790: BMP-7 is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

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

Frontiers in Oncology ◽

10.3389/fonc.2021.795712 ◽

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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In Vivo Models of Human Prostate Cancer Bone Metastasis

Prostate Cancer Methods and Protocols ◽

10.1385/1-59259-372-0:149 ◽

2003 ◽

pp. 149-162

Author(s):

Julie M. Brown

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Human Prostate ◽

Human Prostate Cancer ◽

In Vivo Models

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Study on the cellular internalization mechanisms and in vivo anti-bone metastasis prostate cancer efficiency of the peptide T7-modified polypeptide nanoparticles

Drug Delivery ◽

10.1080/10717544.2019.1709923 ◽

2020 ◽

Vol 27 (1) ◽

pp. 161-169

Author(s):

Yongwei Gu ◽

Xinmei Chen ◽

Haiyan Zhang ◽

Heyi Wang ◽

Hang Chen ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cellular Internalization

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PSMA-Targeting Redox Hyperbranched Poly (Amido Amine)-Mediated miR-133a-3p Delivery to Inhibit Bone Metastasis of Prostate Cancer

10.21203/rs.3.rs-36954/v1 ◽

2020 ◽

Author(s):

Yongheng Ye ◽

Lingli Zhang ◽

Yuhu Dai ◽

Zhi Wang ◽

Cuie Li ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Therapeutic Potential ◽

Tumor Model ◽

Lncap Cells ◽

Systemic Delivery ◽

Formidable Challenge ◽

Hyperbranched Poly

Abstract Treatment of bone metastasis of prostate cancer remains a formidable challenge. The skeleton has a poorer blood supply, leading to inadequate drug distribution into the bone after administration. This study aimed to develop aptamer-anchored hyperbranched poly (amido amine) (HPAA) for the systemic delivery of miRNA-133a-3p and to evaluate its therapeutic potential against bone metastasis of prostate cancer in vivo and in vitro. A glutathione (GSH)-responsive cationic HPAA was prepared by the Michael addition reaction. Furthermore, HPAA-PEG was produced by PEGylation, and then the aptamer targeted to prostate-specific membrane antigen (PSMA) was conjugated to the HPAA-PEG. The obtained HPAA-PEG-APT could form nanocomplexes with miRNA-133a-3p through electrostatic adsorption. The results of immunocytochemistry indicated that the complexes could target PSMA-expressing LNCaP cells. The ability of HPAA-PEG-APT to facilitate the delivery of miRNA-133a-3p into LNCaP cells was proven, and HPAA-PEG-APT/miRNA-133a-3p demonstrated enhanced antitumor activity, lower cytotoxicity and better biocompatibility in vitro. Moreover, in a mouse tibial injection tumor model, the intravenous injection of the HPAA-PEG-APT/miRNA-133a-3p complex significantly inhibited cancer growth and extended the survival time. In summary, this study provided an aptamer-anchored HPAA-loaded gene system to deliver miRNA-133a-3p for better therapeutic efficacy of bone metastasis of prostate cancer.

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16576 ◽

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.

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The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-015-0240-8 ◽

2015 ◽

Vol 34 (1) ◽

Cited By ~ 27

Author(s):

Ning Wang ◽

Kimberley J. Reeves ◽

Hannah K. Brown ◽

Anne C M Fowles ◽

Freyja E. Docherty ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

In Vivo Models ◽

Osteolytic Bone Metastasis ◽

Breast And Prostate Cancer ◽

Number Of Seeds

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Wnt5a induces and maintains prostate cancer cells dormancy in bone

Journal of Experimental Medicine ◽

10.1084/jem.20180661 ◽

2018 ◽

Vol 216 (2) ◽

pp. 428-449 ◽

Cited By ~ 27

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.

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