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18 pages, 5214 KiB

Open AccessArticle

A Comprehensive Analysis of FUT8 Overexpressing Prostate Cancer Cells Reveals the Role of EGFR in Castration Resistance

by Naseruddin Höti, Tung-Shing Lih, Jianbo Pan, Yangying Zhou, Ganglong Yang, Ashely Deng, Lijun Chen, Mingmimg Dong, Ruey-Bing Yang, Cheng-Fen Tu, Michael C. Haffner, Qing Kay Li and Hui Zhang

Cancers 2020, 12(2), 468; https://doi.org/10.3390/cancers12020468 - 18 Feb 2020

Cited by 25 | Viewed by 4001

Abstract

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none [...] Read more.

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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13 pages, 1472 KiB

Open AccessArticle

Expression of GP88 (Progranulin) Protein Is an Independent Prognostic Factor in Prostate Cancer Patients

by Amer Abdulrahman, Markus Eckstein, Rudolf Jung, Juan Guzman, Katrin Weigelt, Ginette Serrero, Binbin Yue, Carol Geppert, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Sven Wach, Helge Taubert and Verena Lieb

Cancers 2019, 11(12), 2029; https://doi.org/10.3390/cancers11122029 - 16 Dec 2019

Cited by 9 | Viewed by 2692

Abstract

Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study [...] Read more.

Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS < 2) and 209 cases (47.3%) with positive GP88 staining (IRS ≥ 2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analyses (Kaplan–Meier, univariate and multivariate Cox’s regression analysis). Increased GP88 protein expression appeared as an independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (≤65 years), GP88 positivity was associated with a 3.8-fold (p = 0.004), a 6.0-fold (p = 0.008) and a 3.7-fold (p = 0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. In the PCa subgroup with negative CK20 staining, GP88 positivity was associated with a 1.8-fold (p = 0.018) and a 2.8-fold increased risk for death and disease-specific death (p = 0.028). Altogether, GP88 protein positivity appears to be an independent prognostic factor for PCa patients. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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18 pages, 5770 KiB

Open AccessArticle

Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer

by Shashwat Sharad, Zsófia M. Sztupinszki, Yongmei Chen, Claire Kuo, Lakshmi Ravindranath, Zoltan Szallasi, Gyorgy Petrovics, Taduru L. Sreenath, Albert Dobi, Inger L. Rosner, Alagarsamy Srinivasan, Shiv Srivastava, Jennifer Cullen and Hua Li

Cancers 2019, 11(12), 1995; https://doi.org/10.3390/cancers11121995 - 12 Dec 2019

Cited by 11 | Viewed by 3626

Abstract

Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. [...] Read more.

Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-β responsive PC3 cells. TGF-β signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-β-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-β signaling. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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21 pages, 6120 KiB

Open AccessArticle

Multi-Features Classification of Prostate Carcinoma Observed in Histological Sections: Analysis of Wavelet-Based Texture and Colour Features

by Subrata Bhattacharjee, Cho-Hee Kim, Hyeon-Gyun Park, Deekshitha Prakash, Nuwan Madusanka, Nam-Hoon Cho and Heung-Kook Choi

Cancers 2019, 11(12), 1937; https://doi.org/10.3390/cancers11121937 - 4 Dec 2019

Cited by 23 | Viewed by 10367

Abstract

Microscopic biopsy images are coloured in nature because pathologists use the haematoxylin and eosin chemical colour dyes for biopsy examinations. In this study, biopsy images are used for histological grading and the analysis of benign and malignant prostate tissues. The following PCa grades [...] Read more.

Microscopic biopsy images are coloured in nature because pathologists use the haematoxylin and eosin chemical colour dyes for biopsy examinations. In this study, biopsy images are used for histological grading and the analysis of benign and malignant prostate tissues. The following PCa grades are analysed in the present study: benign, grade 3, grade 4, and grade 5. Biopsy imaging has become increasingly important for the clinical assessment of PCa. In order to analyse and classify the histological grades of prostate carcinomas, pixel-based colour moment descriptor (PCMD) and gray-level co-occurrence matrix (GLCM) methods were used to extract the most significant features for multilayer perceptron (MLP) neural network classification. Haar wavelet transformation was carried out to extract GLCM texture features, and colour features were extracted from RGB (red/green/blue) colour images of prostate tissues. The MANOVA statistical test was performed to select significant features based on F-values and P-values using the R programming language. We obtained an average highest accuracy of 92.7% using level-1 wavelet texture and colour features. The MLP classifier performed well, and our study shows promising results based on multi-feature classification of histological sections of prostate carcinomas. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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14 pages, 3271 KiB

