scholarly journals Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance

The Prostate ◽  
2020 ◽  
Vol 81 (1) ◽  
pp. 58-71
Author(s):  
Yi Ding ◽  
MinJae Lee ◽  
Yan Gao ◽  
Ping Bu ◽  
Christian Coarfa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Neuropeptide Y ◽  
Therapy Resistance ◽  
Paracrine Regulation

scholarly journals SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Trnski ◽  
Maja Sabol ◽  
Sanja Tomić ◽  
Ivan Štefanac ◽  
Milanka Mrčela ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Therapy Resistance ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Androgen Independence ◽  
Androgen Receptor Activity ◽  
Signaling Activation ◽  
Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

scholarly journals NUMB suppression by miR-9-5P enhances CD44+ prostate cancer stem cell growth and metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuan Wang ◽  
Jun Cai ◽  
Lei Zhao ◽  
Dejun Zhang ◽  
Guojie Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Bioinformatics Analysis ◽  
Therapy Resistance ◽  
Therapeutic Strategies ◽  
Self Renewal ◽  
Tumor Relapse ◽  
The Past ◽  
Overwhelming Evidence ◽  
Novel Therapeutic Strategies

AbstractExperimental and clinical studies over the past two decades have provided overwhelming evidence that human cancers, including prostate cancer (PCa), harbor cancer stem cells (CSCs) that sustain tumor growth, drive tumor progression and mediate therapy resistance and tumor relapse. Recent studies have also implicated NUMB as a PCa suppressor and an inhibitor of PCa stem cells (PCSCs); however, exactly how NUMB functions in these contexts remains unclear. Here, by employing bioinformatics analysis and luciferase assays and by conducting rescue experiments, we first show that NUMB is directly targeted by microRNA-9-5p (miR-9-5p), an oncogenic miR associated with poor prognosis in many malignancies. We further show that miR-9-5p levels are inversely correlated with NUMB expression in CD44+ PCSCs. miR-9-5p reduced NUMB expression and inhibited numerous PCSC properties including proliferation, migration, invasion as well as self-renewal. Strikingly, overexpression of NUMB in CD44+ PCSCs overcame all of the above PCSC properties enforced by miR-9-5p. Taken together, our results suggest that inhibiting the expression of the oncomiR miR-9-5p and overexpressing NUMB may represent novel therapeutic strategies to target PCSCs and PCa metastasis.

scholarly journals Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3272
Author(s):  
Lauren K. Jillson ◽  
Gabriel A. Yette ◽  
Teemu D. Laajala ◽  
Wayne D. Tilley ◽  
James C. Costello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Targeted Therapies ◽  
Meta Analysis ◽  
Therapy Resistance ◽  
Androgen Receptor Signaling ◽  
Genomic Changes ◽  
Risk Patients ◽  
Important Pathway ◽  
Therapy Option

While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.

scholarly journals Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2795
Author(s):  
Sofia Papanikolaou ◽  
Aikaterini Vourda ◽  
Spyros Syggelos ◽  
Kostis Gyftopoulos
Keyword(s):  
Prostate Cancer ◽  
Cancer Therapy ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Therapy Resistance ◽  
Cellular Process ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

scholarly journals Depression-Induced Neuropeptide Y Secretion Promotes Prostate Cancer Growth by Recruiting Myeloid Cells

2018 ◽  
Vol 25 (8) ◽  
pp. 2621-2632 ◽  
Author(s):  
Yan Cheng ◽  
Xin-Ying Tang ◽  
Yi-Xuan Li ◽  
Dan-Dan Zhao ◽  
Qiu-Hua Cao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Neuropeptide Y ◽  
Myeloid Cells ◽  
Cancer Growth

scholarly journals The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1887 ◽  
Author(s):  
Francesco Bonollo ◽  
George N. Thalmann ◽  
Marianna Kruithof-de Julio ◽  
Sofia Karkampouna
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Metastatic Progression ◽  
Normal Prostate ◽  
Prostate Tumorigenesis

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

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