Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs

Neuroendocrine prostate cancer (NEPC) represents a variant of prostate cancer that occurs in response to treatment resistance or, to a much lesser extent, de novo. Unravelling the molecular mechanisms behind transdifferentiation of cancer cells to neuroendocrine-like cancer cells is essential for development of new treatment opportunities. This review focuses on summarizing the role of small molecules, predominantly microRNAs, in this phenomenon. A published literature search was performed to identify microRNAs, which are reported and experimentally validated to modulate neuroendocrine markers and/or regulators and to affect the complex neuroendocrine phenotype. Next, available patients’ expression datasets were surveyed to identify deregulated microRNAs, and their effect on NEPC and prostate cancer progression is summarized. Finally, possibilities of miRNA detection and quantification in body fluids of prostate cancer patients and their possible use as liquid biopsy in prostate cancer monitoring are discussed. All the addressed clinical and experimental contexts point to an association of NEPC with upregulation of miR-375 and downregulation of miR-34a and miR-19b-3p. Together, this review provides an overview of different roles of non-coding RNAs in the emergence of neuroendocrine prostate cancer.

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Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Cancers ◽

10.3390/cancers13040692 ◽

2021 ◽

Vol 13 (4) ◽

pp. 692

Author(s):

Roosa Kaarijärvi ◽

Heidi Kaljunen ◽

Kirsi Ketola

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Treatment Resistance ◽

Research Field ◽

Phenotypic Change ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Treatment Resistant ◽

Molecular Features ◽

Neuroendocrine Prostate Cancer

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

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Circulating tumor cell heterogeneity in neuroendocrine prostate cancer by single cell copy number analysis

npj Precision Oncology ◽

10.1038/s41698-021-00211-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Vincenza Conteduca ◽

Sheng-Yu Ku ◽

Luisa Fernandez ◽

Angel Dago-Rodriquez ◽

Jerry Lee ◽

...

Keyword(s):

Prostate Cancer ◽

Single Cell ◽

De Novo ◽

Genomic Analysis ◽

Treatment Resistance ◽

Circulating Tumor Cell ◽

Prostate Adenocarcinoma ◽

Neuroendocrine Prostate Cancer ◽

Patient Heterogeneity ◽

Tumor Cell Heterogeneity

AbstractNeuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.

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Androgen-Driven Fusion Genes and Chimeric Transcripts in Prostate Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.623809 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mauro Scaravilli ◽

Sonja Koivukoski ◽

Leena Latonen

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

De Novo ◽

Fusion Gene ◽

Fusion Genes ◽

Protein Coding ◽

Leading Role ◽

Number Of Patients ◽

Androgen Regulation ◽

Non Coding Rnas

Androgens are steroid hormones governing the male reproductive development and function. As such, androgens and the key mediator of their effects, androgen receptor (AR), have a leading role in many diseases. Prostate cancer is a major disease where AR and its transcription factor function affect a significant number of patients worldwide. While disease-related AR-driven transcriptional programs are connected to the presence and activity of the receptor itself, also novel modes of transcriptional regulation by androgens are exploited by cancer cells. One of the most intriguing and ingenious mechanisms is to bring previously unconnected genes under the control of AR. Most often this occurs through genetic rearrangements resulting in fusion genes where an androgen-regulated promoter area is combined to a protein-coding area of a previously androgen-unaffected gene. These gene fusions are distinctly frequent in prostate cancer compared to other common solid tumors, a phenomenon still requiring an explanation. Interestingly, also another mode of connecting androgen regulation to a previously unaffected gene product exists via transcriptional read-through mechanisms. Furthermore, androgen regulation of fusion genes and transcripts is not linked to only protein-coding genes. Pseudogenes and non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) can also be affected by androgens and de novo functions produced. In this review, we discuss the prevalence, molecular mechanisms, and functional evidence for androgen-regulated prostate cancer fusion genes and transcripts. We also discuss the clinical relevance of especially the most common prostate cancer fusion gene TMPRSS2-ERG, as well as present open questions of prostate cancer fusions requiring further investigation.

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Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Cancers ◽

10.3390/cancers13122965 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2965

Author(s):

Cinzia Antognelli ◽

Martina Mandarano ◽

Enrico Prosperi ◽

Angelo Sidoni ◽

Vincenzo Nicola Talesa

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Metastatic Prostate Cancer ◽

Molecular Mechanisms ◽

Curative Therapy ◽

Glyoxalase 1 ◽

Immunosuppressive Microenvironment ◽

Novel Therapeutic Strategies

Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.

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Prostate Cancer Progression and Surrounding Microenvironment

The International Journal of Biological Markers ◽

10.1177/172460080602100204 ◽

2006 ◽

Vol 21 (2) ◽

pp. 88-95 ◽

Cited By ~ 12

Author(s):

C. Alberti

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Immune Escape ◽

Tumor Stem Cell ◽

Cellular Interactions ◽

Immune Mediated ◽

Immune Escape Mechanisms

Bidirectional cellular interactions between prostate cancer and prostate or bone stroma are needed for local tumor growth and distant metastasis. The genetics of cancer cells is affected by the host microenvironment and, reciprocally, permanent gene expression changes occur in the stroma surrounding epithelial cancer cells. The immune-mediated micromilieu also affects the progression of prostate cancer; the role of the immune system in controlling the growth of prostate cancer cells is complex, with immune escape mechanisms prevailing over effective antitumor response. Moreover, tumor stem cell models to explain the origin and progression of prostate cancer require appropriate environmental conditions. On the basis of a review of the literature, this article aims to outline the recent advances in the elucidation of the molecular mechanisms underlying the interactions between prostate cancer and its microenvironment.

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Imaging of Neuroendocrine Prostatic Carcinoma

Cancers ◽

10.3390/cancers13225765 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5765

Author(s):

Ahmed Taher ◽

Corey T. Jensen ◽

Sireesha Yedururi ◽

Devaki Shilpa Surasi ◽

Silvana C. Faria ◽

...

Keyword(s):

Prostate Cancer ◽

Poor Prognosis ◽

Prostatic Carcinoma ◽

De Novo ◽

Treatment Resistance ◽

Metastatic Potential ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Neuroendocrine Prostate Cancer ◽

Aggressive Subtype

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that typically has a high metastatic potential and poor prognosis in comparison to the adenocarcinoma subtype. Although it can arise de novo, NEPC much more commonly occurs as a mechanism of treatment resistance during therapy for conventional prostatic adenocarcinoma, the latter is also termed as castration-resistant prostate cancer (CRPC). The incidence of NEPC increases after hormonal therapy and they represent a challenge, both in the radiological and pathological diagnosis, as well as in the clinical management. This article provides a comprehensive imaging review of prostatic neuroendocrine tumors.

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MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer

Scientific Reports ◽

10.1038/s41598-021-92552-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

En-Chi Hsu ◽

Michelle Shen ◽

Merve Aslan ◽

Shiqin Liu ◽

Manoj Kumar ◽

...

Keyword(s):

Prostate Cancer ◽

De Novo ◽

Treatment Resistance ◽

Dna Helicase ◽

Tumor Xenograft ◽

Primary Tumors ◽

Neuroendocrine Prostate Cancer ◽

And Migration

AbstractNeuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.

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