can be treated by an appropriate therapy, such as radical prostatectomy or irradiation. On the other hand, androgen deprivation therapy (ADT) is the standard systemic therapy given to patients with advanced prostate cancer. ADT induces temporary remission, but the majority of patients (approximately 60%) eventually progress to castration-resistant prostate cancer (CRPC), which is associated with a high mortality rate.

Generally, well-differentiated prostate cancer cells are androgen-dependent, i.e., androgen receptor (AR) signalling regulates cell cycle and differentiation. Loss of AR signalling after ADT triggers androgen-independent outgrowth, generating poorly differentiated, uncontrollable prostate cancer cells. Once prostate cancer cells lose their sensitivity to ADT, effective therapies are limited. In the last few years, however, several new options for the treatment of CRPC have been approved, e.g., the CYP17 inhibitor, the AR antagonist, and the taxane. Despite this progress in development of new drugs, there is a high medical need for optimizing the sequence and combination of approved drugs. Thus, identification of predictive biomarkers may help in the context of personalized medicine to guide treatment decisions, improve clinical outcomes, and prevent unnecessary side effects.

In this Special Issue, we will focus on the cytobiology of human prostate cancer cells and its clinical applications to develop a major step towards personalized medicine matched to the individual needs of patients with early-stage and advanced prostate cancer, and CRPC.

Dr. Kenichiro Ishii
Guest Editor

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Keywords

  • Prostate cancer
  • Cytobiology of cancer cells
  • Androgen receptor signaling
  • Castration-resistant prostate cancer (CRPC)
  • Predictive biomarkers
  • Personalized medicine

Published Papers (12 papers)

