Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes

Bone is the primarily preferred site for breast and prostate cancer to metastasize. Bone metastases are responsible for most deaths related to breast and prostate cancer. The bone’s particular microenvironment makes it conducive for the growth of cancer cells. Studies on bone metastasis have focused on the interaction between cancer cells and the bone microenvironment. Osteocytes, the most common cell type of bone tissue, have received little attention in bone metastasis, although they are master signal sensors, integrators, and skeleton transducers. They play an important role in regulating bone mass by acting on both osteoblasts and osteoclasts, through the release of proteins such as sclerostin, Dickkopf-1 (DKK-1), and fibroblast growth factor 23 (FGF23). Osteocytes have been extensively re-evaluated, in light of their multiple functions: with different experimental approaches, it has been shown that, indeed, osteocytes are actively involved in the colonization of bone tissue by cancer cells. The present review focuses on recent research on the role that osteocytes play in bone metastasis of breast and prostate cancers. Moreover, the studies here summarized open up perspectives for new therapeutic approaches focused on modulating the activity of osteocytes to improve the condition of the bone metastatic patients. A better understanding of the complex interactions between cancer cells and bone-resident cells is indispensable for identifying potential therapeutic targets to stop tumor progression and prevent bone metastases.

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The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms20163899 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3899 ◽

Cited By ~ 3

Author(s):

Mari I. Suominen ◽

Timothy Wilson ◽

Sanna-Maria Käkönen ◽

Arne Scholz

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Bone Metastases ◽

Cancer Cells ◽

Bone Cells ◽

Metastatic Cancer ◽

Signal Molecules ◽

Targeted Alpha Therapy ◽

Radium 223 ◽

Alpha Therapy

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest.

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Incidence and Prognosis of Bone Metastases in Common Solid Cancers at Initial Diagnosis: A Population-Based Study

10.21203/rs.3.rs-27692/v1 ◽

2020 ◽

Author(s):

Jing Zhang ◽

Qingde Wa ◽

Song Hong ◽

Dongfeng Cai ◽

Jiachen Peng

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Nasopharyngeal Carcinoma ◽

Bone Metastases ◽

Patient Survival ◽

Treatment Options ◽

Population Based ◽

Initial Diagnosis ◽

Breast And Prostate Cancer ◽

Primary Type

Abstract Background Bone is one of the most common sites of advanced tumors. However, there is currently a lack of population-based surveys for the incidence and prognosis of bone metastases in common solid cancers.Methods Patients with 12 types of primary cancer and bone metastases at initial diagnosis between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method and Cox logistic regression were conducted to analyze survival and the effect of bone metastases on different cancers.Results We included 89,782 patients with bone metastases at cancer diagnosis. Lung cancer had the highest incidence (17.61%) of bone metastases at diagnosis in any stage, followed by liver cancer (6.29%), nasopharyngeal carcinoma (6.22%) and renal cancer (5.19%). Among patients with breast and prostate cancer, only 3.4% and 4.39%, respectively, were identified as having bone metastases at diagnosis. Breast cancer (32.1%), prostate cancer (25.2%), thyroid cancer (46.8%) and nasopharyngeal carcinoma (24.8%) patients with only bone metastasis have an over 20% five-year survival rate. Compared with patients at a stage previous to metastasis, bone metastasis significantly increased the risk of mortality and reduced survival time, especially for patients with prostate cancer (HR: 19.64, 95% CI 18.36 to 21.02). Concomitant other organ metastases make patient survival worse. Regarding the metastases of prostate cancer, bone metastases are the main type, while for colorectal cancer, bone metastases and concomitant visceral metastases mainly occur.Conclusions The findings of this study provide estimates of the incidence and prognosis of patients with bone metastases during the initial diagnosis of common solid cancers. In addition, we also clarified the degree to which bone metastasis affects patient survival. Patient prognosis depends on the primary type of cancer. These results can be used as a reference for the screening of metastases, and the optimization of personalized treatment options to improve the quality of life and survival of patients.

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Overexpression of Interferon Regulatory Factor 7 (IRF7) Reduces Bone Metastasis of Prostate Cancer Cells in Mice

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504016x14756226781802 ◽

2017 ◽

Vol 25 (4) ◽

pp. 511-522 ◽

Cited By ~ 10

Author(s):

Yang Zhao ◽

Wenxia Chen ◽

Weiliang Zhu ◽

Hui Meng ◽

Jie Chen ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Bone Metastases ◽

Nk Cells ◽

Cancer Cells ◽

Interferon Regulatory Factor ◽

Target Cells ◽

Regulatory Factor ◽

Prostate Cancer Cells ◽

Interferon Regulatory Factor 7

The purpose of this study was to identify the role of interferon regulatory factor 7 (IRF7) in the bone metastasis of prostate cancer. Herein we demonstrated the lower expression of IRF7 in bone metastases of prostate cancer. Overexpression of IRF7 in prostate cancer cells had a marked effect on inhibiting bone metastases but not on tumor growth in xenograft nude mice. While in vitro, upregulation of IRF7 had little effect on the malignant phenotype of prostate cancer cells including proliferation, apoptosis, migration, and invasion. However, prostate cancer cells overexpressing IRF7 significantly enhanced the activity of NK cells, which resulted in the cytolysis of prostate cancer target cells. The underlying mechanism may be relevant to the increasing expression of IFN-β induced by IRF7, as the downregulation of which could inversely inhibit the activity of NK cells. In conclusion, our findings indicate that IRF7 plays a role in reducing bone metastasis of prostate cancer by IFN-β-mediated NK activity.

