scholarly journals Wnt5a induces and maintains prostate cancer cells dormancy in bone

2018 ◽  
Vol 216 (2) ◽  
pp. 428-449 ◽  
Author(s):  
Dong Ren ◽  
Yuhu Dai ◽  
Qing Yang ◽  
Xin Zhang ◽  
Wei Guo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Orphan Receptor ◽  
Free Survival ◽  
Ubiquitin Protein Ligase ◽  
Signaling Axis ◽  
Canonical Wnt

In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/β-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/β-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/β-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis–free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.

Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Marianna Kruithof-de Julio ◽  
Letizia Astrologo ◽  
Eugenio Zoni ◽  
Sofia Karkampouna ◽  
Peter C Gray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cells ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Primary Prostate Cancer ◽  
The Impact

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.

scholarly journals MiR-154-5p Inhibits Prostate Cancer Bone Metastasis by Inactivating PI3K/AKT Signaling

2021 ◽  
Author(s):  
Dong Ren ◽  
Xiangwei Yuan ◽  
Jiazheng Cao ◽  
Bin Wang ◽  
Ruixiao Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Tumor Type ◽  
Free Survival ◽  
And Migration

Abstract Background: Generally, both strands of a single pre-miRNA have been demonstrated to play a similar role in the same tumor type. However, there are no available literatures yet so far clarifying the opposite roles of both strands froma single miRNAin one tumor type. The purpose of this study is to investigate the functional role of both strands of miR-154 in bone metastasis of prostate cancer (PCa). Methods: miR-154-5p expression was examinedin 285 clinicalPCa tissuesby in situ hybridization. The clinical correlation ofmiR-154-5p expression with clinicopathological features,and overall and bone metastasis-free survival inPCa patients was evaluated by Kaplan-Meier survival and statisticalanalysis. The biological roles of miR-154-3p and miR-154-5p in the bone metastasis of PCa were investigated both in vitroand in vivo.Bioinformatics analysis, western blot and luciferase reporter analysis were used to determinethe potential targets of miR-154-5p.Luciferase assay and Western blotting were performed to clarify the underlying pathway implicated in the role of miR-154-5p in bone metastasis of PCa.Results: Contrary to the well established pro-bone metastatic role of miR-154-3p in PCa, we found that miR-154-5p expression was reduced in PCa tissues with bone metastasis andbone metastatic PCa cell lines. Downexpression of miR-154-5p was positively associated with bone metastasis status, and predicted poorer bone metastasis-free survival in PCa patients. Gain of function experiments showed that upregulating miR-154-5p repressed, while silencing miR-154-5p promoted invasion, migration and proliferation capacities of PCa cells in vitro. Conversely, miR-154-3p yielded an opposite effect oninvasion and migration capacities of PCa cells. Importantly, administration of agomir-154-5p effectivelyinhibited bone metastasis of PCa cellsin vivo. Mechanistic dissection further demonstrated miR-154-5p inhibited invasion, migration and proliferation by targeting EGFR and FGFR1, leading to inactivation of PI3K/AKT signaling. However, the autocrine levels of corresponding ligands in the supernantant of PCa cells were not affected by the changed expression of miR-154-5p.Conclusion: Our results for the first time reveal the different role of both strands froma single miRNA in bone metastasis of PCa, which will facilitate the development of anti-bone metastatic therapeutic strategy in PCa.

scholarly journals Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Navatha Shree Polavaram ◽  
Samikshan Dutta ◽  
Ridwan Islam ◽  
Arup K. Bag ◽  
Sohini Roy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Potential Effect ◽  
Tumor Burden ◽  
Bone Lesions ◽  
Prostate Cancer Cells

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.

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

scholarly journals Tumor- and Osteoblast-Derived Periostin in Prostate Cancer bone Metastases

2022 ◽  
Vol 11 ◽  
Author(s):  
Chuan-Yu Sun ◽  
Yuan-Yuan Mi ◽  
Sheng-Yang Ge ◽  
Qing-Feng Hu ◽  
Ke Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Integrin Αvβ3 ◽  
Integrin Receptors ◽  
Secreted Expression ◽  
Metastatic Lesions ◽  
Promising Therapeutic Target ◽  
Pet Ct

Exploring the biological function of periostin (POSTN) in prostate cancer (PCa) bone metastasis is of importance. It was observed that the expression of POSTN was high in PCa, especially highest in PCa metastasized to bone. In this study, we found that inhibiting POSTN in PCa cells could significantly alleviate PCa bone metastasis in vivo, suggesting POSTN is a promising therapeutic target. Since, due to the secreted expression of POSTN in osteoblasts and PCa, we hypothesized the positive feedback loop between osteoblasts and PCa mediated by POSTN in PCa bone metastasis. The in vitro experiments demonstrated that osteoblast-derived POSTN promoted PCa cell proliferation and invasion and PCa cell-derived POSTN promotes proliferation of osteoblasts. Furthermore, we found that POSTN regulated PCa and osteoblast function through integrin receptors. Finally, 18F-Alfatide II was used as the molecule probe of integrin αvβ3 in PET-CT, revealing high intake in metastatic lesions. Our findings together indicate that targeting POSTN in PCa cells as well as in the osteoblastic may be an effective treatment for PCa bone metastasis.

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