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Research

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Open AccessArticle
Consecutive Prostate Cancer Specimens Revealed Increased Aldo–Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer
J. Clin. Med. 2019, 8(5), 601; https://doi.org/10.3390/jcm8050601
Received: 27 March 2019 / Revised: 23 April 2019 / Accepted: 26 April 2019 / Published: 1 May 2019
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Abstract
Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study [...] Read more.
Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression. Full article
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Open AccessArticle
Higher Serum Testosterone Levels Associated with Favorable Prognosis in Enzalutamide- and Abiraterone-Treated Castration-Resistant Prostate Cancer
J. Clin. Med. 2019, 8(4), 489; https://doi.org/10.3390/jcm8040489
Received: 1 March 2019 / Revised: 5 April 2019 / Accepted: 8 April 2019 / Published: 11 April 2019
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Abstract
Testosterone plays a significant role in maintaining the tumor microenvironment. The role of the target serum testosterone (TST) level in enzalutamide- (Enza) and abiraterone (Abi)-treated castration-resistant prostate cancer (CRPC) patients was studied. In total, 107 patients treated with Enza and/or Abi at Chiba [...] Read more.
Testosterone plays a significant role in maintaining the tumor microenvironment. The role of the target serum testosterone (TST) level in enzalutamide- (Enza) and abiraterone (Abi)-treated castration-resistant prostate cancer (CRPC) patients was studied. In total, 107 patients treated with Enza and/or Abi at Chiba University Hospital and affiliated hospitals were studied. The relationships between progression-free survival (PFS), overall survival (OS), and clinical factors were studied by Cox proportional hazard and Kaplan–Meier models. In the Abi and Enza groups overall, TST ≥ 13 ng/dL (median) (Hazard Ratio (HR) 0.43, p = 0.0032) remained an independent prognostic factor for PFS. In the Enza group, TST ≥ 13 ng/dL (median) was found to be a significant prognostic factor (HR 0.28, p = 0.0044), while, in the Abi group, TST ≥ 12 ng/dL (median) was not significant (HR 0.40, p = 0.0891). TST showed significant correlation with PFS periods (r = 0. 32, p = 0.0067), whereas, for OS, TST ≥ 13 ng/dL (median) showed no significant difference in the Abi and Enza groups overall. According to Kaplan–Meier analysis, a longer PFS at first-line therapy showed a favorable prognosis in the Enza group (p = 0.0429), while no difference was observed in the Abi group (p = 0.6051). The TST level and PFS of first-line therapy may be considered when determining the treatment strategy for CRPC patients. Full article
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Open AccessArticle
NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy
J. Clin. Med. 2019, 8(4), 442; https://doi.org/10.3390/jcm8040442
Received: 12 March 2019 / Revised: 25 March 2019 / Accepted: 27 March 2019 / Published: 31 March 2019
Cited by 1 | PDF Full-text (2909 KB) | HTML Full-text | XML Full-text
Abstract
Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC [...] Read more.
Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC. Full article
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Open AccessArticle
Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1
J. Clin. Med. 2019, 8(3), 348; https://doi.org/10.3390/jcm8030348
Received: 10 February 2019 / Revised: 5 March 2019 / Accepted: 6 March 2019 / Published: 12 March 2019
Cited by 1 | PDF Full-text (2342 KB) | HTML Full-text | XML Full-text
Abstract
Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of [...] Read more.
Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance. Here we investigated whether fibroblast secreted anti-apoptotic proteins could induce radiation resistance of prostate cancer cells in a CAV1-dependent manner and identified TRIAP1 (TP53 Regulated Inhibitor of Apoptosis 1) as a resistance-promoting CAV1-dependent factor. TRIAP1 expression and secretion was significantly higher in CAV1-deficient fibroblasts and secreted TRIAP1 was able to induce radiation resistance of PC3 and LNCaP prostate cancer cells in vitro, as well as of PC3 prostate xenografts derived from co-implantation of PC3 cells with TRIAP1-expressing fibroblasts in vivo. Immunohistochemical analyses of irradiated PC3 xenograft tumours, as well as of human prostate tissue specimen, confirmed that the characteristic alterations in stromal-epithelial CAV1 expression were accompanied by increased TRIAP1 levels after radiation in xenograft tumours and within advanced prostate cancer tissues, potentially mediating resistance to radiation treatment. In conclusion, we have determined the role of CAV1 alterations potentially induced by the CAV1-deficient, and more reactive, stroma in radio sensitivity of prostate carcinoma at a molecular level. We suggest that blocking TRIAP1 activity and thus avoiding drug resistance may offer a promising drug development strategy for inhibiting resistance-promoting CAV1-dependent signals. Full article
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Open AccessArticle
KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer
J. Clin. Med. 2019, 8(2), 225; https://doi.org/10.3390/jcm8020225
Received: 26 December 2018 / Revised: 22 January 2019 / Accepted: 5 February 2019 / Published: 9 February 2019
Cited by 1 | PDF Full-text (979 KB) | HTML Full-text | XML Full-text
Abstract
Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 [...] Read more.
Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance. Full article
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Open AccessArticle
Pirfenidone, an Anti-Fibrotic Drug, Suppresses the Growth of Human Prostate Cancer Cells by Inducing G1 Cell Cycle Arrest
J. Clin. Med. 2019, 8(1), 44; https://doi.org/10.3390/jcm8010044
Received: 11 December 2018 / Revised: 25 December 2018 / Accepted: 28 December 2018 / Published: 4 January 2019
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Abstract
Pirfenidone (PFD) is an anti-fibrotic drug used to treat idiopathic pulmonary fibrosis by inducing G1 cell cycle arrest in fibroblasts. We hypothesize that PFD can induce G1 cell cycle arrest in different types of cells, including cancer cells. To investigate the [...] Read more.
Pirfenidone (PFD) is an anti-fibrotic drug used to treat idiopathic pulmonary fibrosis by inducing G1 cell cycle arrest in fibroblasts. We hypothesize that PFD can induce G1 cell cycle arrest in different types of cells, including cancer cells. To investigate the effects of PFD treatment on the growth of human prostate cancer (PCa) cells, we used an androgen-sensitive human PCa cell line (LNCaP) and its sublines (androgen-low-sensitive E9 and F10 cells and androgen-insensitive AIDL cells), as well as an androgen-insensitive human PCa cell line (PC-3). PFD treatment suppressed the growth of all PCa cells. Transforming growth factor β1 secretion was significantly increased in PFD-treated PCa cells. In both LNCaP and PC-3 cells, PFD treatment increased the population of cells in the G0/G1 phase, which was accompanied by a decrease in the S/G2 cell population. CDK2 protein expression was clearly decreased in PFD-treated LNCaP and PC-3 cells, whereas p21 protein expression was increased in only PFD-treated LNCaP cells. In conclusion, PFD may serve as a novel therapeutic drug that induces G1 cell cycle arrest in human PCa cells independently of androgen sensitivity. Thus, in the tumor microenvironment, PFD might target not only fibroblasts, but also heterogeneous PCa cells of varying androgen-sensitivity levels. Full article
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Open AccessArticle
Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy
J. Clin. Med. 2018, 7(11), 444; https://doi.org/10.3390/jcm7110444
Received: 13 October 2018 / Revised: 13 November 2018 / Accepted: 14 November 2018 / Published: 16 November 2018
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Abstract
Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been [...] Read more.
Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes. Full article
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Review