Open AccessArticle

Automated Gleason Scoring and Tumor Quantification in Prostate Core Needle Biopsy Images Using Deep Neural Networks and Its Comparison with Pathologist-Based Assessment

by Han Suk Ryu, Min-Sun Jin, Jeong Hwan Park, Sanghun Lee, Joonyoung Cho, Sangjun Oh, Tae-Yeong Kwak, Junwoo Isaac Woo, Yechan Mun, Sun Woo Kim, Soohyun Hwang, Su-Jin Shin and Hyeyoon Chang

Cancers 2019, 11(12), 1860; https://doi.org/10.3390/cancers11121860 - 25 Nov 2019

Cited by 41 | Viewed by 6466

Abstract

The Gleason grading system, currently the most powerful prognostic predictor of prostate cancer, is based solely on the tumor’s histological architecture and has high inter-observer variability. We propose an automated Gleason scoring system based on deep neural networks for diagnosis of prostate core [...] Read more.

The Gleason grading system, currently the most powerful prognostic predictor of prostate cancer, is based solely on the tumor’s histological architecture and has high inter-observer variability. We propose an automated Gleason scoring system based on deep neural networks for diagnosis of prostate core needle biopsy samples. To verify its efficacy, the system was trained using 1133 cases of prostate core needle biopsy samples and validated on 700 cases. Further, system-based diagnosis results were compared with reference standards derived from three certified pathologists. In addition, the system’s ability to quantify cancer in terms of tumor length was also evaluated via comparison with pathologist-based measurements. The results showed a substantial diagnostic concordance between the system-grade group classification and the reference standard (0.907 quadratic-weighted Cohen’s kappa coefficient). The system tumor length measurements were also notably closer to the reference standard (correlation coefficient, R = 0.97) than the original hospital diagnoses (R = 0.90). We expect this system to assist pathologists to reduce the probability of over- or under-diagnosis by providing pathologist-level second opinions on the Gleason score when diagnosing prostate biopsy, and to support research on prostate cancer treatment and prognosis by providing reproducible diagnosis based on the consistent standards. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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21 pages, 3235 KiB

Open AccessArticle

Characterization of HMGB1/2 Interactome in Prostate Cancer by Yeast Two Hybrid Approach: Potential Pathobiological Implications

by Aida Barreiro-Alonso, María Cámara-Quílez, Martín Salamini-Montemurri, Mónica Lamas-Maceiras, Ángel Vizoso-Vázquez, Esther Rodríguez-Belmonte, María Quindós-Varela, Olaia Martínez-Iglesias, Angélica Figueroa and María-Esperanza Cerdán

Cancers 2019, 11(11), 1729; https://doi.org/10.3390/cancers11111729 - 5 Nov 2019

Cited by 12 | Viewed by 4487

Abstract

High mobility group box B (HMGB) proteins are pivotal in the development of cancer. Although the proteomics of prostate cancer (PCa) cells has been reported, the involvement of HMGB proteins and their interactome in PCa is an unexplored field of considerable interest. We [...] Read more.

High mobility group box B (HMGB) proteins are pivotal in the development of cancer. Although the proteomics of prostate cancer (PCa) cells has been reported, the involvement of HMGB proteins and their interactome in PCa is an unexplored field of considerable interest. We describe herein the results of the first HMGB1/HMGB2 interactome approach to PCa. Libraries constructed from the PCa cell line, PC-3, and from patients’ PCa primary tumor have been screened by the yeast 2-hybrid approach (Y2H) using HMGB1 and HMGB2 baits. Functional significance of this PCa HMGB interactome has been validated through expression and prognosis data available on public databases. Copy number alterations (CNA) affecting these newly described HMGB interactome components are more frequent in the most aggressive forms of PCa: those of neuroendocrine origin or castration-resistant PCa. Concordantly, adenocarcinoma PCa samples showing CNA in these genes are also associated with the worse prognosis. These findings open the way to their potential use as discriminatory biomarkers between high and low risk patients. Gene expression of a selected set of these interactome components has been analyzed by qPCR after HMGB1 and HMGB2 silencing. The data show that HMGB1 and HMGB2 control the expression of several of their interactome partners, which might contribute to the orchestrated action of these proteins in PCa Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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25 pages, 1809 KiB

