Cancer to bone: a fatal attraction

Abstract

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.

Figure 1. Bone remodelling

The bone is a dynamic hard tissue that undergoes a continuous remodelling process to maintain skeletal strength and integrity, with 10% of the skeleton being replaced annually. In a finely balanced, coupled and sequential process (indicated by the dashed arrows), haematopoietic stem cell (HSC)-derived osteoclasts resorb bone (releasing growth factors and calcium) and mesenchymal stem cell (MSC)-derived osteoblasts replace the voids with new bone, a process that is dependent on osteoblast commitment, proliferation and differentiation coupled with osteoblast production of type I collagen and its subsequent mineralization to form the calcified matrix of bone. Osteocytes, which are terminally differentiated osteoblasts that are embedded in bone, sense mechanical strain, signal to osteoclasts and osteoblasts, and participate in the remodelling process. Bone lining cells are osteoblastic in origin and have been proposed to form both a canopy over remodelling sites and a layer over bone surfaces, as well as a conduit to communicate with osteocytes. The endosteum and periosteum (the lining on the inner and outer bone surfaces) contain a population of tissue macrophages, termed osteomacs, which are likely to have important roles in bone remodelling. M-CSF, macrophage colony stimulating factor; RANK, receptor activator of NF-κB; RANKL, RANK ligand.

Figure 2. Cross-section of bone depicting stages of bone metastases

Schematic representation of tumour cell interactions within the bone microenvironment during stages of tumour metastasis to bone — tumour cell homing, dormancy, colonization and expansion. Tumour cells home to and enter the bone marrow cavity and either remain quiescent or dormant or begin growth and colonization. Tumour-mediated recruitment and modulation of bone-residing cells (osteoclasts, osteoblasts, fibroblasts, blood vessels, mesenchymal stem cells, haematopoetic stem cells (HSCs), lymphocytes, macrophages, platelets, neurons and osteocytes) and bone matrix modifications alter the bone environment thus favouring tumour growth and invasion and resulting in pain, fracture and further tumour dissemination.

Figure 3. Tumour–osteoblast interactions

Tumours produce various factors that regulate bone formation at different levels of osteoblast development. Bone morphogenetic proteins (BMPs), WNTs and transforming growth factor-β (TGFβ) provide signals to mesenchymal stem cells (MSCs) to move to areas of bone formation and to differentiate to the osteoblast lineage. Osteoblast progenitors and pre-osteoblastic cells respond to positive osteoblastic factors that are produced by tumour cells, such as BMPs, endothelin 1 (ET1), insulin-like growth factors (IGFs), platelet-derived growth factor (PDGF), urinary plasminogen activator (uPA) and fibroblast growth factors (FGFs), as well as the negative regulator dickkopf 1 (DKK1). Osteoblast-associated transcription factors include RUNX2, osterix (OSX) and activating transcription factor 4 (ATF4). Once osteoblasts produce and mineralize a collagen matrix (shown in blue) they may undergo apoptosis, become lining cells or be sequestered in the bone matrix as terminally differentiated osteocytes. TGFβ can function at multiple stages that include recruiting stem cells and promoting stem cell renewal, coupling osteoclastic bone resorption to bone formation and inhibiting osteoblast differentiation. The BMP inhibitor, noggin, as well as endothelin A receptor antagonists, can block osteoblastic metastases. Little is known of the potential interactions between tumours and osteocytes.

Figure 4. Mechanisms of tumour-associated osteolysis

Tumours secrete osteolytic factors (such as, parathyroid hormone-related protein (PTHRP), interleukin-11 (IL-11), IL-6, IL-8, vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF), Jagged 1 and epidermal growth factor (EGF)-like ligands) that stimulate osteoclastic bone resorption either directly (indicated by solid arrows) or indirectly (indicated by dashed arrows) by increasing the ratio of receptor activator of NF-κB ligand (RANKL) to osteoprotegerin (OPG). Osteoclastic bone resorption causes the release and activation of growth factors (transforming growth factor-β (TGFβ) and insulin-like growth factors (IGFs)) and ions (calcium) that are stored in mineralized bone matrix to further enhance the local milieu. Tumour-associated hypoxia and hypoxia-inducible factor 1α (HIF1α) in conjunction with TGFβ can increase tumour production of VEGF and the chemokine CXCR4 to increase angiogenesis and tumour homing. Tumour-produced matrix metalloproteinases (MMPs) can cleave membrane-bound RANKL (blue balls) or EGF-like growth factors (red diamonds), which can increase the ratio of RANKL to OPG to favour osteoclastogenesis. Platelet-derived lysophosphatidic acid (LPA) and ADP act on tumour cells to induce growth and the release of osteolytic factors IL-8 and IL-6.

