scholarly journals Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy!

2018 ◽  
Author(s):  
Leslie C. Costello ◽  
Renty B. Franklin
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Prostate Gland ◽  
Peripheral Zone ◽  
Metabolic Function ◽  
Androgen Ablation ◽  
Prolactin Signaling ◽  
Maintenance Metabolism

Hormone-independent malignancy is a major issue of morbidity and deaths that confronts prostate cancer. Despite decades of research, the oncogenic and hormonal implications in the development and progression of prostate malignancy remain mostly speculative. This is largely due to the absence and/or lack of consideration by contemporary clinicians and biomedical investigators regarding the established implications of the co-regulation of testosterone and prolactin in the development, maintenance, metabolism and functions of the prostate gland. Especially relevant is the major metabolic function of production of high levels of citrate by the peripheral zone acinar epithelial cells. Citrate production, along with growth and proliferation by these cells, is regulated by co-existing testosterone and prolactin signaling pathways; and by the oncogenic down-regulation of ZIP1 transporter/zinc/citrate in the development of malignancy. These relationships had not been considered in the issues of hormonedependent malignancy. This review provides the relevant background that has established the dual role of testosterone and prolactin regulation of the prostate gland; which is essential to address the implications in the oncogenic development and progression of hormone-dependent malignancy. The oncogenic factor along with testosterone-dependent and prolactin-dependent relationships leads to the plausible concept that androgen ablation for the treatment of testosterone-dependent malignancy results in the development of prolactin-dependent malignancy; which is testosterone-independent malignancy. Consequently, both testosterone ablation and prolactin ablation are required to prevent and/or abort terminal hormonedependent prostate cancer.

scholarly journals Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault.

2002 ◽  
pp. 61-73 ◽  
Author(s):  
J T Arnold ◽  
J T Isaacs
Keyword(s):  
Prostate Cancer ◽  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Stromal Cells ◽  
Growth Control ◽  
Death Sentence ◽  
Control Mechanisms ◽  
Androgen Ablation ◽  
Androgen Independent

The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote "It is not the cell itself that is disorderly, but its relationship with the rest of the tissue". We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention.

scholarly journals Signaling Pathways That Control Apoptosis in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 937
Author(s):  
Amaal Ali ◽  
George Kulik
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Receptor Activation ◽  
Castration Resistant Prostate Cancer ◽  
Paracrine Factors ◽  
Androgen Independence ◽  
Androgen Ablation ◽  
Prostate Epithelial Cells

Prostate cancer is the second most common malignancy and the fifth leading cancer-caused death in men worldwide. Therapies that target the androgen receptor axis induce apoptosis in normal prostates and provide temporary relief for advanced disease, yet prostate cancer that acquired androgen independence (so called castration-resistant prostate cancer, CRPC) invariably progresses to lethal disease. There is accumulating evidence that androgen receptor signaling do not regulate apoptosis and proliferation in prostate epithelial cells in a cell-autonomous fashion. Instead, androgen receptor activation in stroma compartments induces expression of unknown paracrine factors that maintain homeostasis of the prostate epithelium. This paradigm calls for new studies to identify paracrine factors and signaling pathways that control the survival of normal epithelial cells and to determine which apoptosis regulatory molecules are targeted by these pathways. This review summarizes the recent progress in understanding the mechanism of apoptosis induced by androgen ablation in prostate epithelial cells with emphasis on the roles of BCL-2 family proteins and “druggable” signaling pathways that control these proteins. A summary of the clinical trials of inhibitors of anti-apoptotic signaling pathways is also provided. Evidently, better knowledge of the apoptosis regulation in prostate epithelial cells is needed to understand mechanisms of androgen-independence and implement life-extending therapies for CRPC.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals LINC01006 facilitates cell proliferation, migration and invasion in prostate cancer through targeting miR-34a-5p to up-regulate DAAM1

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Enhui Ma ◽  
Qianqian Wang ◽  
Jinhua Li ◽  
Xinqi Zhang ◽  
Zhenjia Guo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Gland ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Protein Coding ◽  
Novel Target