Open AccessArticle

A Novel Predictor Tool of Biochemical Recurrence after Radical Prostatectomy Based on a Five-MicroRNA Tissue Signature

by Zhongwei Zhao, Sabine Weickmann, Monika Jung, Michael Lein, Ergin Kilic, Carsten Stephan, Andreas Erbersdobler, Annika Fendler and Klaus Jung

Cancers 2019, 11(10), 1603; https://doi.org/10.3390/cancers11101603 - 21 Oct 2019

Cited by 24 | Viewed by 4505

Abstract

Within five to ten years after radical prostatectomy (RP), approximately 15–34% of prostate cancer (PCa) patients experience biochemical recurrence (BCR), which is defined as recurrence of serum levels of prostate-specific antigen >0.2 µg/L, indicating probable cancer recurrence. Models using clinicopathological variables for predicting [...] Read more.

Within five to ten years after radical prostatectomy (RP), approximately 15–34% of prostate cancer (PCa) patients experience biochemical recurrence (BCR), which is defined as recurrence of serum levels of prostate-specific antigen >0.2 µg/L, indicating probable cancer recurrence. Models using clinicopathological variables for predicting this risk for patients lack accuracy. There is hope that new molecular biomarkers, like microRNAs (miRNAs), could be potential candidates to improve risk prediction. Therefore, we evaluated the BCR prognostic capability of 20 miRNAs, which were selected by a systematic literature review. MiRNA expressions were measured in formalin-fixed, paraffin-embedded (FFPE) tissue RP samples of 206 PCa patients by RT-qPCR. Univariate and multivariate Cox regression analyses were performed, to assess the independent prognostic potential of miRNAs. Internal validation was performed, using bootstrapping and the split-sample method. Five miRNAs (miR-30c-5p/31-5p/141-3p/148a-3p/miR-221-3p) were finally validated as independent prognostic biomarkers. Their prognostic ability and accuracy were evaluated using C-statistics of the obtained prognostic indices in the Cox regression, time-dependent receiver-operating characteristics, and decision curve analyses. Models of miRNAs, combined with relevant clinicopathological factors, were built. The five-miRNA-panel outperformed clinically established BCR scoring systems, while their combination significantly improved predictive power, based on clinicopathological factors alone. We conclude that this miRNA-based-predictor panel will be worth to be including in future studies. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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13 pages, 2987 KiB

Open AccessArticle

Docetaxel Combined with Thymoquinone Induces Apoptosis in Prostate Cancer Cells via Inhibition of the PI3K/AKT Signaling Pathway

by Santosh Kumar Singh, Tejumola Apata, Jennifer B. Gordetsky and Rajesh Singh

Cancers 2019, 11(9), 1390; https://doi.org/10.3390/cancers11091390 - 18 Sep 2019

Cited by 44 | Viewed by 4946

Abstract

Toxicity and the development of resistance by cancer cells are impediments for docetaxel (DTX), a primary drug for treating prostate cancer (PCa). Since the combination of DTX with natural compounds can increase its effectiveness by reducing its toxic concentrations, we evaluated a combination [...] Read more.

