The Biology of Bone Metastasis

Abstract

Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease.

Figure 1.

The balance between dormancy and outgrowth of bone-resident cancer cells. Multiple lines of research suggest that dormant cancer cells within the bone maintain a prosurvival mesenchymal state characterized by high thrombospondin-1 (TSP1), transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) signaling and SRC activity, as well as Dickkopf-1 (DKK1)-suppressed Wnt activity. On stimulation by various stromal signaling and adhesion interactions, such as POSTN, JAG1–NOTCH, E-cadherin (CDH1)–N-cadherin (CDH2), and colony-stimulating factor 1 (CSF1)–FMS, these cells enter a proliferative and epithelial state that is vulnerable to immune surveillance as well as cytotoxic agents. The processes underlying this transition remain poorly described but are thought to rely on key factors from both the endosteal niche and the osteoblastic niche. Transit and homing between these two niches appears to be regulated by high CXCL12 levels at the endosteal site and high receptor activator of nuclear factor (NF)-κB ligand (RANKL) or parathyroid hormone–related protein (PTHrP) levels at the osteoblastic site. NK, Natural killer; pDC, plasmacytoid dendritic cell.

Figure 2.

The “vicious cycles” of osteolytic and osteogenic bone metastases. A positive-feedback cycle develops during late-stage bone metastasis in which the normal processes regulating bone homeostasis are disrupted and hijacked by tumor cells. The core process of the vicious cycle of bone metastasis involves several secreted factors. Parathyroid hormone–related protein (PTHrP) secreted by tumor cells induces receptor activator of nuclear factor (NF)-κB ligand (RANKL) secretion by osteoblasts. This stimulates the maturation of monocytes into osteoclasts, which are responsible for degrading the bone matrix. This matrix is replete with growth factors such as calcium and transforming growth factor (TGF)-β, which then bind tumor cells to induce more production of metastasis-promoting factors, such as PTHrP and Jagged1. Jagged1 directly promotes osteoclastogenesis and stimulates the production of tumor-promoting interleukin (IL)-6 from osteoblasts, leading to more bone destruction and metastatic tumor growth. This cycle is further augmented by direct interaction with monocytic or osteoblastic cells via integrin, epidermal growth factor receptor (EGFR) and other signaling pathways. Less is known about osteoblastic metastases, except that cancer cells mimic the transcriptional programs used by osteoblasts to generate various osteogenic signals. CsR, calcium-sensing receptor; ER, estrogen receptor.