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Targeting Bone Metastasis in Cancers

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 52677

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Dr. Edith Bonnelye

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Guest Editor

Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
Interests: bone metastases; breast cancer; prostate cancer; bone physiology; osteoblasts; osteoclasts; chondrocytes

Dr. Patricia Juárez

E-Mail Website
Guest Editor

Center for Scientific Research and Higher Education at Ensenada (CICESE). Baja California, México
Interests: bone metastases; homing and tumor microenvironment; bone remodeling; anti-resortive agents; targeted therapy

Special Issue Information

Dear Colleagues,

Multiple clinical studies have provided evidence that bone is a preferred site of metastasis for breast and prostate cancers. An increase in the incidence of bone metastases combined with new treatments that improve the survival of patients affected by thyroid, lung, and colon cancers has also been documented, suggesting that the management of bone metastases is becoming a major heath issue. The presence of bone metastasis can dramatically affect the quality of life of patients, and indeed, when breast cancer cells metastasize to bone, the five-year survival rate decreases from 80% to 8%. At present, there are no “cures” for bone metastases; thus, there is an urgent need for a better understanding of the mechanisms involved in this pathology to allow the design of alternative therapies.

For this Special Issue of Cancers, we particularly welcome authors to submit original research articles, concise reviews, or shorter perspective articles on the different characteristics of primary tumors (CTC, bone tropism properties, microRNA signature); bone metastases (DTC), their microenvironment (osteoblasts, osteoclasts, osteocytes), and their relationship with physiological stressors such as hypoxia and acidification (pH); and metabolic switches and their interactions with the nervous, muscle, and immune systems. Articles that include mechanistic and functional insights from cellular and molecular biological perspectives are especially welcome.

Dr. Edith Bonnelye
Dr. Patricia Juárez
Guest Editors

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 metastases
bone microenvironment
osteoblasts
osteoclasts
osteocytes
immune cells
nerves
muscles
osteomimicry
microRNA
energetic metabolism
stress
epigenetics

Published Papers (13 papers)

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Editorial

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4 pages, 169 KiB

Open AccessEditorial

Targeting Bone Metastasis in Cancers

by Edith Bonnelye and Patricia Juárez

Cancers 2021, 13(17), 4490; https://doi.org/10.3390/cancers13174490 - 06 Sep 2021

Cited by 2 | Viewed by 1656

Abstract

This Special Issue of Cancers covers different aspects of bone physiopathology in oncology that combine the microenvironment and the factors involved in bone metastasis dormancy and progression [...] Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

Research

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16 pages, 1418 KiB

Open AccessArticle

Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases

by Soraia Lobo-Martins, Arlindo R. Ferreira, André Mansinho, Sandra Casimiro, Kim Leitzel, Suhail Ali, Allan Lipton and Luís Costa

Cancers 2020, 12(8), 2034; https://doi.org/10.3390/cancers12082034 - 24 Jul 2020

Cited by 5 | Viewed by 2190

Abstract

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01–1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06–1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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15 pages, 1104 KiB

Open AccessArticle

A Retrospective Observational Study of Risk Factors for Denosumab-Related Osteonecrosis of the Jaw in Patients with Bone Metastases from Solid Cancers

by Satoe Okuma, Yuhei Matsuda, Yoshiki Nariai, Masaaki Karino, Ritsuro Suzuki and Takahiro Kanno

Cancers 2020, 12(5), 1209; https://doi.org/10.3390/cancers12051209 - 12 May 2020

Cited by 20 | Viewed by 3636

Abstract

This single-center retrospective observational study aimed to identify risk factors for developing denosumab-related osteonecrosis of the jaw (DRONJ) in stage IV solid cancer patients with bone metastases. In total, 123 consecutive patients who had received 120 mg of denosumab every 4 weeks at least twice between July 2014 and October 2018 were included. We surveyed their demographics, medical history, blood test, underlying disease, and intraoral findings. Fourteen patients (11.4%) developed DRONJ within a mean denosumab administration period of 4 months (range: 2–52 months). Univariate analyses showed a statistically significant correlation between DRONJ and hormone therapy, chemotherapy/molecular target drug, apical periodontitis, periodontal disease, sex and body mass index. Multivariate analysis showed a statistically significant correlation between DRONJ and hormone therapy (odds ratio [OR], 22.07; 95% confidence interval [CI], 2.86–170.24), chemotherapy and/or molecular targeted therapy (OR, 18.61; 95% CI, 2.54–136.27), and apical periodontitis (OR, 22.75; 95% CI, 3.20–161.73). These findings imply that collaborative oral examinations by oral specialists may reduce the risk of development of DRONJ in patients treated with denosumab for bone metastases from solid cancers. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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20 pages, 3937 KiB

