Cancer to Bone: A Fatal Attraction
When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour-bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases.
Tumors are generally incurable once they have metastasized to bone. Devastating consequences of bone metastases include pathological bone fractures, pain, hypercalcaemia, and spinal cord and nerve-compression syndromes1. Bone metastases are a common complication of cancer and occur in 65–80% of patients with metastatic breast and prostate cancers. The incidence of bone metastases is also increasing in other cancers, probably owing to improved tumour control at other disease sites4.
Tumour invasion into bone is associated with osteoclast and osteoblast recruitment, resulting in the liberation of growth factors from the bone matrix, which can feed back to enhance tumour growth resulting in the 'vicious cycle' of bone metastases. Indeed, the successful suppression of bone turnover with bisphosphonates in patients who had bone metastases that resulted in high levels of bone resorption markers was associated with improved survival. Beyond the effects on osteoclasts and osteoblasts, tumours in the bone microenvironment recruit and modulate the function of platelets, myeloid cells, immune cells and nerve cells, and induce the formation of new blood vessels. The bone marrow also serves as a reservoir for dormant tumour cells that can resist chemotherapeutic attack, and these tumour cells can emerge later as full-blown metastases in bone or other organs.
Drugs, such as bisphosphonates or receptor activator of NF-kB ligand (RANKL; also known as TNFSF11) antibodies, that target osteoclastogenesis significantly decrease the incidence of skeletal complications and are the current standard of care for patients with bone metastases. There are emerging data that these anti-resorptive agents can also have direct antitumour effects. However, 30–50% of patients on such therapies still develop new bone metastases, skeletal complications and disease progression, emphasizing the need for new therapies. Important advances in understanding the basic biology of bone remodelling, haematopoiesis, haematopoietic cell egress and homing to bone marrow have uncovered new therapeutic targets for the prevention and treatment of bone metastasis.