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Bone Metastasis: Its Cellular and Molecular Mechanisms

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 14016

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Special Issue Editor

Prof. Dr. Naofumi Mukaida

E-Mail Website1 Website2
Guest Editor

Kanazawa University, Division of Molecular Bioregulation, Kanazawa, Japan
Interests: chemokine; tumor microenvironment; metastasis; invasion; Immunology; Laboratory medicine; Experimental Pathology; Pathological Medical Biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bone metastasis frequently complicates patients suffering from cancer in various organs, particularly, breast, prostate, and lung, and worsens patients’ quality of life and reduces their life expectancy. Bone metastasis proceeds via the interaction between cancer cells and the bone microenvironments composed of osteoclasts, osteoblasts, the mineralized bone matrix, endothelial cells, stroma cells, and hematopoietic cells. Evidence is accumulating to indicate the involvement of osteoclast activation in bone metastasis, and consequently, bone metastasis is frequently treated with drugs with a capacity to inhibit osteoclast activation, such as bisphosphonates and the monoclonal antibody targeting the receptor activator of NF-κB (RANK) ligand. However, these drugs do not directly target cancer cells and, as a consequence, are palliative, rather than curative. A novel strategy against bone metastasis is, therefore, required to be developed based on the understanding of the molecular and cellular mechanisms underlying bone metastasis.

This Special Issue of Cancers therefore encompasses new research articles and timely reviews on cellular and molecular mechanisms underlying bone metastasis, which can contribute to an advancement in our understanding of the pathophysiology of bone metastasis and the subsequent development of a novel strategy for bone metastasis control.

Prof. Dr. Naofumi Mukaida
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Bone metastasis;
Osteoclast;
Tumor microenvironment;
Circulating tumor cell;
Extravasation;
Intravasation.

Published Papers (5 papers)

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Research

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17 pages, 2744 KiB

Open AccessArticle

The Stage-Specific Plasticity of Descending Modulatory Controls in a Rodent Model of Cancer-Induced Bone Pain

by Mateusz Wojciech Kucharczyk, Diane Derrien, Anthony Henry Dickenson and Kirsty Bannister

Cancers 2020, 12(11), 3286; https://doi.org/10.3390/cancers12113286 - 06 Nov 2020

Cited by 7 | Viewed by 2545

Abstract

Pain resulting from metastatic bone disease is a major unmet clinical need. Studying spinal processing in rodent models of cancer pain is desirable since the percept of pain is influenced in part by modulation at the level of the transmission system in the dorsal horn of the spinal cord. Here, a rodent model of cancer-induced bone pain (CIBP) was generated following syngeneic rat mammary gland adenocarcinoma cell injection in the tibia of male Sprague Dawley rats. Disease progression was classified as “early” or “late” stage according to bone destruction. Even though wakeful CIBP rats showed progressive mechanical hypersensitivity, subsequent in vivo electrophysiological measurement of mechanically evoked deep dorsal horn spinal neuronal responses revealed no change. Rather, a dynamic reorganization of spinal neuronal modulation by descending controls was observed, and this was maladaptive only in the early stage of CIBP. Interestingly, this latter observation corresponded with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting CIBP in a stage-specific manner. Finally, the data herein have translational potential since the descending control pathways measured are present also in humans. Full article

(This article belongs to the Special Issue Bone Metastasis: Its Cellular and Molecular Mechanisms)

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26 pages, 7066 KiB

Open AccessArticle

Cx43 Present at the Leading Edge Membrane Governs Promigratory Effects of Osteoblast-Conditioned Medium on Human Prostate Cancer Cells in the Context of Bone Metastasis

by Jonathan Boucher, Annie-Claire Balandre, Marjolaine Debant, Justine Vix, Thomas Harnois, Nicolas Bourmeyster, Elodie Péraudeau, Amandine Chépied, Jonathan Clarhaut, Françoise Debiais, Arnaud Monvoisin and Laurent Cronier

Cancers 2020, 12(10), 3013; https://doi.org/10.3390/cancers12103013 - 16 Oct 2020