Toxicity and the development of resistance by cancer cells are impediments for docetaxel (DTX), a primary drug for treating prostate cancer (PCa). Since the combination of DTX with natural compounds can increase its effectiveness by reducing its toxic concentrations, we evaluated a combination of thymoquinone (TQ) with DTX and determined its cytotoxicity against PCa cells (DU145 and C4-2B). This combination, in a concentration-dependent manner, resulted in synergistic cytotoxicity and apoptosis in comparison to either DTX or TQ alone. In addition, inhibition of cell survival pathways by PI3K/AKT inhibitors conferred sensitivity of DU145 and C4-2B cells to the combination as compared to the individual drugs. Moreover, the combined drugs (DTX+TQ) with inhibitors of PI3K/AKT increased the expression of pro-apoptotic markers (BAX and BID) along with caspase-3, PARP and decreased expression of the anti-apoptotic marker, BCL-XL. These data show that, for PCa cells, the cytotoxic effect of the DTX and TQ combination correlates with a block of the PI3K/AKT signaling pathway. These findings indicate that the combination of DTX and TQ, by blocking of the PI3K/AKT pathway, will improve the survival rate and quality of life of PCa patients. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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16 pages, 1580 KiB

Open AccessArticle

Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer

by Bogdan Mitran, Zohreh Varasteh, Ayman Abouzayed, Sara S. Rinne, Emmi Puuvuori, Maria De Rosa, Mats Larhed, Vladimir Tolmachev, Anna Orlova and Ulrika Rosenström

Cancers 2019, 11(9), 1371; https://doi.org/10.3390/cancers11091371 - 14 Sep 2019

Cited by 34 | Viewed by 5307

Abstract

Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging [...] Read more.

Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis. NOTA-DUPA-RM26 was labeled with ¹¹¹In and ⁶⁸Ga, with yields >98%, and demonstrated a high stability and binding specificity to PSMA and GRPR. IC₅₀ values for ^natIn-NOTA-DUPA-RM26 were 4 ± 1 nM towards GRPR and 824 ± 230 nM towards PSMA. An in vivo binding specificity 1 h pi of ¹¹¹In-NOTA-DUPA-RM26 in PC3-PIP-xenografted mice demonstrated partially blockable tumor uptake when co-injected with an excess of PSMA- or GRPR-targeting agents. Simultaneous co-injection of both agents induced pronounced blocking. The biodistribution of ¹¹¹In-NOTA-DUPA-RM26 and ⁶⁸Ga-NOTA-DUPA-RM26 revealed fast activity clearance from the blood and normal organs via the kidneys. Tumor uptake exceeded normal organ uptake for both analogs 1 h pi. ⁶⁸Ga-NOTA-DUPA-RM26 had a significantly lower tumor uptake (8 ± 2%ID/g) compared to ¹¹¹In-NOTA-DUPA-RM26 (12 ± 2%ID/g) 1 h pi. Tumor-to-organ ratios increased 3 h pi, but decreased 24 h pi, for ¹¹¹In-NOTA-DUPA-RM26. MicroPET/CT and microSPECT/CT scans confirmed biodistribution data, suggesting that ⁶⁸Ga-NOTA-DUPA-RM26 and ¹¹¹In-NOTA-DUPA-RM26 are suitable candidates for the imaging of GRPR and PSMA expression in PCa shortly after administration. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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10 pages, 1658 KiB

Open AccessArticle

Role of Circulating Tumor Cells (CTC), Androgen Receptor Full Length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a Prospective Cohort of Castration-Resistant Metastatic Prostate Cancer Patients

by Carlo Cattrini, Alessandra Rubagotti, Linda Zinoli, Luigi Cerbone, Elisa Zanardi, Matteo Capaia, Paola Barboro and Francesco Boccardo

Cancers 2019, 11(9), 1365; https://doi.org/10.3390/cancers11091365 - 13 Sep 2019

Cited by 24 | Viewed by 3567

Abstract

Background: Circulating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi). Methods: We assessed the association of [...] Read more.

Background: Circulating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi). Methods: We assessed the association of CTC, AR-FL, and AR-V7 with prostate-specific antigen (PSA) response and overall survival (OS). We used a modified AdnaTest CTC-based AR-FL and AR-V7 mRNA assay. Chi-square test, Fisher Exact test, Kaplan–Meier method, log-rank test, Cox proportional hazards models were used as appropriate. Results: We enrolled 39 mCRPC pts, of those 24 started a first-line treatment for mCRPC (1L subgroup) and 15 had received at least two lines for mCRPC (>2L subgroup). CTC, AR-FL, and AR-V7 were enriched in >2L compared to 1L subgroup. Detection of these biomarkers was associated with a lower percentage of biochemical responses. Only 1/7 AR-V7+ pts had a PSA response and received cabazitaxel. Median OS was 4.7 months (95% CI 0.6–8.9) in AR-V7+ pts and not reached in AR-V7− pts. AR-V7 was the only variable with prognostic significance in the Cox model. Conclusion: AR-V7, CTC, and AR-FL are associated with advanced mCRPC and AR-V7+ predicts for shorter OS. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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9 pages, 1080 KiB

