Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline-and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

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BACKGROUND:Patients with advanced prostate cancer frequently have a poor prognosis as a result of metastasis and present with high serum PSA levels. There is evidence suggesting that the serine protease activity of PSA could be involved in the invasion and metastasis of prostate cancer. In this study, we determined the effects of PSA and its precursor, pro-PSA, on invasion and the type of bone metastasis. METHODS:We stably transfected prostate adenocarcinoma cells, human DU-145 and rat MatLyLu, with either the fulllength prepro-PSA sequence or pre-PSA DNA, to generate subclones of cells that secrete pro-PSA or free PSA, respectively. Secretion of PSA was measured by western blot analysis and enzyme-linked immunosorbent assay (ELISA). The invasive and migratory properties of the cells were determined using a basement membrane extract and were compared with corresponding empty vector control cells. Twelve days after injection of PSA-secreting MatLyLu cells into the femora of nude mice, bone tumor burden and histomorphometry were determined using a stereological technique. RESULTS:The transfected cells secreted 0.15-2.23 ng PSA/10 6 cells/day. Pro-PSA-secreting subclones increased invasion and migration by 24-263%. Conversely, the PSA-secreting subclones significantly reduced both invasion and migration by 59-70%. The divergent effects on invasion and migration observed in pro-PSA-and PSA-secreting subclones indicate that different forms of PSA may have different functions. Intrafemoral injections with PSA-secreting MatLyLu cells resulted in an increase in osteoblastic parameters when compared with non-PSA-secreting subclones as measured by bone histomorphometry. Concomitantly, a decrease in osteoclasts and eroded surface was observed.CONCLUSIONS: Our in vitro data suggest that PSA, dependent on the predominant form secreted, may decrease or increase invasive properties of prostate cancer cells. The in vivo results indicate that PSA in the bone microenvironment may contribute to the osteoblastic phenotype of bone metastasis frequently observed in prostate cancer.

Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP-1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.

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