Breast cancer cells can secrete factors that oppose bone metastasis formation (14). These factors are often decreased in breast cancer cells or increased as a host anti-tumor defense response. Increasing these factors in breast cancer patients might be another means to treat breast cancer bone metastases. Osteoprotegerin (OPG) is a secreted decoy receptor for RANKL (71). OPG is expressed by breast cancer cells, osteoblasts, and bone stromal cells (72). Binding of OPG to RANKL prevents RANKL from binding to its receptor RANK on osteoclast precursor cells and osteoclasts, preventing the formation and activation of osteoclasts (71). Therefore, OPG is a potent inhibitor of osteoclast formation and bone resorption. Breast cancer cells may reduce OPG and increase RANKL expression in the bone to increase osteolysis (72). Inhibiting RANKL signaling with OPG may inhibit the actions of multiple bone-resorbing tumor factors (e.g., PTHrP, IL-11, and VEGF) that induce osteolysis through the RANKL pathway and therefore may be more effective than inhibiting one of these factors alone. Recombinant OPG treatment reduced osteolytic lesion formation, skeletal tumor burden, and tumor-associated osteoclasts formed by MDA-MB-231 breast cancer cells after intracardiac injection in nude mice (73). A recombinant OPG construct (AMGN-0007) decreased bone resorption without significant adverse effects in a phase I trial using 26 patients with breast carcinoma and established lytic bone lesions (74). However, OPG constructs have not succeeded through clinical trials so far. Small molecule stimulators of OPG expression have also been developed (75). The small molecule OPG stimulator (Cmpd 5) decreeased lytic bone lesions formed by 13762 rat mammary carcinoma cells after intracardiac injection of Fischer-344 rats (75). However, overexpressing OPG in breast cancer cells increased tumor growth in the tibiae of mice (71), contraindicating the use of small molecule OPG stimulators. Anti-RANKL antibodies have been more successful. The humanized anti-RANKL antibody, denosumab, reduced bone resorption and was well tolerated in patients with multiple myeloma and breast cancer bone metastases (76).
Interleukin-18 (IL-18) enhances the anti-tumor immune response and inhibits osteoclast formation and bone resorption via a mechanism involving granulocyte/macrophage colony-stimulating factor (77-79). IL-18 upre-gulates OPG expression by osteoblastic and stromal cells (80). Patients with breast cancer have higher serum IL-18 levels than patients without breast cancer (78). Higher IL-18 levels were also found in metastatic patients compared to nonmetastatic with the highest levels found in patients with bone metastasis (78, 81). IL-18 injections into nude mice reduced osteolytic bone metastases formed by intracardiac injection of MDA-MB-231 breast cancer cells but had no effect on subcutaneous tumor growth (82). Systemic administration of recombinant IL-18 in humans could reduce breast cancer bone metastases.
Soluble frizzled related protein 1 (Sfrp1) is a breast cancer secreted protein that inhibits the Wnt signaling pathway (83). The Wnt signaling pathway has a known role in osteogenesis and oncogenesis (84). Wnt signaling activates osteoblasts and Wnt signaling inhibitors like Sfrp1 and dickkopf-1 (DKK-1) inhibit this activation (84). Activation of the Wnt signaling pathway also promotes mammary carcinogenesis (83, 85). Down-regulation of repressors of Wnt signaling, Sfrp1 and the transcription factor TCF-4, was identified in a subset of breast cancers (83). Deletion of the chromosomal region containing Sfrp 1 is often detected in breast cancer
(86). Aberrant hypermethylation (gene-silencing) of Sfrp1 was also associated with an unfavorable prognosis for breast cancer (86). Increasing Wnt activity by knocking down DKK-1 expression with DKK-1 short hairpin RNA caused osteolytic PC3 prostate cancer cells to induce osteoblast activity (87). Decreasing Wnt activity by overexpressing DKK-1 converts prostate cancer cells with a mixed osteolytic/osteoblastic phenotype to an osteolytic phenotype (87). Wnt signaling contributes to prostate cancer osteoblastic bone metastasis formation (87) and may in the same way contribute to breast cancer bone metastasis. Suppression of the Wnt signaling pathway may reduce osteoblastic bone metastasis. A green tea compound (-)-epigallocatchin 3-gallate (EGCG) inhibits Wnt signaling and reduces breast cancer cell proliferation and invasiveness (88). Green tea consumption has been correlated with reduced recurrence of breast cancers in Japanese women. Oral administration of EGCG reduced breast cancer tumor progression in animal models (88). EGCG may reduce osteoblastic bone metastases. However, Wnt signaling inhibition has also been suggested to be one of the mechanisms that multiple myeloma induces bone destruction by inhibiting bone formation (89, 90). Multiple myeloma cells and multiple myeloma patients with advanced osteolytic lesions secreted the Wnt inhibitor, secreted frizzled related protein-2 (Sfrp-2) and Sfrp-2 inhibits bone formation (89). Further research is needed to test the role of the Wnt signaling inhibitors in breast cancer bone metastasis.
