• CME Information
• Introduction
• Biology of Bone Metastasis
• Current Treatment for Metastatic Disease
• Novel Bone-Targeted Therapies
• Preserving Normal Bone Health
• Conclusion
• References
• Printer Friendly Activity (PDF)
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Biology of Bone Metastasis

Theresa A. Guise, MD
Gerald D. Aurbach Professor of Endocrinology
Division of Endocrinology and Medicine
University of Virginia Charlottesville,Virginia

The development of micrometastasis to bone probably occurs early in the malignant process. Vessella and co-workers have reported that 71% of patients have detectable prostate cancer cells in their peripheral blood prior to undergoing radical prostatectomy.⁸ Thus early dissemination of tumor cells appears to occur in the majority of patients with prostate cancer. Similarly, many patients with breast cancer that have apparent isolated disease clinically have micrometastasis at the time of diagnosis.⁹ To effectively treat and prevent bone metastasis and related complications, including bone loss, it is necessary to elucidate and target pathways by which cancer cells establish themselves and proliferate in the bone microenvironment.

Cancer Stem Cells

Like self-renewing adult tissues, tumors appear to be maintained by stem cells, which provide a mechanism for cancer cell dormancy and the development of heterogeneity within a specific tumor.¹⁰ When tumor stem cells home to the bone marrow via receptors such as CXCR-4, they home to areas that have high levels of stromal cell derived factor 1 (SDF-1) which are present in hematopoietic niches. Osteoblasts appear to play an important role in these niches. To treat and prevent bone metastasis, it will be necessary to eradicate tumor stem cells that reside in this osteoblast niche and to block the expression or activity of factors that determine or trigger reentry into the cell cycle. Expanding our understanding of cancer stem cell dormancy and how these cancer stem cells reenter the cell cycle is an important area of investigation.

How cancer cells home to bone is another area of investigation that has made important strides. In addition to the CXCR-4/SDF-1 axis mentioned above, recently the RANK receptor has been found to be expressed on cancer cells and play a role in tumor cell homing.¹¹ RANK ligand (RANK L) is expressed in the bone marrow microenvironment by marrow stromal cells and immature osteoblasts, and recent studies have shown that breast cancer cells and other tumor cells can also express RANK and utilize this receptor to home to bone.

Bone Microenvironment “Vicious Cycles”

Another advance in our understanding of the bone metastatic process over the last several years has been the realization and documentation of the importance of the bone microenvironment in regulating both normal bone formation and the progression of bone metastasis. Identification of the roles that cytokines, chemokines and hormones made by tumor cells play in bone destruction, and recognition that the bone destructive process results in the release of growth factors from the bone microenvironment to increase tumor growth, have resulted in the concept of the “vicious cycle,“that theorizes how tumor cells metastasize to bone, and the bone destructive process amplifies the growth of the tumor.

As illustrated in Figure 1, the four major players in this vicious cycle include metastatic cancer cells, osteoblasts, osteoclasts and mineralized bone matrix, a major source of immobilized growth factors. Cancer cells secrete both osteoblastic factors and osteolytic factors. Osteoblastic factors (ET-1,AM,VEGF, PDGF, CCNs) stimulate osteoblast proliferation, differentiation and the secretion of more growth factors, which are deposited into the bone matrix, and also enrich the local tumor cell microenvironment. Most of the osteolytic factors secreted by the tumor act via the osteoclast differentiation factor, RANK L. RANK L, in turn, increases osteoclast formation and bone resorption.

Increased bone resorption releases growth factors from the bone matrix that increase tumor growth, establishing a “vicious cycle“between tumor stimulation of bone destruction and tumor growth. Bisphosphonates are hypothesized to interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption and inhibiting the effects of bone-derived growth factors. Inhibitors of RANK L are hypothesized to block osteoclast formation.

One of the principal identified osteolytic factors, parathyroid hormone related protein (PTHrP) has been shown to play an important role in bone metastasis in breast cancer and prostate cancer through its induction of RANK L.¹² In addition, tumor cells produce other factors, which can enhance osteoclast activity including Interleukins 6, 11, 8 and 1 (IL-6, IL-11, IL-8 and IL-1), tumor necrosis factor alpha (TNF-α), granulocyte macrophage colony stimulating factor (GM-CSF), macrophage inflammatory protein-1 alpha (MIP-1α), and MCP-1. All these factors can expand the pool of osteoclast precursors, and either alone or in combination can enhance osteoclast formation and bone destruction.

In addition, the pathophysiology underlying osteoblastic bone metastasis has also begun to be clarified. Factors have been identified such as endothelin-1, which stimulates osteoblast activity by suppression of the Wnt pathway inhibitor, dickopf 1 protein (DKK1), appear to play important roles in the expression of the osteoblastic phenotype in bone metastasis.^13,14 Although the phenotype of these metastases is osteoblastic, there is ongoing bone destruction. Patients with prostate cancer have the highest bone resorption markers of all the cancers studied in a recent trial.¹⁵ Thus, identification of osteoblastic factors produced by tumors as well as the relative importance of bone resorption in osteoblastic metastasis is a topic of active investigation.