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Novel approaches to target the microenvironment of bone metastasis

Nature Reviews Clinical Oncology volume 18, pages 488–505 (2021)Cite this article

Subjects

Abstract

Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell–osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.

Key points

  • Bone metastases are frequent events associated with advanced-stage malignancies, particularly breast and prostate cancers, and often result in pathological fractures, pain, disability, reduced quality of life and a poor prognosis.

  • Circulating tumour cells can be detected in the blood using standardized liquid biopsy assays and can provide insights into the metastatic process, inform clinical risk stratification, and enable monitoring and tracing of resistance to therapy.

  • Disseminated tumour cells (DTCs) can be detected in the bone marrow through bone marrow aspiration. Their fate is variable and can include apoptosis or immune-mediated cell death, persistence and dormancy, or progression to overt bone metastases.

  • DTCs mutually interact with diverse components of the bone microenvironment, including bone cells, adipocytes, endothelial cells and various immune cells as well as the extracellular matrix. Survival strategies of DTCs involve interference with bone cell and adipocyte functions, immune evasion and neoangiogenesis.

  • On the basis of emerging knowledge of the biology of bone metastasis, several bone-targeted therapies are currently under evaluation in preclinical studies and clinical trials.

  • Approved therapies for patients with established bone metastases include bisphosphonates, the anti-receptor activator of NF-κB ligand (RANKL) antibody denosumab and radium-223.

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Fig. 1: CTCs, DTCs and bone metastasis and emerging diagnostic opportunities.
Fig. 2: Bone remodelling and the key regulatory signalling proteins.
Fig. 3: Interactions of tumour cells with the bone microenvironment.

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Acknowledgements

All authors acknowledge funding of their original research by the Deutsche Forschungsgemeinschaft Priority Programme SPP 2084 µBONE. In addition, the work of L.C.H. has been supported by grant HO 1875/27-1 and that of A.B. by grant project-A01, FOR2886 TP02 of the Collaborative Research Centre (CRC) 1181, both from Deutsche Forschungsgemeinschaft. K.P. has received funding from the EFPIA and European Union Innovative Medicines Initiative Joint Undertaking for the research project CANCER-ID (grant 115749), the Deutsche Krebshilfe (grant 70112504) and the European Research Council (ERC; Advanced Investigator Grant INJURMET/834974). The authors thank F. Lademann and A. Offermann for assistance with the figures for this article and T. Reiche and A. Strehle for secretarial support.

Review criteria

We performed a PubMed search for full original and review papers in English published up to September 2020, using the key words “breast cancer”, “prostate cancer”, “bone metastases”, “bone cells”, “bone marrow niches”, “circulating tumour cells” and “disseminated tumour cells”. From this initial search, all authors selected the most recent (generally no older than 2014) and most relevant papers for inclusion, but also included seminal studies published since 2001.

Author information

Authors and Affiliations

  1. University Center for Healthy Aging, Dresden University of Technology, Dresden, Germany

    Lorenz C. Hofbauer & Martina Rauner

  2. Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany

    Lorenz C. Hofbauer & Martina Rauner

  3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) partner site Dresden, Dresden, Germany

    Lorenz C. Hofbauer

  4. Department of Internal Medicine 3 — Rheumatology and Immunology, Friedrich–Alexander University Erlangen–Nürnberg and University Hospital Erlangen, Erlangen, Germany

    Aline Bozec

  5. Department of Orthopedic Surgery, Julius Maximilians University of Würzburg, Würzburg, Germany

    Franz Jakob

  6. Department of Functional Materials in Medicine and Dentistry, Julius Maximilians University of Würzburg, Würzburg, Germany

    Franz Jakob

  7. Institute of Pathology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

    Sven Perner

  8. Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany

    Sven Perner

  9. Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg–Eppendorf, Hamburg, Germany

    Klaus Pantel

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  1. Lorenz C. Hofbauer
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  2. Aline Bozec
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Contributions

All authors made substantial contributions to each stage of the preparation of the manuscript for publication.

Corresponding authors

Correspondence to Lorenz C. Hofbauer or Klaus Pantel.

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Competing interests

L.C.H. has received honoraria for clinical trials from Alexion, Amgen, Ascendis Pharma, Novartis and Shire, and as a member of advisory boards from Amgen, Kyowa Kirin International, Shire and UCB. M.R. has received honoraria as a member of advisory boards and for lectures from Amgen and Diasorin. F.J. has received unrestricted grants and support for clinical studies from Alexion, Amgen, Lilly and Novartis, and honoraria for lectures and as a member of advisory boards from Alexion, Amgen, Kyowa Kirin International and Lilly. S.P. has received honoraria as a member of advisory boards and for lectures from AstraZeneca, Bristol Myers Squibb, MetaSystems, MSD, Novartis, Roche and Ventana Medical Systems, and research funds from Boehringer Ingelheim, Bristol Myers Squibb, MSD, Roche and Ventana Medical Systems. K.P. has ongoing patent applications related to circulating tumour cells (pending EU patent application no. 18705153.7 (PCT/EP2018/054052)) and has received honoraria from Agena, Illumina, Menarini, Novartis, Roche and Sanofi, and research funding from European Federation of Pharmaceutical Industries and Associations (EFPIA) partners (Angle, Menarini and Servier) of the CANCER-ID programme of the European Union Innovative Medicines Initiative (IMI) Joint Undertaking. A.B. declares no competing interests.

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Nature Reviews Clinical Oncology thanks R. Coleman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Hofbauer, L.C., Bozec, A., Rauner, M. et al. Novel approaches to target the microenvironment of bone metastasis. Nat Rev Clin Oncol 18, 488–505 (2021). https://doi.org/10.1038/s41571-021-00499-9

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