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Cancers
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Cytokine and Steroid Hormone Signaling in Prostate Cancer
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Cytokine and Steroid Hormone Signaling in Prostate Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 27047

Special Issue Editors

Prof. Dr. Marja T. Nevalainen

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Guest Editor
Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Interests: prostate cancer; jak-stat signaling; androgen receptor; therapy development; biomarkers/predictive markers; clinical trials; radiation and dna-repair
Prof. Scott Dehm

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Guest Editor
Professor and Apogee Enterprises Chair in Cancer Research, Department of Laboratory Medicine and Pathology, University of Minnesota Twin Cities, Minneapolis, MN, USA
Interests: prostate cancer; androgen receptor signaling; molecular pathology and genomic engineering
Prof. Dr. Vincent C. O. Njar

E-Mail Website
Guest Editor
Department of Pharmacology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
Interests: prostate cancer; medicinal chemistry; oncopharmacology; anti-cancer drug discovery and development

Special Issue Information

Dear Colleagues,

Currently, one out of every five US men is diagnosed with prostate cancer, therefore representing a significant public health burden. The standard treatment for localized prostate cancer is surgery or radiation therapy. However, after these treatments, approximately 30–60% of prostate cancer patients experience biochemical disease recurrence as evidenced by rising post-operative serum PSA levels, which triggers follow-up treatments aiming to prevent clinical prostate cancer recurrence and development of metastatic lethal disease. Androgen deprivation therapy (ADT) is the predominant treatment for advanced prostate cancer A major challenge in the management of advanced prostate cancer is progression of the disease to lethal castrate-resistant prostate cancer in virtually all patients. In the majority of cases, castrate-resistant prostate cancer results from a failure of ADT to maintain durable suppression of androgen receptor (AR), which is the molecular target of ADT. This is supported by the clinical observation that AR is the most frequently altered gene in castrate-resistant prostate cancer genomes, AR is persistently expressed in the nucleus of the majority of the cells in castrate-resistant prostate tumors, and serum levels of the AR target gene, PSA, continue to rise in these patients. More potent second-generation AR antagonists (such as enzalutamide, apalutamide, and darolutamide) were developed to re-target the persistent AR activity in castrate-resistant prostate cancer and have become the standard of care in this setting. Mechanisms underlying prostate cancer resistance to anti-androgens are incompletely understood. The current proposed mechanisms include emergence of AR splice variants, glucocorticoid receptor expression, a ligand-binding domain mutation F876L in the AR that promotes an antagonist-to-agonist switch of anti-androgens, neuroendocrine differentiation, and cytokine signaling that induces prostate cancer growth either via AR or independently of the AR. However, no single mechanism has been reliably shown to completely account for progression of castrate-resistant prostate cancer, and it is likely that additional molecular mechanisms are involved.

For this Special Issue, we invite authors to submit contributions that provide novel findings in steroid receptor and cytokine signaling in prostate cancer and pharmacological targeting of the associated mechanisms for therapy development for castrate-resistant prostate cancer.

Prof. Marja T. Nevalainen
Prof. Scott Dehm
Prof. Vincent C. O. Njar
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • prostate cancer
  • castrate-resistant growth
  • metastases
  • androgen receptor
  • glucocorticoid receptor
  • cytokines
  • transmembrane receptors
  • cell signaling
  • pharmacological targeting
  • neuroendocrine differentiation
  • lineage plasticity
  • prostate cancer stem cells
  • stemness inhibitors

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Published Papers (6 papers)