Open AccessArticle

TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases

by Florian Drescher, Patricia Juárez, Danna L. Arellano, Nicolás Serafín-Higuera, Felipe Olvera-Rodriguez, Samanta Jiménez, Alexei F. Licea-Navarro and Pierrick G.J. Fournier

Cancers 2020, 12(4), 868; https://doi.org/10.3390/cancers12040868 - 03 Apr 2020

Cited by 10 | Viewed by 4649

Abstract

Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G₀/G₁ phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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Review

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18 pages, 632 KiB

Open AccessReview

Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis

by Maria-Bernadette Madel and Florent Elefteriou

Cancers 2021, 13(12), 2887; https://doi.org/10.3390/cancers13122887 - 09 Jun 2021

Cited by 13 | Viewed by 3736

Abstract

The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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15 pages, 311 KiB

Open AccessReview

Bone Marrow Adipocytes: A Link between Obesity and Bone Cancer

by Michaela R. Reagan, Heather Fairfield and Clifford J. Rosen

Cancers 2021, 13(3), 364; https://doi.org/10.3390/cancers13030364 - 20 Jan 2021

Cited by 20 | Viewed by 2968

Abstract

Cancers that grow in the bone marrow are for most patients scary, painful, and incurable. These cancers are especially hard to treat due to the supportive microenvironment provided by the bone marrow niche in which they reside. New therapies designed to target tumor cells have extended the life expectancy for these patients, but better therapies are needed and new ideas for how to target these cancers are crucial. This need has led researchers to interrogate whether bone marrow adipocytes (BMAds), which increase in number and size during aging and in obesity, contribute to cancer initiation or progression within the bone marrow. Across the globe, the consensus in the field is a unified “yes”. However, how to target these adipocytes or the factors they produce and how BMAds interact with different tumor cells are open research questions. Herein, we review this research field, with the goal of accelerating research in the network of laboratories working in this area and attracting bright scientists with new perspectives and ideas to the field in order to bring about better therapies for patients with bone cancers. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

20 pages, 1069 KiB

Open AccessReview

Diagnosis and Treatment of Bone Metastases in Breast Cancer: Radiotherapy, Local Approach and Systemic Therapy in a Guide for Clinicians

by Fabio Marazzi, Armando Orlandi, Stefania Manfrida, Valeria Masiello, Alba Di Leone, Mariangela Massaccesi, Francesca Moschella, Gianluca Franceschini, Emilio Bria, Maria Antonietta Gambacorta, Riccardo Masetti, Giampaolo Tortora and Vincenzo Valentini

Cancers 2020, 12(9), 2390; https://doi.org/10.3390/cancers12092390 - 24 Aug 2020

Cited by 20 | Viewed by 4731

Abstract

The standard care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive settings are even more common—paving the way to a paradigm change of focal treatments role. In fact, according to immunophenotype, radiotherapy can be considered with radical intent in these settings of patients. The aim of this literature review is to analyze available clinical data on prognosis of bone metastases from breast cancer and benefits of available treatments for developing a practical guide for clinicians. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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24 pages, 1275 KiB

Open AccessReview

Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases

by Steven L. Wood and Janet E. Brown

Cancers 2020, 12(8), 2109; https://doi.org/10.3390/cancers12082109 - 29 Jul 2020

Cited by 19 | Viewed by 3743

Abstract

Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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41 pages, 1804 KiB

