Bone metastasis: mechanisms and therapeutic opportunities

Abstract

The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy.

Conflict of interest statement

Competing interests

The authors declare no competing interests.

© 2011 Macmillan Publishers Limited. All rights reserved

Figures

Figure 1

Steps involved in tumor cell metastasis from a primary site to the skeleton. Each of the steps in the metastatic process offer potential points of therapeutic intervention to reverse or prevent the development of bone metastasis. a | In the primary tumor, both tumor cells (shown in green) and local stroma (shown in brown) interact via a variety of mechanisms to enhance tumor cell migration and escape into the systemic circulation. b | Once in the vasculature, tumor cells interact with resident host blood-borne cells, such as erythrocytes, T cells and neutrophils and with platelets, which facilitate survival in the circulation. c | In the bone marrow, the tumor cells escape from the vasculature (extravasation) into the bone marrow where they interact with resident bone marrow cells for subsequent survival and eventual activation of resident bone cells, such as osteoclasts (shown in red). As a result, a bone metastatic foci is formed.

Figure 2

Biochemical markers of bone turnover are released during bone remodeling. In humans, bone is repeatedly removed and replaced by the continuous and well-managed processes of bone resorption (by osteoclasts) and bone formation (by osteoblasts). Collectively, these coupled processes comprise the bone remodeling cycle that is the fundamental physiologic process responsible for the maintenance of bone mass and strength. The process of bone remodeling is highly ordered and is mediated by changes in the activities of multinucleated osteoclasts (monocyte/macrophage-derived cells) and osteoblasts (mesenchymal-derived cells). Following activation of osteoclastogenesis and recruitment to the bone surface, activated precursors fuse, become multinucleated, form a ruffled border and begin excavation of the bone surface. During the process of bone resorption, catalytic fragments of bone matrix type I collagen (NTx and CTx) are released and enter the systemic circulation. As resorption is completed, mesenchymal osteoblast precursors are recruited to the previously resorbed bone surface and osteoblastogenesis occurs, which results in the differentiation of active, cuboidal osteoblasts. These secretory cells lay down osteoid that is eventually mineralized so that the previously resorbed surface is replaced with an equal quantity of newly formed bone. During the process of bone formation, the osteoblasts secrete characteristic protein markers, alkaline phosphatase (ALP), osteocalcin (OC) and procollagen type 1 aminoterminal propeptide (P1NP), which are the clinical markers correlated with bone formation activity. In cancer patients with bone metastases, tumor cells disrupt the normal process of bone resorption and bone formation, leading to increased bone destruction and/or aberrant bone formation. Abbreviations: CTx, carboxyterminal crosslinking telopeptide of type I collagen; NTx, aminoterminal crosslinking telopeptide of type I collagen.

Figure 3

The stimulation of bone cell activity by tumors in the bone marrow. Interactions between tumor cells, bone marrow components (for example, stromal cells, platelets, immune cells and hematopoietic progenitors) and resident bone cells results in activation of both osteoclasts and osteoblasts, causing bone resorption, as well as robust bone formation. Tumor-derived activation of host bone cells also supports the aggressive growth and behavior of tumor cells. (1) The release of tumor-derived factors, such as parathyroid hormone-related protein (PTHrP), interleukin 8 (IL-8), tumor necrosis factor (TNF), transforming growth factor β (TGF-β), heparanase and many others, enhances osteoclast activation and bone resorption via RANKL-dependent and RANKL-independent mechanisms. Bone resorption results in the release of bone-derived growth factors that support tumor proliferation. Tumor activation also drives the activation of local stromal cells and platelets that may also enhance tumor proliferation. (2) The production of growth factors such as fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), TGF-β and Wnt family members by metastatic tumors stimulates osteoblast activity, leading to increased bone formation. The result of the enhanced osteoblast proliferation and activity is again tumor stimulation, as well as the normal coupling responses to help enhance osteoclastogenesis and bone resorption. Collectively, these numerous cellular interactions drive all of the well-described skeletal consequences of bone metastasis and result in the inappropriate bone formation and bone resorption characteristic of bone metastasis.