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Open AccessReview
Research Evidence on High-Fat Diet-Induced Prostate Cancer Development and Progression
J. Clin. Med. 2019, 8(5), 597; https://doi.org/10.3390/jcm8050597
Received: 22 March 2019 / Revised: 27 April 2019 / Accepted: 29 April 2019 / Published: 30 April 2019
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Abstract
Although recent evidence has suggested that a high-fat diet (HFD) plays an important role in prostate carcinogenesis, the underlying mechanisms have largely remained unknown. This review thus summarizes previous preclinical studies that have used prostate cancer cells and animal models to assess the [...] Read more.
Although recent evidence has suggested that a high-fat diet (HFD) plays an important role in prostate carcinogenesis, the underlying mechanisms have largely remained unknown. This review thus summarizes previous preclinical studies that have used prostate cancer cells and animal models to assess the impact of dietary fat on prostate cancer development and progression. Large variations in the previous studies were found during the selection of preclinical models and types of dietary intervention. Subcutaneous human prostate cancer cell xenografts, such as LNCaP, LAPC-4, and PC-3 and genetic engineered mouse models, such as TRAMP and Pten knockout, were frequently used. The dietary interventions had not been standardized, and distinct variations in the phenotype were observed in different studies using distinct HFD components. The use of different dietary components in the research models is reported to influence the effect of diet-induced metabolic disorders. The proposed underlying mechanisms for HFD-induced prostate cancer were divided into (1) growth factor signaling, (2) lipid metabolism, (3) inflammation, (4) hormonal modulation, and others. A number of preclinical studies proposed that dietary fat and/or obesity enhanced prostate cancer development and progression. However, the relationship still remains controversial, and care should be taken when interpreting the results in a human context. Future studies using more sophisticated preclinical models are imperative in order to explore deeper understanding regarding the impact of dietary fat on the development and progression of prostate cancer. Full article
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Open AccessReview
Suppressive Role of Androgen/Androgen Receptor Signaling via Chemokines on Prostate Cancer Cells
J. Clin. Med. 2019, 8(3), 354; https://doi.org/10.3390/jcm8030354
Received: 20 February 2019 / Revised: 10 March 2019 / Accepted: 11 March 2019 / Published: 13 March 2019
PDF Full-text (536 KB) | HTML Full-text | XML Full-text
Abstract
Androgen/androgen receptor (AR) signaling is a significant driver of prostate cancer progression, therefore androgen-deprivation therapy (ADT) is often used as a standard form of treatment for advanced and metastatic prostate cancer patients. However, after several years of ADT, prostate cancer progresses to castration-resistant [...] Read more.
Androgen/androgen receptor (AR) signaling is a significant driver of prostate cancer progression, therefore androgen-deprivation therapy (ADT) is often used as a standard form of treatment for advanced and metastatic prostate cancer patients. However, after several years of ADT, prostate cancer progresses to castration-resistant prostate cancer (CRPC). Androgen/AR signaling is still considered an important factor for prostate cancer cell survival following CRPC progression, while recent studies have reported dichotomic roles for androgen/AR signaling. Androgen/AR signaling increases prostate cancer cell proliferation, while simultaneously inhibiting migration. As a result, ADT can induce prostate cancer metastasis. Several C-C motif ligand (CCL)-receptor (CCR) axes are involved in cancer cell migration related to blockade of androgen/AR signaling. The CCL2-CCR2 axis is negatively regulated by androgen/AR signaling, with the CCL22-CCR4 axis acting as a further downstream mediator, both of which promote prostate cancer cell migration. Furthermore, the CCL5-CCR5 axis inhibits androgen/AR signaling as an upstream mediator. CCL4 is involved in prostate carcinogenesis through macrophage AR signaling, while the CCL21-CCR7 axis in prostate cancer cells is activated by tumor necrotic factor, which is secreted when androgen/AR signaling is inhibited. Finally, the CCL2-CCR2 axis has recently been demonstrated to be a key contributor to cabazitaxel resistance in CRPC. Full article
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Open AccessReview
Obesity, Inflammation, and Prostate Cancer
J. Clin. Med. 2019, 8(2), 201; https://doi.org/10.3390/jcm8020201
Received: 19 January 2019 / Revised: 2 February 2019 / Accepted: 4 February 2019 / Published: 6 February 2019
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Abstract
