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Osteolysis and cancer
David Goltzman
Calcium Research Laboratory, Department of Medicine, McGill University Health Center, and Departments of Medicine and Physiology, McGill University, Montreal, Quebec Canada
Address correspondence to: David Goltzman, Calcium Research Laboratory, Room H4.67, Royal Victoria Hospital, McGill University Health Center, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Phone: (514) 843-1632; Fax: (514) 843-1712; E-mail: david.goltzman@mcgill.ca.
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Published May 15, 2001 - More info
J Clin Invest. 2001;107(10):1219–1220. https://doi.org/10.1172/JCI13073.
© 2001 The American Society for Clinical Investigation
Bone is a highly hospitable environment for colonization and growth of metastatic tumors, and some of the most common human malignancies, notably breast cancer and prostate cancer, have a strong propensity to produce skeletal metastases (1). Tumor cells, in turn, can produce a spectrum of skeletal manifestations which spans diffuse osteopenia, focal osteolysis, focal osteogenesis, and osteomalacia (2).
The most common skeletal manifestation of malignancy is focal osteolysis in association with metastases. In order for tumor cells to grow and invade mineralized bone, osteolysis must occur. Osteoclasts appear uniquely adapted to produce the microenvironment and the biochemical milieu that are needed to resorb bone. Although previous reports have indicated that some tumor cells appear capable of assuming an osteoclast phenotype and directly resorbing bone (3), the bulk of the evidence suggests that most tumor cells act indirectly by co-opting the physiologic mechanisms that normally favor bone resorption. Thus, they release agents such as hormones, eicosanoids, growth factors, and cytokines into the bone microenvironment, which act on osteoblastic stromal cells to enhance the production of osteoclast activating factors. Most notable of these is the cell membrane–associated protein termed receptor activator of NF-κB ligand (RANKL), which is a member of the TNF family of cytokines. RANKL can then bind to its cognate receptor (RANK) on osteoclast precursors and, in the presence of M-CSF, enhance the differentiation and fusion of these cells to produce functioning multinucleated osteoclasts (4) (Figure 1). Concomitantly, production of a soluble decoy receptor for RANKL, termed osteoprotegerin (OPG) (5), may be downregulated (6), thus eliminating one means by which the ensuing osteolysis could be repressed.
Figure 1Schematic representation of tumor-cell induced osteolysis. A tumor cell may release soluble mediators such as hormones (e.g., PTHrP), eicosanoids, cytokines (e.g., IL-6), or growth factors (e.g., TGF-α) that act on an osteoblastic stromal cell. The stromal cell produces RANKL, which binds to its cognate receptor, RANK, expressed on osteoclast (Oc) precursors. In the presence of M-CSF, which acts on its receptor, c-fms, RANKL can enhance the formation of active osteoclasts that carry out bone resorption. Tumor cells have also been occasionally reported to directly release sRANKL, a soluble form of RANKL. Additionally, proteases can be produced by tumor cells and facilitate their invasion of nonmineralized tissue.
Mineralized bone matrix is a rich source of stored growth factors such as TGF-β. Such growth factors, once released from degraded bone matrix, may further accelerate growth of the tumor, which can now expand within the lysed area. Such growth factors also appear capable of further increasing the release from tumor cells of osteolytic mediators, such as parathyroid hormone–related peptide (PTHrP) (7, 8). A cycle may therefore be initiated that consists of release of osteolytic mediators by tumor cells, bone degradation, release of growth factors from degraded bone, enhanced tumor cell growth, and further release of osteolytic mediators (9).
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