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Manganese-enhanced MRI (MEMRI) in breast and prostate cancers: exploring the potential role of calcium receptors

10.1101/806448 ◽

2019 ◽

Author(s):

Gabriella Baio ◽

Marina Fabbi ◽

Michele Cilli ◽

Francesca Rosa ◽

Simona Boccardo ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Animal Models ◽

Cancer Cells ◽

Before And After ◽

Breast And Prostate Cancer ◽

Prostate Cancers ◽

Calcium Receptors ◽

Manganese Enhanced Mri

ABSTRACTProceduresTo assess the relationship between Manganese Enhanced Magnetic Resonance Imaging (MEMRI) and the expression of calcium receptors in human prostate and breast cancer animal models.MethodsNOD/SCID mice were inoculated with MDA-MB-231 breast cancer cells and prostate PC3 cancer cells to develop orthotopic or pseudometastatic cancer animal models. Mice were studied on a clinical 3T scanner by using a prototype birdcage coil before and after intravenous injection of MnCl2. Assessment of receptor’s status was carried out after the MR images acquisition by immunohistochemistry on excised tumours.ResultsManganese contrast enhancement in breast or prostate cancer animal models well correlated with CaSR expression (p<0.01), whereas TRPV6 expression levels appeared not relevant to the Mn uptake.ConclusionMEMRI appears an efficient tool to characterize human breast and prostate cancer animal models in the presence of different expression level of CaSR.

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Bone Metastasis: Molecular Mechanisms Implicated in Tumour Cell Dormancy in Breast and Prostate Cancer

Current Cancer Drug Targets ◽

10.2174/1568009615666150506092443 ◽

2015 ◽

Vol 15 (6) ◽

pp. 469-480 ◽

Cited By ~ 20

Author(s):

Lewis Quayle ◽

Penelope Ottewell ◽

Ingunn Holen

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Tumour Cell ◽

Molecular Mechanisms ◽

Breast And Prostate Cancer ◽

Cell Dormancy

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

Bone Research ◽

10.1038/s41413-021-00136-2 ◽

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.

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Recruitment of β-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells

Molecular Endocrinology ◽

10.1210/me.2003-0436 ◽

2004 ◽

Vol 18 (10) ◽

pp. 2388-2401 ◽

Cited By ~ 46

Author(s):

David Masiello ◽

Shao-Yong Chen ◽

Youyuan Xu ◽

Manon C. Verhoeven ◽

Eunis Choi ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Nuclear Receptor ◽

Specific Antigen ◽

Prostate Cancer Cells ◽

Prostate Cell ◽

Nuclear Receptor Corepressor ◽

Prostate Cancers

Abstract Prostate cancers respond to treatments that suppress androgen receptor (AR) function, with bicalutamide, flutamide, and cyproterone acetate (CPA) being AR antagonists in clinical use. As CPA has substantial agonist activity, it was examined to identify AR coactivator/corepressor interactions that may mediate androgen-stimulated prostate cancer growth. The CPA-liganded AR was coactivated by steroid receptor coactivator-1 (SRC-1) but did not mediate N-C terminal interactions or recruit β-catenin, indicating a nonagonist conformation. Nonetheless, CPA did not enhance AR interaction with nuclear receptor corepressor, whereas the AR antagonist RU486 (mifepristone) strongly stimulated AR-nuclear receptor corepressor binding. The role of coactivators was further assessed with a T877A AR mutation, found in LNCaP prostate cancer cells, which converts hydroxyflutamide (HF, the active flutamide metabolite) into an agonist that stimulates LNCaP cell growth. The HF and CPA-liganded T877A ARs were coactivated by SRC-1, but only the HF-liganded T877A AR was coactivated by β-catenin. L-39, a novel AR antagonist that transcriptionally activates the T877A AR, but still inhibits LNCaP growth, similarly mediated recruitment of SRC-1 and not β-catenin. In contrast, β-catenin coactivated a bicalutamide-responsive mutant AR (W741C) isolated from a bicalutamide-stimulated LNCaP subline, further implicating β-catenin recruitment in AR-stimulated growth. Androgen-stimulated prostate-specific antigen gene expression in LNCaP cells could be modulated by β-catenin, and endogenous c-myc expression was repressed by dihydrotestosterone, but not CPA. These results indicate that interactions between AR and β-catenin contribute to prostate cell growth in vivo, although specific growth promoting genes positively regulated by AR recruitment of β-catenin remain to be identified.

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