The prevalence of obesity is increasing in the world, and obesity-induced disease, insulin-resistance, cardiovascular disease, and malignancies are becoming a problem. Epidemiological studies have shown that obesity is associated with advanced prostate cancer and that obese men with prostate cancer have a poorer [...] Read more.
The prevalence of obesity is increasing in the world, and obesity-induced disease, insulin-resistance, cardiovascular disease, and malignancies are becoming a problem. Epidemiological studies have shown that obesity is associated with advanced prostate cancer and that obese men with prostate cancer have a poorer prognosis. Obesity induces systemic inflammation via several mechanisms. High-fat diet-induced prostate cancer progresses via adipose-secretory cytokines or chemokines. Inflammatory cells play important roles in tumor progression. A high-fat diet or obesity changes the local profile of immune cells, such as myeloid-derived suppressor cells and macrophages, in prostate cancer. Tumor-associated neutrophils, B cells, and complements may promote prostate cancer in the background of obesity. Interventions to control systemic and/or local inflammation and changes in lifestyle may also be viable therapies for prostate cancer. Full article
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Open AccessReview
Fibroblast Growth Factor Family in the Progression of Prostate Cancer
J. Clin. Med. 2019, 8(2), 183; https://doi.org/10.3390/jcm8020183
Received: 10 January 2019 / Revised: 23 January 2019 / Accepted: 31 January 2019 / Published: 4 February 2019
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Abstract
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) play an important role in the maintenance of tissue homeostasis and the development and differentiation of prostate tissue through epithelial-stromal interactions. Aberrations of this signaling are linked to the development and progression of prostate cancer [...] Read more.
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) play an important role in the maintenance of tissue homeostasis and the development and differentiation of prostate tissue through epithelial-stromal interactions. Aberrations of this signaling are linked to the development and progression of prostate cancer (PCa). The FGF family includes two subfamilies, paracrine FGFs and endocrine FGFs. Paracrine FGFs directly bind the extracellular domain of FGFRs and act as a growth factor through the activation of tyrosine kinase signaling. Endocrine FGFs have a low affinity of heparin/heparan sulfate and are easy to circulate in serum. Their biological function is exerted as both a growth factor binding FGFRs with co-receptors and as an endocrine molecule. Many studies have demonstrated the significance of these FGFs and FGFRs in the development and progression of PCa. Herein, we discuss the current knowledge regarding the role of FGFs and FGFRs—including paracrine FGFs, endocrine FGFs, and FGFRs—in the development and progression of PCa, focusing on the representative molecules in each subfamily. Full article
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Open AccessReview
The Importance of Time to Prostate-Specific Antigen (PSA) Nadir after Primary Androgen Deprivation Therapy in Hormone-Naïve Prostate Cancer Patients
J. Clin. Med. 2018, 7(12), 565; https://doi.org/10.3390/jcm7120565
Received: 26 November 2018 / Revised: 8 December 2018 / Accepted: 18 December 2018 / Published: 18 December 2018
PDF Full-text (882 KB) | HTML Full-text | XML Full-text
Abstract
Prostate-specific antigen (PSA) is currently the most useful biomarker for detection of prostate cancer (PCa). The ability to measure serum PSA levels has affected all aspects of PCa management over the past two decades. The standard initial systemic therapy for advanced PCa is [...] Read more.
Prostate-specific antigen (PSA) is currently the most useful biomarker for detection of prostate cancer (PCa). The ability to measure serum PSA levels has affected all aspects of PCa management over the past two decades. The standard initial systemic therapy for advanced PCa is androgen-deprivation therapy (ADT). Although PCa patients with metastatic disease initially respond well to ADT, they often progress to castration-resistant prostate cancer (CRPC), which has a high mortality rate. We have demonstrated that time to PSA nadir (TTN) after primary ADT is an important early predictor of overall survival and progression-free survival for advanced PCa patients. In in vivo experiments, we demonstrated that the presence of fibroblasts in the PCa tumor microenvironment can prolong the period for serum PSA decline after ADT, and enhance the efficacy of ADT. Clarification of the mechanisms that affect TTN after ADT could be useful to guide selection of optimal PCa treatment strategies. In this review, we discuss recent in vitro and in vivo findings concerning the involvement of stromal–epithelial interactions in the biological mechanism of TTN after ADT to support the novel concept of “tumor regulating fibroblasts”. Full article
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