Abstract Background Prostate cancer (PCa) is a kind of malignancy occurring in the prostate gland. Substantial researches have proved the major role of long noncoding RNAs (lncRNAs) in PCa. However, the role of long intergenic non-protein coding RNA 1006 (LINC01006) in PCa has not been investigated yet. Methods RT-qPCR was used to examine the expression levels of LINC01006 and its downstream targets. The function of LINC01006 in PCa was tested by in vitro and in vivo assays. With application of RNA pull down, RNA immunoprecipitation (RIP) and luciferase reporter assays, the interaction among LINC01006, miR-34a-5p and disheveled associated activator of morphogenesis 1 (DAAM1) were verified. Results LINC01006 expression presented high in PCa cell lines. LINC01006 silencing suppressed cell proliferative, migratory, invasive capacities while accelerated apoptotic rate. Besides, LINC01006 knockdown also suppressed tumor growth and metastasis in vivo. Furthermore, miR-34a-5p, a tumor suppressor in PCa, was sponged by LINC01006. Moreover, DAAM1 was targeted by miR-34a-5p and promoted PCa progression. More intriguingly, rescue assays suggested that the inhibitory effect of LINC01006 knockdown on PCa development was offset by DAAM1 overexpression. Conclusions LINC01006 promoted PCa progression by sponging miR-34a-5p to up-regulate DAAM1, providing a novel target for PCa therapy.

The role of WNT10B in normal prostate gland development and prostate cancer

The Prostate ◽  
2019 ◽  
Vol 79 (14) ◽  
pp. 1692-1704 ◽  
Author(s):  
Ikenna Madueke ◽  
Wen‐Yang Hu ◽  
Danping Hu ◽  
Steven M. Swanson ◽  
Donald Vander Griend ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Gland ◽  
Normal Prostate ◽  
Gland Development

Vitamin D and prostate cancer: The role of membrane initiated signaling pathways in prostate cancer progression

2010 ◽  
Vol 121 (1-2) ◽  
pp. 413-416 ◽  
Author(s):  
Sandra Karlsson ◽  
Josefin Olausson ◽  
Dan Lundh ◽  
Peter Sögård ◽  
Abul Mandal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Prostate Cancer Progression

scholarly journals Inducible Expression of Human β-Defensin 2 byFusobacterium nucleatum in Oral Epithelial Cells: Multiple Signaling Pathways and Role of Commensal Bacteria in Innate Immunity and the Epithelial Barrier

2000 ◽  
Vol 68 (5) ◽  
pp. 2907-2915 ◽  
Author(s):  
Suttichai Krisanaprakornkit ◽  
Janet R. Kimball ◽  
Aaron Weinberg ◽  
Richard P. Darveau ◽  
Brian W. Bainbridge ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cell Wall ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Inducible Expression ◽  
Periodontal Pathogen ◽  
Gingival Tissue ◽  
Necrosis Factor Alpha ◽  
Tnf Α

ABSTRACT Human gingival epithelial cells (HGE) express two antimicrobial peptides of the β-defensin family, human β-defensin 1 (hBD-1) and hBD-2, as well as cytokines and chemokines that contribute to innate immunity. In the present study, the expression and transcriptional regulation of hBD-2 was examined. HBD-2 mRNA was induced by cell wall extract of Fusobacterium nucleatum, an oral commensal microorganism, but not by that of Porphyromonas gingivalis, a periodontal pathogen. HBD-2 mRNA was also induced by the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) and phorbol myristate acetate (PMA), an epithelial cell activator. HBD-2 mRNA was also expressed in 14 of 15 noninflamed gingival tissue samples. HBD-2 peptide was detected by immunofluorescence in HGE stimulated with F. nucleatum cell wall, consistent with induction of the mRNA by this stimulant. Kinetic analysis indicates involvement of multiple distinct signaling pathways in the regulation of hBD-2 mRNA; TNF-α and F. nucleatum cell wall induced hBD-2 mRNA rapidly (2 to 4 h), while PMA stimulation was slower (∼10 h). In contrast, each stimulant induced interleukin 8 (IL-8) within 1 h. The role of TNF-α as an intermediary in F. nucleatum signaling was ruled out by addition of anti-TNF-α that did not inhibit hBD-2 induction. However, inhibitor studies show that F. nucleatum stimulation of hBD-2 mRNA requires both new gene transcription and new protein synthesis. Bacterial lipopolysaccharides isolated from Escherichia coli andF. nucleatum were poor stimulants of hBD-2, although they up-regulated IL-8 mRNA. Collectively, our findings show inducible expression of hBD-2 mRNA via multiple pathways in HGE in a pattern that is distinct from that of IL-8 expression. We suggest that different aspects of innate immune responses are differentially regulated and that commensal organisms have a role in stimulating mucosal epithelial cells in maintaining the barrier that contributes to homeostasis and host defense.

