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

Patel, Girijesh Kumar; Chugh, Natasha; Tripathi, Manisha

doi:10.3390/cancers11101405

Cited by 87 publications

(81 citation statements)

References 216 publications

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“…It is worthy to note that neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic prostate cancer [5,7]. Moreover, ADT was shown to be a key driver of the neuroendocrine differentiation of the prostate adenocarcinoma to NEPC [8], and so it is not surprising that the incidence of treatment-induced NEPC is rising because of the widespread use of more potent androgen receptor (AR) pathway inhibitors [9]. These latter tumor types are refractory to hormonal therapies and are thought to represent a resistance driven by cellular lineage plasticity [3].…”

Section: Introductionmentioning

confidence: 99%

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Sánchez

Vara-Ciruelos

Díaz‐Laviada

2020

Cells

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In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring.

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Section: Introductionmentioning

confidence: 99%

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Sánchez

Vara-Ciruelos

Díaz‐Laviada

2020

Cells

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“…The tumor microenvironment includes blood vessels, stromal cells namely, cancer-associated fibroblasts (CAFs), endothelial cells, neuroendocrine cells and infiltrating immune cells, growth factors and chemokines secreted by either tumor cells or stromal cells and many extracellular matrix proteins such as laminin, fibronectin, and collagen (Yates, 2011). Apart from the dynamic interaction between tumor and stromal cells, physical (elasticity and stiffness) and biochemical properties (protein composition) of the extracellular matrix (ECM), as well as access to nutrients and oxygen also governs the cellular plasticity of the tumor cells (Yates, 2011;Davies et al, 2018;Patel et al, 2019). Among the different stromal cells, CAFs play a critical role in modulating the plasticity of the cancer cells.…”

Section: Cell-extrinsic Factorsmentioning

confidence: 99%

Dynamics of Cellular Plasticity in Prostate Cancer Progression

Tiwari

Manzar

Ateeq

2020

Front. Mol. Biosci.

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Despite the current advances in the treatment for prostate cancer, the patients often develop resistance to the conventional therapeutic interventions. Therapy-induced drug resistance and tumor progression have been associated with cellular plasticity acquired due to reprogramming at the molecular and phenotypic levels. The plasticity of the tumor cells is mainly governed by two factors: cell-intrinsic and cell-extrinsic. The cell-intrinsic factors involve alteration in the genetic or epigenetic regulators, while cell-extrinsic factors include microenvironmental cues and drug-induced selective pressure. Epithelial-mesenchymal transition (EMT) and stemness are two important hallmarks that dictate cellular plasticity in multiple cancer types including prostate. Emerging evidence has also pinpointed the role of tumor cell plasticity in driving anti-androgen induced neuroendocrine prostate cancer (NEPC), a lethal and therapy-resistant subtype. In this review, we discuss the role of cellular plasticity manifested due to genetic, epigenetic alterations and cues from the tumor microenvironment, and their role in driving therapy resistant prostate cancer.

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“…NEPC is a highly aggressive subtype of PCa [10] . It has been shown to progress aggressively, metastasizing primarily to the visceral organs, tissues and sometimes to the bone [32] . Histologically, it is characterized by poor differentiation in tumors, coil-like, or organoid shaped cells which appear basophilic with distinct nucleoli [32] .…”

Section: Nepc: Molecular Features and Epigeneticsmentioning

confidence: 99%

“…It has been shown to progress aggressively, metastasizing primarily to the visceral organs, tissues and sometimes to the bone [32] . Histologically, it is characterized by poor differentiation in tumors, coil-like, or organoid shaped cells which appear basophilic with distinct nucleoli [32] . In addition, studies have shown that, patients confirmed with NEPC usually develop visceral metastases, have low PSA levels and have frequent loss of retinoblastoma 1 (Rb1) and tumor suppressor p53 (TP53) genes [10,33,34] .…”

Section: Nepc: Molecular Features and Epigeneticsmentioning

confidence: 99%

MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer

Akoto¹,

Bhagirath²,

Saini³

2020

CDR

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Prostate cancer is a condition commonly associated with men worldwide. Androgen deprivation therapy remains one of the targeted therapies. However, after some years, there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer (CRPC). CRPC cases are treated with second-line androgen deprivation therapy, after which, these CRPCs transdifferentiate to form neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. NEPC arises via a reversible transdifferentiation process, known as neuroendocrine differentiation (NED), which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2, chromogranin A and synaptophysin. The etiological factors and molecular basis for NED are poorly understood, contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy. Therefore, there is a need to fully understand the underlying molecular basis for this cancer. Recent studies have shown that microRNAs (miRNAs) play a key epigenetic role in driving therapy-induced NED in prostate cancer. In this review, we briefly describe the role of miRNAs in prostate cancer and CRPCs, discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC. This understanding will contribute to better clinical management of the disease.

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

Cited by 87 publications

References 216 publications

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

Dynamics of Cellular Plasticity in Prostate Cancer Progression

MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer

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