Open AccessArticle

Increased Soluble CMG2 Serum Protein Concentration Is Associated with the Progression of Prostate Carcinoma

by Thomas Greither, Marios Marcou, Paolo Fornara and Hermann M. Behre

Cancers 2019, 11(8), 1059; https://doi.org/10.3390/cancers11081059 - 26 Jul 2019

Cited by 2 | Viewed by 2881

Abstract

Prostate carcinoma (PCa) is one of the leading causes of cancer-related death in males, but biomarkers for the prognosis are rare. Capillary morphogenesis gene 2 (CMG2) is a modulator of extracellular matrix remodeling during angiogenesis. Four isoforms of CMG2 have been described so [...] Read more.

Prostate carcinoma (PCa) is one of the leading causes of cancer-related death in males, but biomarkers for the prognosis are rare. Capillary morphogenesis gene 2 (CMG2) is a modulator of extracellular matrix remodeling during angiogenesis. Four isoforms of CMG2 have been described so far, one secreted in the serum as soluble CMG2 (sCMG2). The aim of this study was to evaluate the sCMG2 serum concentrations in 179 PCa patients and 163 age-matched control subjects by ELISA and correlate it to clinical and demographic parameters. We observed that sCMG2 concentration is increased in the serum of PCa patients with metastases, while no significant differences in the concentrations were detected between the control subjects and patients with localized PCa. Furthermore, elevated sCMG2 concentrations were significantly associated with the highest T stage. Increased sCMG2 serum concentrations tended to be associated with a worsened overall and disease-specific survival of the PCa patients. In conclusion, sCMG2 may be an interesting additive biomarker for the prediction of the progression of PCa and the patients’ outcome. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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23 pages, 4659 KiB

Open AccessArticle

Nerve Growth Factor Induces Proliferation and Aggressiveness in Prostate Cancer Cells

by Marzia Di Donato, Gustavo Cernera, Antimo Migliaccio and Gabriella Castoria

Cancers 2019, 11(6), 784; https://doi.org/10.3390/cancers11060784 - 6 Jun 2019

Cited by 53 | Viewed by 15447

Abstract

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effects, but PC gradually develops resistance, relapses and spreads. Most patients who fail primary [...] Read more.

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effects, but PC gradually develops resistance, relapses and spreads. Most patients who fail primary therapy and have recurrences eventually develop castration-resistant prostate cancer (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, tropomyosin receptor kinase A (TrkA). NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its crosstalk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchymal transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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Review

Jump to: Research

26 pages, 1161 KiB

Open AccessReview

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

by Sirin Saranyutanon, Sanjeev Kumar Srivastava, Sachin Pai, Seema Singh and Ajay Pratap Singh

Cancers 2020, 12(1), 51; https://doi.org/10.3390/cancers12010051 - 23 Dec 2019

Cited by 42 | Viewed by 8345

Abstract

Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the [...] Read more.

Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the men of European origin. Since androgens play an important role in the growth of normal prostate and prostate tumors, targeting of androgen signaling has remained a mainstay for the treatment of aggressive prostate cancer. Over the years, multiple approaches have been evaluated to effectively target the androgen signaling pathway that include direct targeting of the androgens, androgen receptor (AR), AR co-regulators or other alternate mechanisms that impact the outcome of androgen signaling. Several of these approaches are currently in clinical practice, while some are still pending further development and clinical evaluation. This remarkable progress has resulted from extensive laboratory, pre-clinical and clinical efforts, and mechanistic learnings from the therapeutic success and failures. In this review, we describe the importance of androgen signaling in prostate cancer biology and advances made over the years to effectively target this signaling pathway. We also discuss emerging data on the resistance pathways associated with the failure of various androgen signaling- targeted therapies and potential of this knowledge for translation into future therapies for prostate cancer. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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18 pages, 1884 KiB

Open AccessReview

How Prostate Cancer Cells Use Strategy Instead of Brute Force to Achieve Metastasis

by Darron Tharp and Srinivas Nandana

Cancers 2019, 11(12), 1928; https://doi.org/10.3390/cancers11121928 - 3 Dec 2019

Cited by 5 | Viewed by 5994

Abstract

Akin to many other cancers, metastasis is the predominant cause of lethality in prostate cancer (PCa). Research in the past decade or so has revealed that although metastatic manifestation is a multi-step and complex process that is orchestrated by distinct cellular and molecular [...] Read more.

