Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

Mao, Yifeng; Yang, Gaowei; Li, Yingbang; Liang, Guowu; Xu, Wangwang; Hu, Mingqiu

doi:10.3390/cancers14153744

Cited by 11 publications

(14 citation statements)

References 200 publications

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“…Mechanisms leading to PC progression and ADR resistance are usually associated with amplifications, mutations, altered splicing, or epigenetic reprogramming in the AR gene [ 27 , 28 , 29 ]. Another potential driver is the increase in androgen biosynthesis, which can occur through the mutation in the HSD3B1 gene [ 30 ].…”

Section: Diagnosis and Therapy Of Pcmentioning

confidence: 99%

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

Petrić

Sabol

2023

IJMS

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Prostate cancer (PC) is the third most frequently diagnosed cancer worldwide and the second most frequent in men. Several risk factors can contribute to the development of PC, and those include age, family history, and specific genetic mutations. So far, drug testing in PC, as well as in cancer research in general, has been performed on 2D cell cultures. This is mainly because of the vast benefits these models provide, including simplicity and cost effectiveness. However, it is now known that these models are exposed to much higher stiffness; lose physiological extracellular matrix on artificial plastic surfaces; and show changes in differentiation, polarization, and cell–cell communication. This leads to the loss of crucial cellular signaling pathways and changes in cell responses to stimuli when compared to in vivo conditions. Here, we emphasize the importance of a diverse collection of 3D PC models and their benefits over 2D models in drug discovery and screening from the studies done so far, outlining their benefits and limitations. We highlight the differences between the diverse types of 3D models, with the focus on tumor–stroma interactions, cell populations, and extracellular matrix composition, and we summarize various standard and novel therapies tested on 3D models of PC for the purpose of raising awareness of the possibilities for a personalized approach in PC therapy.

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Section: Diagnosis and Therapy Of Pcmentioning

confidence: 99%

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

Petrić

Sabol

2023

IJMS

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“…common in primary tumors and is reported in just 2% of PCa patients who had not undergone ADT [78]. Another cause of increased AR signaling is due to increased level of AR protein via post-transcriptional or post-translational deregulation, which may lead to increased stabilization of AR mRNA and/or protein [79,80]. Consequently, the increased level of AR protein in CRPC cells enables the cells to be hypersensitive to the low level of androgens [79,81,82].…”

Section: Adt In the Treatment Of Advanced Pcamentioning

confidence: 99%

“…Another mechanism for the re-activation of AR signaling in CRPC is AR mutations. While some mutations have been identified in the amino-terminal (NTD) and DNAbinding (DBD) domains of AR, most of the activating mutations are localized to the ligand-binding domain (LBD) of AR [79,83]. Although mutations in LBD are rare in hormone-responsive PCa cells, they have been detected in about 20% of CRPC tumor cells [84].…”

Section: Adt In the Treatment Of Advanced Pcamentioning

confidence: 99%

“…Although mutations in LBD are rare in hormone-responsive PCa cells, they have been detected in about 20% of CRPC tumor cells [84]. Mutations in LBD alters the ligand specificity of AR and facilitate its activation with other steroid hormones, in the absence of androgen [70,79]. Furthermore, it has been shown that antiandrogens may act as agonist on some AR with mutated LBD [83].…”

Section: Adt In the Treatment Of Advanced Pcamentioning

confidence: 99%

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Dissecting the effects of androgen deprivation therapy on cadherin switching in advanced prostate cancer: A molecular perspective