Open AccessReview

Contribution of Macrophages and T Cells in Skeletal Metastasis

by Veronica Mendoza-Reinoso, Laurie K. McCauley and Pierrick G.J. Fournier

Cancers 2020, 12(4), 1014; https://doi.org/10.3390/cancers12041014 - 20 Apr 2020

Cited by 19 | Viewed by 4822

Abstract

Bone is a common site for metastases with a local microenvironment that is highly conducive for tumor establishment and growth. The bone marrow is replete with myeloid and lymphoid linage cells that provide a fertile niche for metastatic cancer cells promoting their survival and growth. Here, we discuss the role of macrophages and T cells in pro- and anti-tumoral mechanisms, their interaction to support cancer cell growth, and their contribution to the development of skeletal metastases. Importantly, immunotherapeutic strategies targeting macrophages and T cells in cancer are also discussed in this review as they represent a great promise for patients suffering from incurable bone metastases. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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24 pages, 1227 KiB

Open AccessReview

GP130 Cytokines in Breast Cancer and Bone

by Tolu Omokehinde and Rachelle W. Johnson

Cancers 2020, 12(2), 326; https://doi.org/10.3390/cancers12020326 - 31 Jan 2020

Cited by 27 | Viewed by 6483

Abstract

Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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29 pages, 1836 KiB

Open AccessReview

What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence

by Francesca Salamanna, Veronica Borsari, Deyanira Contartese, Viviana Costa, Gianluca Giavaresi and Milena Fini

Cancers 2019, 11(12), 2018; https://doi.org/10.3390/cancers11122018 - 13 Dec 2019

Cited by 15 | Viewed by 3023

Abstract

Breast cancer cells produce stimulators of bone resorption known as interleukins (ILs). However, data on the functional roles of ILs in the homing of metastatic breast cancer to bone are still fragmented. A systematic search was carried out in three databases (PubMed, Scopus, Web of Science Core Collection) to identify preclinical reports, and in three clinical registers (ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, European Union (EU) Clinical Trials Register) to identify clinical trials, from 2008 to 2019. Sixty-seven preclinical studies and 11 clinical trials were recognized as eligible. Although preclinical studies identified specific key ILs which promote breast cancer bone metastases, which have pro-metastatic effects (e.g., IL-6, IL-8, IL-1β, IL-11), and whose inhibition also shows potential preclinical therapeutic effects, the clinical trials focused principally on ILs (IL-2 and IL-12), which have an anti-metastatic effect and a potential to generate a localized and systemic antitumor response. However, these clinical trials are yet to post any results or conclusions. This inconsistency indicates that further studies are necessary to further develop the understanding of cellular and molecular relations, as well as signaling pathways, both up- and downstream of ILs, which could represent a novel strategy to treat tumors that are resistant to standard care therapies for patients affected by breast cancer bone disease. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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20 pages, 1609 KiB

Open AccessReview

Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management

by Barbara Altieri, Carla Di Dato, Chiara Martini, Concetta Sciammarella, Antonella Di Sarno, Annamaria Colao and Antongiulio Faggiano

Cancers 2019, 11(9), 1332; https://doi.org/10.3390/cancers11091332 - 08 Sep 2019

Cited by 28 | Viewed by 4565

Abstract

Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient’s quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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17 pages, 1817 KiB

Open AccessReview

Skeletal Metastases of Unknown Primary: Biological Landscape and Clinical Overview

by Antonella Argentiero, Antonio Giovanni Solimando, Oronzo Brunetti, Angela Calabrese, Francesco Pantano, Michele Iuliani, Daniele Santini, Nicola Silvestris and Angelo Vacca

Cancers 2019, 11(9), 1270; https://doi.org/10.3390/cancers11091270 - 29 Aug 2019

Cited by 26 | Viewed by 5565

Abstract

Skeletal metastases of unknown primary (SMUP) represent a clinical challenge in dealing with patients diagnosed with bone metastases. Management of these patients has improved significantly in the past few years. however, it is fraught with a lack of evidence. While some patients have achieved impressive gains, a more systematic and tailored treatment is required. Nevertheless, in real-life practice, the outlook at the beginning of treatment for SMUP is decidedly somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidence; three key points emerged. The characterization of the SMUP biological profile is essential to driving clinical decisions by integrating genetic and molecular profiles into a multi-step diagnostic work-up. Nonetheless, a pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials. The discussion in this review points out that greater efforts are required to face the unmet needs present in SMUP patients in oncology. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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