Akin to many other cancers, metastasis is the predominant cause of lethality in prostate cancer (PCa). Research in the past decade or so has revealed that although metastatic manifestation is a multi-step and complex process that is orchestrated by distinct cellular and molecular mechanisms, the process in itself is an extremely inefficient one. It is now becoming increasingly evident that PCa cells employ a plethora of strategies to make the most of this inefficient process. These strategies include priming the metastatic sites ahead of colonization, devising ways to metastasize to specific organs, outsmarting the host defense surveillance, lying in a dormant state at the metastatic site for prolonged periods, and widespread reprogramming of the gene expression to suit their needs. Based on established, recent, and evolving lines of research, this review is an attempt to understand PCa metastasis from the perspective of military combat, wherein strategic maneuvering instead of brute force often plays a decisive role in the outcome. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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22 pages, 3801 KiB

Open AccessReview

Racial Differences in Immunological Landscape Modifiers Contributing to Disparity in Prostate Cancer

by Jeronay King Thomas, Hina Mir, Neeraj Kapur and Shailesh Singh

Cancers 2019, 11(12), 1857; https://doi.org/10.3390/cancers11121857 - 25 Nov 2019

Cited by 28 | Viewed by 4916

Abstract

Prostate cancer affects African Americans disproportionately by exhibiting greater incidence, rapid disease progression, and higher mortality when compared to their Caucasian counterparts. Additionally, standard treatment interventions do not achieve similar outcome in African Americans compared to Caucasian Americans, indicating differences in host factors [...] Read more.

Prostate cancer affects African Americans disproportionately by exhibiting greater incidence, rapid disease progression, and higher mortality when compared to their Caucasian counterparts. Additionally, standard treatment interventions do not achieve similar outcome in African Americans compared to Caucasian Americans, indicating differences in host factors contributing to racial disparity. African Americans have allelic variants and hyper-expression of genes that often lead to an immunosuppressive tumor microenvironment, possibly contributing to more aggressive tumors and poorer disease and therapeutic outcomes than Caucasians. In this review, we have discussed race-specific differences in external factors impacting internal milieu, which modify immunological topography as well as contribute to disparity in prostate cancer. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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18 pages, 2552 KiB

Open AccessReview

Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

by Baylee A. Porter, Maria A. Ortiz, Gennady Bratslavsky and Leszek Kotula

Cancers 2019, 11(12), 1852; https://doi.org/10.3390/cancers11121852 - 23 Nov 2019

Cited by 47 | Viewed by 15413

Abstract

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, [...] Read more.

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer, the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible to develop than others due to the ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT). Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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27 pages, 1459 KiB

Open AccessReview

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

by Girijesh Kumar Patel, Natasha Chugh and Manisha Tripathi

Cancers 2019, 11(10), 1405; https://doi.org/10.3390/cancers11101405 - 20 Sep 2019

Cited by 73 | Viewed by 12002

Abstract

Our understanding of neuroendocrine prostate cancer (NEPC) has assumed a new perspective in light of the recent advances in research. Although classical NEPC is rarely seen in the clinic, focal neuroendocrine trans-differentiation of prostate adenocarcinoma occurs in about 30% of advanced prostate cancer [...] Read more.