6. CURRENT PROBLEMS AND POSSIBLE FUTURE TREATMENT DIRECTIONS: IDENTIFYING UPSTREAM REGULATORS TO TARGET MULTIPLE FACTORS INVOLVED IN BREAST CANCER BONE METASTASIS
The approved treatment for breast cancer bone metastases is anti-resorptive bisphosphonates (2). Bisphosphonates bind to bone matrix and reduce osteoclastic bone resorption (14). They promote osteoclast apopto-sis, while their effects in vivo on osteoblasts and tumor growth remain controversial (14). Bisphosphonates reduce bone pain and skeletal fractures but do not improve overall survival (2). Additional classes of antiresorptive agents include anti-RANKL antibodies and cathepsin K inhibitors. These are in clinical development but are not yet approved for patient use. Anti-RANKL antibodies prevent interaction of RANKL with RANK, interfering with formation and activation of osteoclasts (76). Cathepsin K inhibitors inhibit one of the proteolytic enzymes secreted by osteoclasts, cathepsin K, that is necessary for bone resorption (91). Out of the three groups, Cathepsin K inhibitors are the only agents that do not prevent osteoclast formation or induce osteoclast death. If osteoclasts have other functions in bone beyond osteolysis, drugs that allow osteoclast formation, but block their bone resorptive activity, may have fewer side effects.
Current treatment flaws leave the need for the development of more effective therapies. This chapter has demonstrated a method of targeting tumor-secreted factors such as PTHrP to treat breast cancer bone metastases. Many additional factors are involved in breast cancer bone metastases. The important question is: How to find the best target(s) out of the long list of factors to effectively cure breast cancer bone metastases? The best strategy may be to target multiple tumor-secreted factors. Kang et al. (2003) demonstrated that not one, but a combination of four to five factors were necessary for bone metastasis formation (17). They identified a bone metastatic gene profile consisting of 43 genes with varying functions, among which included the bone-resorbing factor IL-11 and the bone-forming, angiogenic factor CTGF (17). These genes only in combination enhanced bone metastasis formation produced by poorly meta-static MDA-MB-231 cells (17). Therefore, multiple factors are important in bone metastasis formation and targeting multiple factors may be more effective in treating breast cancer bone metastases than targeting one factor alone. Indeed, breast cancers secrete multiple factors from the lists of both bone-resorbing and bone-forming proteins (6). Therefore, a more effective treatment may be to target an upstream regulator of multiple factors. Many of the known tumor-secreted factors, both osteolytic and osteoblastic, are regulated by the hypoxia-induced Hif-1a pathway and the TGFp signaling pathway (8, 17, 92). Both pathways are active in the bone microenvironment and are important targets for treatment of bone metastases. TGFp inhibitors have been effective in blocking bone metastases in preclinical models (9-12). Additional upstream regulators need to be identified and may prove to be more effective treatment targets for breast cancer bone metastasis treatment. Combining this approach of targeting tumor-secreted factors with other therapies (bisphosphonates and chemotherapeutics) may improve treatment (93). Inhibitors of tumor-secreted factors may be important adjuvant therapies for breast cancer bone metastasis.
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