Cancer to bone: a fatal attraction

Abstract

Bone metastases are a common complication of cancer and are generally incurable. They cause considerable pain, pathological bone fractures and hypercalcaemia. Up to 50% of patients prescribed anti-resorptive drugs to treat bone metastases develop new bone metastases, skeletal complications and disease progression, emphasizing the need for new therapies. Tumour invasion into bone is associated with osteoclast and osteoblast recruitment. Osteoclasts secrete acid, collagenases and proteases that demineralize the bone matrix and degrade matricellular proteins. Macrophage colony stimulating factor and receptor activator of NF-κB ligand (RANKL) are important growth factors that support osteoclastogenesis, and they are primarily produced by osteoblasts. Osteoprotegerin is an endogenous decoy receptor of RANKL that inhibits osteoclastogenesis. Bone marrow mesenchymal stem cells are directed along the osteoblast lineage through local factors, such as transforming growth factor-β (TGFβ), bone morphogenetic proteins (BMPs) and WNT proteins. These pathways lead to the expression of three key transcriptional regulators of osteoblast function, including RUNX2. The osteoblast-stimulating activity of metastatic tumour cells is thought to be due to the ability of these cells to express many of the factors that can drive osteoblast formation. Osteoblasts and bone marrow stromal cells may attract metastatic tumour cells to bone and provide a niche through protein interactions that include integrins, such as α4β1–vascular cell adhesion molecule 1; chemokines, such as CXCL12–CXCR4; BMPs; Notch; nestin; and osteopontin. These mechanisms are similar to the physiological recruitment of haematopoietic stem cells. The invasion and growth of metastatic tumour cells in the bone involves the modulation of a large number of genes and proteins that include matrix metalloproteinases, parathyroid hormone-related protein, TGFβ, interleukin-6, Jagged 1–Notch, GLI2, RUNX2, hypoxia-induced growth factor 1α, calcium and the calcium-sensing receptor. 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. These changes all help to ensure the growth and survival of metastatic tumour cells in bone and represent important therapeutic targets. Drugs, such as bisphosphonates or RANKL antibodies, that target osteoclastogenesis decrease the incidence of skeletal complications and are the current standard of care for patients with bone metastases. These anti-resorptive agents might also have direct antitumour effects. Advances in our understanding of the basic biology of bone remodelling, biomechanics and haematopoiesis, coupled with the advances in cancer genetics and tumour imaging should yield new therapeutic targets and insights into cancer metastasis in bone.