Cited by 3 | Viewed by 2392

Abstract

Among the different interacting molecules implicated in bone metastases, connexin43 (Cx43) may increase sensitivity of prostate cancer (PCa) cells to bone microenvironment, as suggested by our in silico and human tissue samples analyses that revealed increased level of Cx43 expression with PCa progression and a Cx43 specific expression in bone secondary sites. The goal of the present study was to understand how Cx43 influences PCa cells sensitivity and aggressiveness to bone microenvironment. By means of Cx43-overexpressing PCa cell lines, we revealed a Cx43-dependent promigratory effect of osteoblastic conditioned media (ObCM). This effect on directional migration relied on the presence of Cx43 at the plasma membrane and not on gap junctional intercellular communication and hemichannel functions. ObCM stimulation induced Rac1 activation and Cx43 interaction with cortactin in protrusions of migrating PCa cells. Finally, by transfecting two different truncated forms of Cx43 in LNCaP cells, we determined that the carboxy terminal (CT) part of Cx43 is crucial for the responsiveness of PCa cells to ObCM. Our study demonstrates that Cx43 level and its membrane localization modulate the phenotypic response of PCa cells to osteoblastic microenvironment and that its CT domain plays a pivotal role. Full article

(This article belongs to the Special Issue Bone Metastasis: Its Cellular and Molecular Mechanisms)

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18 pages, 2959 KiB

Open AccessArticle

Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone

by Di Zhang, Sadahiro Iwabuchi, Tomohisa Baba, Shin-ichi Hashimoto, Naofumi Mukaida and So-ichiro Sasaki

Cancers 2020, 12(10), 3003; https://doi.org/10.3390/cancers12103003 - 16 Oct 2020

Cited by 11 | Viewed by 2482

Abstract

Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment. Full article

(This article belongs to the Special Issue Bone Metastasis: Its Cellular and Molecular Mechanisms)

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19 pages, 3422 KiB

Open AccessArticle

Modulation of Rat Cancer-Induced Bone Pain is Independent of Spinal Microglia Activity

by Marta Diaz-delCastillo, Rie Bager Hansen, Camilla Kristine Appel, Lykke Nielsen, Sascha Nolsøe Nielsen, Konstantinos Karyniotakis, Louise M. Dahl, Rikke B. Andreasen and Anne-Marie Heegaard

Cancers 2020, 12(10), 2740; https://doi.org/10.3390/cancers12102740 - 24 Sep 2020

Cited by 8 | Viewed by 3330

Abstract

The dissemination of cancer to bone can cause significant cancer-induced bone pain (CIBP), severely impairing the patient’s quality of life. Several rodent models have been developed to explore the nociceptive mechanisms of CIBP, including intratibial inoculation of breast carcinoma cells in syngeneic Sprague Dawley rats. Using this model, we investigated whether resident spinal microglial cells are involved in the transmission and modulation of CIBP, a long-debated disease feature. Immunohistochemical staining of ionizing calcium-binding adaptor molecule 1 (Iba-1) and phosphorylated p38-mitogen-activated protein kinase (P-p38 MAPK) showed no spinal microglial reaction in cancer-bearing rats, independently of disease stage, sex, or carcinoma cell line. As a positive control, significant upregulation of both Iba-1 and P-p38 was observed in a rat model of neuropathic pain. Additionally, intrathecal administration of the microglial inhibitor minocycline did not ameliorate pain-like behaviors in cancer-bearing rats, in contrast to spinal morphine administration. Our results indicate that microglial reaction is not a main player in CIBP, adding to the debate that even within the same models of CIBP, significant variations are seen in disease features considered potential drug targets. We suggest that this heterogeneity may reflect the clinical landscape, underscoring the need for understanding the translational value of CIBP models. Full article

(This article belongs to the Special Issue Bone Metastasis: Its Cellular and Molecular Mechanisms)

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Review

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18 pages, 2317 KiB

Open AccessReview

Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process

by Naofumi Mukaida, Di Zhang and So-ichiro Sasaki

Cancers 2020, 12(10), 2896; https://doi.org/10.3390/cancers12102896 - 09 Oct 2020

Cited by 23 | Viewed by 2748

Abstract

Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients’ quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis. Full article

(This article belongs to the Special Issue Bone Metastasis: Its Cellular and Molecular Mechanisms)

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