Molecular Mechanisms of Therapies for Prostate Cancer with Bone Metastasis

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

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The Osteoblastic and Osteoclastic Interactions in Spinal Metastases Secondary to Prostate Cancer

Cancer Growth and Metastasis ◽

10.4137/cgm.s12769 ◽

2013 ◽

Vol 6 ◽

pp. CGM.S12769 ◽

Cited By ~ 13

Author(s):

Sathana Dushyanthen ◽

Davina A.F. Cossigny ◽

Gerald M.Y. Quan

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Molecular Mechanisms ◽

Spinal Metastases ◽

Bone Destruction ◽

Cord Compression ◽

Intractable Pain ◽

Critical Pathway ◽

Functional Roles ◽

High Propensity

Prostate cancer (PC) is one of the most common cancers arising in men and has a high propensity for bone metastasis, particularly to the spine. At this stage, it often causes severe morbidity due to pathological fracture and/or metastatic epidural spinal cord compression which, if untreated, inevitably leads to intractable pain, neurological deficit, and paralysis. Unfortunately, the underlying molecular mechanisms driving growth of secondary PC in the bony vertebral column remain largely unknown. Further investigation is warranted in order to identify therapeutic targets in the future. This review summarizes the current understanding of PC bone metastasis in the spine, highlighting interactions between key tumor and bone-derived factors which influence tumor progression, especially the functional roles of osteoblasts and osteoclasts in the bone microenvironment through their interactions with metastatic PC cells and the critical pathway RANK/RANKL/OPG in bone destruction.

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Regulation of cell–cell adhesion in prostate cancer cells by microRNA-96 through upregulation of E-Cadherin and EpCAM

Carcinogenesis ◽

10.1093/carcin/bgz191 ◽

2019 ◽

Vol 41 (7) ◽

pp. 865-874

Author(s):

Gjendine Voss ◽

Benedikta S Haflidadóttir ◽

Helena Järemo ◽

Margareta Persson ◽

Tina Catela Ivkovic ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Adhesion ◽

Bone Metastasis ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Cell Interaction ◽

Metastatic Progression ◽

Prostate Cancer Cells ◽

E Cadherin ◽

Cell Cell

Abstract Prostate cancer is one of the most common cancers in men, yet the biology behind lethal disease progression and bone metastasis is poorly understood. In this study, we found elevated levels of microRNA-96 (miR-96) in prostate cancer bone metastasis samples. To determine the molecular mechanisms by which miR-96 deregulation contributes to metastatic progression, we performed an Argonaute2-immunoprecipitation assay, in which mRNAs associated with cell–cell interaction were enriched. The expression of two cell adhesion molecules, E-Cadherin and EpCAM, was upregulated by miR-96, and potential targets sites were identified in the coding sequences of their mRNAs. We further showed that miR-96 enhanced cell–cell adhesion between prostate cancer cells as well as their ability to bind to osteoblasts. Our findings suggest that increased levels of miR-96 give prostate cancer cells an advantage at forming metastases in the bone microenvironment due to increased cell–cell interaction. We propose that miR-96 promotes bone metastasis in prostate cancer patients by facilitating the outgrowth of macroscopic tumours in the bone.

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Identification of Key Gene Signatures Associated With Bone Metastasis in Castration-Resistant Prostate Cancer Using Co-Expression Analysis

Frontiers in Oncology ◽

10.3389/fonc.2020.571524 ◽

2021 ◽

Vol 10 ◽

Author(s):