Varisli¹,

TOLAN²,

CEN³

et al. 2022

Oncology Research

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Prostate cancer is one of the most often diagnosed malignancies in males and its prevalence is rising in both developed and developing countries. Androgen deprivation therapy has been used as a standard treatment approach for advanced prostate cancer for more than 80 years. The primary aim of androgen deprivation therapy is to decrease circulatory androgen and block androgen signaling. Although a partly remediation is accomplished at the beginning of treatment, some cell populations become refractory to androgen deprivation therapy and continue to metastasize.Recent evidences suggest that androgen deprivation therapy may cause cadherin switching, from E-cadherin to Ncadherin, which is the hallmark of epithelial-mesenchymal transition. Diverse direct and indirect mechanisms are involved in this switching and consequently, the cadherin pool changes from E-cadherin to N-cadherin in the epithelial cells. Since E-cadherin represses invasive and migrative behaviors of the tumor cells, the loss of E-cadherin disrupts epithelial tissue structure leading to the release of tumor cells into surrounding tissues and circulation. In this study, we review the androgen deprivation therapy-dependent cadherin switching in advanced prostate cancer with emphasis on its molecular basis especially the transcriptional factors regulated through TFG-β pathway.

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“…Despite the CRPC being unresponsive to androgens, the androgen receptor (AR) signaling axis remains the most critical factor for CRPC development, bypassing the androgen depletion through AR overexpression, de novo androgen synthesis, and AR activation induced by coregulatory proteins, mutation, or altered splicing 4,12 . In addition to AR signaling, other regulatory mechanisms have been described as involved with CRPC, including hedgehog pathway, PI3K‐AKT–mTOR signaling, Wnt pathway, and dynamic of noncoding RNAs such as long noncoding RNAs (lncRNAs) 12 . lncRNAs constitute a class of RNAs with a length of more than 200 nucleotides and rare protein‐coding potential 13 .…”

Section: Introductionmentioning

confidence: 99%

Revealing metastatic castration‐resistant prostate cancer master regulator through lncRNAs‐centered regulatory network

Ferraz,

Cavalcante,

Magalhães

et al. 2023

Cancer Medicine

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BackgroundMetastatic castration‐resistant prostate cancer (mCRPC) is an aggressive form of cancer unresponsive to androgen deprivation therapy (ADT) that spreads quickly to other organs. Despite reduced androgen levels after ADT, mCRPC development and lethality continues to be conducted by the androgen receptor (AR) axis. The maintenance of AR signaling in mCRPC is a result of AR alterations, androgen intratumoral production, and the action of regulatory elements, such as noncoding RNAs (ncRNAs). ncRNAs are key elements in cancer signaling, acting in tumor growth, metabolic reprogramming, and tumor progression. In prostate cancer (PCa), the ncRNAs have been reported to be associated with AR expression, PCa proliferation, and castration resistance. In this study, we aimed to reconstruct the lncRNA‐centered regulatory network of mCRPC and identify the lncRNAs which act as master regulators (MRs).MethodsWe used publicly available RNA‐sequencing to infer the regulatory network of lncRNAs in mCRPC. Five gene signatures were employed to conduct the master regulator analysis. Inferred MRs were then subjected to functional enrichment and symbolic regression modeling. The latter approach was applied to identify the lncRNAs with greater predictive capacity and potential as a biomarker in mCRPC.ResultsWe identified 31 lncRNAs involved in cellular proliferation, tumor metabolism, and invasion‐metastasis cascade. SNHG18 and HELLPAR were the highlights of our results. SNHG18 was downregulated in mCRPC and enriched to metastasis signatures. It accurately distinguished both mCRPC and primary CRPC from normal tissue and was associated with epithelial–mesenchymal transition (EMT) and cell‐matrix adhesion pathways. HELLPAR consistently distinguished mCRPC from primary CRPC and normal tissue using only its expression.ConclusionOur results contribute to understanding the regulatory behavior of lncRNAs in mCRPC and indicate SNHG18 and HELLPAR as master regulators and potential new diagnostic targets in this tumor.

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Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

Cited by 11 publications

References 200 publications

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

Dissecting the effects of androgen deprivation therapy on cadherin switching in advanced prostate cancer: A molecular perspective

Revealing metastatic castration‐resistant prostate cancer master regulator through lncRNAs‐centered regulatory network

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