Figure 5. Clinical presentations of bone metastases

Bone metastases can be detected or indicated by various approaches. The presence of disseminated tumour cells in the bone marrow (shown in part a by immunohistochemical staining for cytokeratin in a bone marrow smear taken from a patient with breast cancer) is associated with an increased risk of bone metastasis. Post-mortem examination (part b) also clearly shows osteoblastic lesions, in this example in the vertebral bodies from a patient who died of mestatatic prostate cancer. A bone biopsy (part c) stained with haematoxylin and eosin from a patient with metastatic breast cancer clearly shows the invasion of the tumour cells into the bone and the presence of osteoclasts (OCs) and osteoblasts (OBs). Computerized tomography (CT) scans (part d) can clearly show the different types of bone lesions: a lytic metastasis present in a vertebral body from a patient with metastatic lung cancer; a blastic metastasis (deposition of new bone) in the pelvis of a patient with metastatic prostate cancer; and a scan that shows a patient with metastatic breast cancer who has both lytic and blastic metastases in the pelvis. Bone metastases can be extensive as indicated by the full-body bone scans (part e) from a patient with metastatic breast cancer. Metastases are clearly present in the skull, ribs, clavicles, spine, pelvis and the tops of the femurs. Positron emission tomography using radiolabelled [18F]-2-fluoro-deoxy-D-glucose combined with CT (part f) also clearly shows active bone metastases, in this case a sacral metastasis in a patient with metastatic renal cancer. BV, blood vessel. Part a courtesy of R. Aft, Washington University School of Medicine, USA. Part b courtesy of K. Pienta, University of Michigan School of Medicine, USA. Part c courtesy of D. Novack, Washington University School of Medicine, USA. Images in parts d–f courtesy of V. Reichert and J. Burkett, Washington University School of Medicine, USA.

Figure 6. Overlapping benefits of targeting tumour and stromal cells for bone metastases

The growth and survival of metastatic cancer cells in bone require the support of numerous cells and molecules within the bone microenvironment. Many of the therapies targeted to cancer cell signalling pathways (part a) have overlapping effects on bone stromal components (part b), which can enhance the antitumour effects. Likewise, stromal-targeted therapies can also target tumour cells. Many therapies target more than these two cell types, such as receptor tyrosine kinase (RTK) inhibitors. Anti-resorptive therapies target genes and proteins that are involved in functional osteoclast development from pre-osteoclasts and haematopoietic progenitor cells, but most of these therapies also have direct antitumour effects. Targeting pro-tumour and antitumour immunity that is mediated by myeloid cells and lymphocytes and the proteins that they secrete can disrupt tumour growth in bone and in other sites. Inhibition of platelet aggregation and activation can limit the release of platelet-derived pro-tumour and pro-angiogenic molecules and can disrupt tumour–platelet aggregates, reducing adhesion to bone vessels. Targeting acid-sensing and sympathetic neurons can decrease bone pain. A reduction in pain levels can improve quality of life, enhance mobility (which can strengthen bones and prevent fracture) and improve nutrition, which can promote improved survival. Anti-angiogenic therapies decrease tumour burden in bone and potential metastasis of metastases. Bone-targeted radiation not only targets tumour cells but can also disrupt fibroblast–stromal support of tumour cells. Numerous protein factors (such as transforming growth factor-β (TGFβ) and bone morphogenetic proteins (BMPs)) that are stored within the bone matrix, as well as calcium, are released during bone metastases and can enhance tumour growth and promote the activation and release of other bone-derived, pro-tumour growth factors. Targeting of osteoblasts through endothelin 1, chemokine disruption, anabolic effects of proteosomes or RTK and SRC inhibition can decrease fractures and decrease the release of tumour chemoattractants and osteoclast growth factors. MMP, matrix metalloproteinase; XRT, radiotherapy.