Bone metastasis: mechanisms, therapies, and biomarkers

Author:

Clézardin Philippe12,Coleman Rob2,Puppo Margherita2,Ottewell Penelope2,Bonnelye Edith1,Paycha Frédéric3,Confavreux Cyrille B.14,Holen Ingunn2

Affiliation:

1. INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, University of Lyon 1, Lyon, France

2. Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom

3. Service de Médecine Nucléaire, Hôpital Lariboisière, Paris, France

4. Service de Rhumatologie Sud, CEMOS—Centre Expert des Métastases Osseuses, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

Abstract

Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability) that negatively affect the patient’s quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process: long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described, and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes, and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.

Funder

French National Institute for Cancer

INSERM LIA/LEA 2016

Weston Park Cancer Charity

French National Research Agency

Research Council UK

Publisher

American Physiological Society

Subject

Physiology (medical),Molecular Biology,Physiology,General Medicine

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