Zhongxiang Yu ◽

Hanlin Zou ◽

Huihao Wang ◽

Qi Li ◽

Dong Yu

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Bone Metastasis ◽

Molecular Mechanisms ◽

Bone Development ◽

Tumor Development ◽

Enrichment Analysis ◽

Castration Resistant Prostate Cancer ◽

Metastatic Colonization ◽

Castration Resistant

About 80–90% of castration-resistant prostate cancer (CRPC) patients would develop bone metastasis. However, the molecular mechanisms of bone metastasis are still not clear. This study aimed to detect the differences between the tumor and normal samples in bone after metastatic colonization. Four transcriptional datasets (GSE32269, GSE101607, GSE29650, and GSE74685) were obtained from the GEO database. 1983 differentially expressed genes (DEGs) were first identified between tumor and normal marrow samples in GSE32269. Most of the top 10 up-regulated DEGs are related with prostate cancer, and the top 10 down-regulated DEGs are mainly related with bone development. Seven co-expression modules were then detected based on the 1469 DEGs shared by the four datasets. Three of them were found highly preserved among the four datasets. Enrichment analysis showed that the three modules were respectively enriched in Cell adhesion molecules (CAMs), Leukocyte transendothelial migration and cell cycle, which might play significantly important roles in the tumor development in bone marrow. Ten, 17, and 99 hub genes for each module were then identified. And four genes (C3AR1, IL10RA, LY86, and MS4A6A) were detect to be tightly related to progression of bone metastatic CRPC. ROC curve was plotted and AUC was calculated to distinguish tumor and normal bone marrow samples as well as bone and non-bone metastatic CRPCs. The present study identified key genes and modules involved in bone metastatic CRPCs, which may provide new insights and biomarkers for understanding of the molecular mechanisms of bone metastatic CRPC.

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Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine

Molecular Cancer ◽

10.1186/s12943-020-01293-4 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Simeng Wen ◽

Yulei Wei ◽

Chong Zen ◽

Wei Xiong ◽

Yuanjie Niu ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Messenger Rna ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Critical Role ◽

Rna Modification ◽

Loss Of Function ◽

Pol Ii

Abstract Background N6-methyladenosine (m6A) is the most prevalent messenger RNA modification in mammalian cells. However, the disease relevant function of m6A on specific oncogenic long non-coding RNAs (ncRNAs) is not well understood. Methods We analyzed the m6A status using patients samples and bone metastatic PDXs. Through m6A high-throughput sequencing, we identified the m6A sites on NEAT1–1 in prostate bone metastatic PDXs. Mass spec assay showed interaction among NEAT1–1, CYCLINL1 and CDK19. RNA EMSA, RNA pull-down, mutagenesis, CLIP, western blot, ChIP and ChIRP assays were used to investigate the molecular mechanisms underlying the functions of m6A on NEAT1–1. Loss-of function and rescued experiments were executed to detect the biological roles of m6A on NEAT1–1 in the PDX cell phenotypes in vivo. Results In this study, we identified 4 credible m6A sites on long ncRNA NEAT1–1. High m6A level of NEAT1–1 was related to bone metastasis of prostate cancer and m6A level of NEAT1–1 was a powerful predictor of eventual death. Transcribed NEAT1–1 served as a bridge to facility the binding between CYCLINL1 and CDK19 and promoted the Pol II ser2 phosphorylation. Importantly, depletion of NEAT1–1or decreased m6A of NEAT1–1 impaired Pol II Ser-2p level in the promoter of RUNX2. Overexpression of NEAT1–1 induced cancer cell metastasis to lung and bone; xenograft growth and shortened the survival of mice, but NEAT1–1 with m6A site mutation failed to do these. Conclusion Collectively, the findings indicate that m6A on ncRNA NEAT1–1 takes critical role in regulating Pol II ser2 phosphorylation and may be novel specific target for bone metastasis cancer therapy and diagnosis. New complex CYCLINL1/CDK19/NEAT1–1 might provide new insight into the potential mechanism of the pathogenesis and development of bone metastatic prostate cancer.

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Hybrid Discrete-Continuum Cellular Automaton (HCA) model of Prostate to Bone Metastasis

10.1101/043620 ◽

2016 ◽

Author(s):

Arturo Araujo ◽

David Basanta

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Molecular Mechanisms ◽

Bone Matrix ◽

Cellular Interactions ◽

Vicious Cycle ◽

Bone Microenvironment ◽

Basic Multicellular Unit ◽

Bone Degradation ◽

The Impact

AbstractProstate to bone metastases induce a “vicious cycle” by promoting excessive osteoclast and osteoblast mediated bone degradation and formation that in turn yields factors that drive cancer growth. Recent advances defining the molecular mechanisms that control the vicious cycle have revealed new therapeutic targeting opportunities. However, given the complex temporal and simultaneous cellular interactions occurring in the bone microenvironment, assessing the impact of putative therapies is challenging. To this end, we have integrated biological and computational approaches to generate an accurate model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model faithfully reproduces the basic multicellular unit (BMU) bone coupling process and introduction of a single prostate cancer cell yields a vicious cycle that is similar in cellular composition and pathophysiology to models of prostate to bone metastasis.

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