Our understanding of neuroendocrine prostate cancer (NEPC) has assumed a new perspective in light of the recent advances in research. Although classical NEPC is rarely seen in the clinic, focal neuroendocrine trans-differentiation of prostate adenocarcinoma occurs in about 30% of advanced prostate cancer (PCa) cases, and represents a therapeutic challenge. Even though our knowledge of the mechanisms that mediate neuroendocrine differentiation (NED) is still evolving, the role of androgen deprivation therapy (ADT) as a key driver of this phenomenon is increasingly becoming evident. In this review, we discuss the molecular, cellular, and therapeutic mediators of NED, and emphasize the role of the tumor microenvironment (TME) in orchestrating the phenotype. Understanding the role of the TME in mediating NED could provide us with valuable insights into the plasticity associated with the phenotype, and reveal potential therapeutic targets against this aggressive form of PCa. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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20 pages, 363 KiB

Open AccessEditor’s ChoiceReview

Current Treatment Options for Metastatic Hormone-Sensitive Prostate Cancer

by Carlo Cattrini, Elena Castro, Rebeca Lozano, Elisa Zanardi, Alessandra Rubagotti, Francesco Boccardo and David Olmos

Cancers 2019, 11(9), 1355; https://doi.org/10.3390/cancers11091355 - 12 Sep 2019

Cited by 57 | Viewed by 10001

Abstract

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase [...] Read more.

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient’s risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

36 pages, 14714 KiB

Open AccessReview

The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer

by Abdullah Hoter, Sandra Rizk and Hassan Y. Naim

Cancers 2019, 11(8), 1194; https://doi.org/10.3390/cancers11081194 - 16 Aug 2019

Cited by 47 | Viewed by 8318

Abstract

Prostate cancer (PCa) is one of the most common cancer types in men worldwide. Heat shock proteins (HSPs) are molecular chaperones that are widely implicated in the pathogenesis, diagnosis, prognosis, and treatment of many cancers. The role of HSPs in PCa is complex [...] Read more.

Prostate cancer (PCa) is one of the most common cancer types in men worldwide. Heat shock proteins (HSPs) are molecular chaperones that are widely implicated in the pathogenesis, diagnosis, prognosis, and treatment of many cancers. The role of HSPs in PCa is complex and their expression has been linked to the progression and aggressiveness of the tumor. Prominent chaperones, including HSP90 and HSP70, are involved in the folding and trafficking of critical cancer-related proteins. Other members of HSPs, including HSP27 and HSP60, have been considered as promising biomarkers, similar to prostate-specific membrane antigen (PSMA), for PCa screening in order to evaluate and monitor the progression or recurrence of the disease. Moreover, expression level of chaperones like clusterin has been shown to correlate directly with the prostate tumor grade. Hence, targeting HSPs in PCa has been suggested as a promising strategy for cancer therapy. In the current review, we discuss the functions as well as the role of HSPs in PCa progression and further evaluate the approach of inhibiting HSPs as a cancer treatment strategy. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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16 pages, 626 KiB

Open AccessReview

Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate Cancer

by Takuji Hayashi, Kazutoshi Fujita, Makoto Matsushita and Norio Nonomura

Cancers 2019, 11(8), 1153; https://doi.org/10.3390/cancers11081153 - 12 Aug 2019

Cited by 39 | Viewed by 8871

Abstract

Prostate cancer is the most common type of cancer and the leading cause of cancer deaths among men in many countries. Preventing progression is a major concern for prostate cancer patients on active surveillance, patients with recurrence after radical therapies, and patients who [...] Read more.

Prostate cancer is the most common type of cancer and the leading cause of cancer deaths among men in many countries. Preventing progression is a major concern for prostate cancer patients on active surveillance, patients with recurrence after radical therapies, and patients who acquired resistance to systemic therapies. Inflammation, which is induced by various factors such as infection, microbiome, obesity, and a high-fat diet, is the major etiology in the development of prostate cancer. Inflammatory cells play important roles in tumor progression. Various immune cells including tumor-associated neutrophils, tumor-infiltrating macrophages, myeloid-derived suppressor cells, and mast cells promote prostate cancer via various intercellular signaling. Further basic studies examining the relationship between the inflammatory process and prostate cancer progression are warranted. Interventions by medications and diets to control systemic and/or local inflammation might be effective therapies for prostate cancer progression. Epidemiological investigations and basic research using human immune cells or mouse models have revealed that non-steroidal anti-inflammatory drugs, metformin, statins, soy isoflavones, and other diets are potential interventions for preventing progression of prostate cancer by suppressing inflammation. It is essential to evaluate appropriate indications and doses of each drug and diet. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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