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Research

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25 pages, 4422 KiB  
Article
Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells
by Manon Baures, Emilia Puig Lombardi, Delphine Di Martino, Wail Zeitouni, Emeline Pacreau, Leïla Dos Santos, Charles Dariane, Florence Boutillon, Jacques-Emmanuel Guidotti and Vincent Goffin
Cancers 2022, 14(15), 3775; https://doi.org/10.3390/cancers14153775 - 3 Aug 2022
Cited by 9 | Viewed by 3014
Abstract
Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of [...] Read more.
Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSCmed cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSCmed cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSCmed cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSCmed marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSCmed cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSCmed cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
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13 pages, 1598 KiB  
Article
Identification of a Steroid Hormone-Associated Gene Signature Predicting the Prognosis of Prostate Cancer through an Integrative Bioinformatics Analysis
by Yo-Liang Lai, Chia-Hsin Liu, Shu-Chi Wang, Shu-Pin Huang, Yi-Chun Cho, Bo-Ying Bao, Chia-Cheng Su, Hsin-Chih Yeh, Cheng-Hsueh Lee, Pai-Chi Teng, Chih-Pin Chuu, Deng-Neng Chen, Chia-Yang Li and Wei-Chung Cheng
Cancers 2022, 14(6), 1565; https://doi.org/10.3390/cancers14061565 - 19 Mar 2022
Cited by 4 | Viewed by 3178
Abstract
The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, [...] Read more.
The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, we sought to identify core genes in regulating steroid hormone pathways and associating them with the disease progression of PC. The selection of steroid hormone-associated genes was identified from functional databases, including gene ontology, KEGG, and Reactome. The gene expression profiles and relevant clinical information of patients with PC were obtained from TCGA and used to examine the genes associated with steroid hormone. The machine-learning algorithm was performed for key feature selection and signature construction. With the integrative bioinformatics analysis, an eight-gene signature, including CA2, CYP2E1, HSD17B, SSTR3, SULT1E1, TUBB3, UCN, and UGT2B7 was established. Patients with higher expression of this gene signature had worse progression-free interval in both univariate and multivariate cox models adjusted for clinical variables. The expression of the gene signatures also showed the aggressiveness consistently in two external cohorts, PCS and PAM50. Our findings demonstrated a validated eight-gene signature could successfully predict PC prognosis and regulate the steroid hormone pathway. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
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11 pages, 988 KiB  
Article
Integrating Serum Biomarkers into Prediction Models for Biochemical Recurrence Following Radical Prostatectomy
by Shirin Moghaddam, Amirhossein Jalali, Amanda O’Neill, Lisa Murphy, Laura Gorman, Anne-Marie Reilly, Áine Heffernan, Thomas Lynch, Richard Power, Kieran J. O’Malley, Kristin A. Taskèn, Viktor Berge, Vivi-Ann Solhaug, Helmut Klocker, T. Brendan Murphy and R. William Watson
Cancers 2021, 13(16), 4162; https://doi.org/10.3390/cancers13164162 - 19 Aug 2021
Cited by 6 | Viewed by 3573
Abstract
This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The [...] Read more.
This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The Cox proportional hazard model with stepwise selection technique was used to develop the model. Model evaluation was quantified by the AUC, calibration, and decision curve analysis. Cross-validation techniques were used to prevent overfitting in the Irish training cohort, and the Austrian and Norwegian independent cohorts were used as validation cohorts. The integration of serum biomarkers with the clinical variables (AUC = 0.695) improved significantly the predictive ability of BCR compared to the clinical variables (AUC = 0.604) or biomarkers alone (AUC = 0.573). This model was well calibrated and demonstrated a significant improvement in the predictive ability in the Austrian and Norwegian validation cohorts (AUC of 0.724 and 0.606), compared to the clinical model (AUC of 0.665 and 0.511). This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict BCR. This model can be employed prior to treatment and could improve clinical decision making, impacting on patients’ outcomes and quality of life. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
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24 pages, 5202 KiB  
Article
Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo
by Cristina Maranto, Vindhya Udhane, Jing Jia, Ranjit Verma, Gerhard Müller-Newen, Peter S. LaViolette, Michael Pereckas, Lavannya Sabharwal, Scott Terhune, Nagarajan Pattabiraman, Vincent C.O. Njar, John D. Imig, Liang Wang and Marja T. Nevalainen
Cancers 2020, 12(11), 3412; https://doi.org/10.3390/cancers12113412 - 18 Nov 2020
Cited by 4 | Viewed by 3276
Abstract
Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo [...] Read more.
Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs. genetic Stat5 knockdown was evaluated by RNA-seq analysis, which showed high similarity with the Pearson correlation coefficient ranging from 0.98–0.99. The potency of IST5 vs. its derivative lacking the phosphate group in suppressing Stat5 was evaluated in two separate but complementary assays. The inhibitory activity of IST5 against kinases was investigated in cell-free assays followed by more focused evaluation in a cell-based assay. IST5 has no specific inhibitory activity against 54 kinases, while suppressing Stat5 phosphorylation and subsequent dimerization in PC cells. The phosphate group was not critical for the biological activity of IST5 in cells. The acute, sub-chronic and chronic toxicity studies of IST5 were carried out in mice. IST5 did not cause any significant toxic effects or changes in the blood profiles. The present work supports further optimization of IST5 for oral bioavailability for clinical development for therapies for solid tumors, hematological and myeloproliferative disorders. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
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Review

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17 pages, 363 KiB  
Review
Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies
by Aasems Jacob, Rishi Raj, Derek B. Allison and Zin W. Myint
Cancers 2021, 13(21), 5417; https://doi.org/10.3390/cancers13215417 - 28 Oct 2021
Cited by 58 | Viewed by 7158
Abstract
Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival [...] Read more.
Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
31 pages, 1327 KiB  
Review
Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?
by Paul Beinhoff, Lavannya Sabharwal, Vindhya Udhane, Cristina Maranto, Peter S. LaViolette, Kenneth M. Jacobsohn, Susan Tsai, Kenneth A. Iczkowski, Liang Wang, William A. Hall, Scott M. Dehm, Deepak Kilari and Marja T. Nevalainen
Cancers 2021, 13(20), 5204; https://doi.org/10.3390/cancers13205204 - 17 Oct 2021
Cited by 13 | Viewed by 5774
Abstract
Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to [...] Read more.
Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
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