Prostate epithelial cell differentiation and its relevance to the understanding of prostate cancer therapies

2004 ◽  
Vol 108 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Ronan M. LONG ◽  
Colm MORRISSEY ◽  
John M. FITZPATRICK ◽  
R. William G. WATSON
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Prostate Gland ◽  
Western World ◽  
Cancer Therapies ◽  
Normal Prostate ◽  
Full Characterization ◽  
Prostate Epithelial Cells ◽  
Common Malignancy

Prostate cancer is the most common malignancy in males in the western world. However, little is known about its origin and development. This review highlights the biology of the normal prostate gland and the differentiation of basal epithelial cells to a secretory phenotype. Alterations in this differentiation process leading to cancer and androgen-independent disease are discussed, as well as a full characterization of prostate epithelial cells. A full understanding of the origin and characteristics of prostate cancer epithelial cells will be important if we are to develop therapeutic strategies to combat the heterogeneous nature of this disease.

Does tumor location affect prostate cancer prognosis?

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 45-45 ◽  
Author(s):  
Jun Akatsuka ◽  
Go Kimura ◽  
Kotaro Obayashi ◽  
Masayuki Sano ◽  
Masato Yanagi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Gland ◽  
Ejaculatory Duct ◽  
Prognostic Significance ◽  
Central Zone ◽  
Peripheral Zone ◽  
Recurrence Risk ◽  
Tumor Location ◽  
Cancer Prognosis ◽  
Prostate Cancer Prognosis

45 Background: Does tumor location affect prostate cancer prognosis? To clarify this question we conducted a retrospective study to characterize the incidence and prognostic significance of tumor location of prostate cancer. Methods: From 2000 to 2017, radical prostatectomy with no neoadjuvant therapy was performed in 916 cases in our hospital. Serial whole mount sections were reviewed to determine the incidence, clinicopathological features and prognostic significance of tumor location in the prostate gland. For the tumor location, we defined the subzones, which were made from subdivision of the McNeal’s zonal anatomy, are shown in Table 1 in detail. The peripheral zone (PZ) is composed of 8 subzones including A1, A2, A3 , M1, M2, M3, M4, M5. The transition zone (TZ) is composed of 5 subzones including T1, T2, T3, T4 and B1. The central zone (CZ) is composed of 3 subzones including M6, B2 and B3. Results: The median age was 67 and PSA was 8.6 ng/ml. The subzonal tumor incidence divided by all cases was the highest in A2, followed by M4, A1, M3, T2 in that order, while the lowest in B3, followed by M6, T4, T3, B1 in that order. The median follow-up time was 67 months. A 5-year PSA failure rate (5Y-PSAFR) was 23%. Among the subzones, the highest 5Y-PSAFR was seen in B3, followed by M6, B2, T4, A3, and the lowest was seen in M4, A2, T2, A1 in that order. A multivariate analysis for PSAF risk among subzones showed that B3 (HR 8.6, p <0.0001) and M6 (HR 3.3, p = 0.03) were the independent high risk subzones. Conclusions: We demonstrated that the cancer incidence and prognosis varies according to the location within the prostate gland. The B3 and M6 around the ejaculatory duct showed the lowest incidence, while these locations also had the highest recurrence risk. [Table: see text]

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