Matrix metalloproteinase-1 is a crucial bone metastasis factor in a human breast cancer-derived highly invasive cell line.

Bone metastasis is one of the most severe cancer complications. To analyze the mechanism of bone metastasis, we established highly invasive cell lines from the human breast cancer cell line MDA-MB-231 using an in vitro sequential selection system. The cell lines, MDA-231-S10 and MDA-231-S5, were more invasive and more motile than the parental cell line. Moreover, MDA-231-S10 metastasized to bone more often when inoculated into the arterial circulation of nude mice. MDA-231-S10-bearing nude mice had a significantly poorer prognosis, and their bony metastatic tumors grew more rapidly than those of the mice bearing the parental cell line (MDA-231-P). Given that a high expression of matrix metalloproteinase (MMP) is reported to be associated with cancer invasiveness, we examined MMP expression. Our results showed that the expression of MMP-3, -5, -7, -9, -13 and -14 was decreased on Multiplex real-time quantitative RT-PCR analysis in the two new cell lines. The zymographic analysis showed no MMP-2 activity and a decreased MMP-9 activity in MDA-231-S10. However, the expression of MMP-1 in MDA-231-S10 was increased. We therefore concluded that MMP-1 plays a crucial role in breast cancer bone metastasis. Furthermore, our MDA-231-derived cell lines are useful analytical models of MMP-1- associated breast cancer bone metastasis.

Calcium phosphate cement in musculoskeletal tumor surgery.

BACKGROUND AND OBJECTIVES: Calcium phosphate cement (CPC) is an injectable biocompatible bone substitute that has been used for various applications in orthopedic surgery. However, no extensive clinical studies of the use of CPC to fill bone cavities after curettage of musculoskeletal tumors have been reported. The present study reviewed the results for 56 musculoskeletal tumors treated by curettage and CPC implantation. METHODS: Assessment was based on clinical examination and radiographic findings. Variables for clinical assessment included pain, limb function, and complications. Median follow-up was 18.5 months (range 6-47 months). RESULTS: One patient experienced post-operative fractures. Three patients displayed local recurrence. One patient developed post-operative superficial wound infection, and two patients with large bony defect exhibited non-infectious serous discharge. No serious adverse effects such as deep venous thrombosis, pulmonary embolism were encountered. In all cases, CPC was radiographically well adapted to the surrounding host bone as of final follow-up. CONCLUSIONS: CPC appears to offer a useful bone substitute for the treatment of musculoskeletal tumors. As the follow-up period for this study was short, further long-term follow-up studies are needed.

MMP-2 expression is associated with rapidly proliferative arteriosclerosis in the flexor tenosynovium and pain severity in carpal tunnel syndrome.

Due to the lack of correlation between symptom severity and electrophysiology or nerve function, the 'container hypothesis' has emerged as a new concept in carpal tunnel syndrome (CTS). This proposes that symptoms relate to connective tissue alteration rather than to nerve fibre pathology. This study was conducted to investigate the pathology of the flexor tenosynovium and its relationship with symptomatology. The subjects comprised 40 patients with electrophysiologically proven CTS who underwent open carpal tunnel release (age range: 31-79 years). In all patients, subjective symptom severity was assessed with a Likert scale and symptom duration was recorded preoperatively. Flexor tenosynovium biopsied during surgery was analysed for arterial and connective tissue alteration. Proliferative arteriosclerosis was graded using the modified Banff score. Gelatin zymography and immunohistochemistry were also performed to investigate the role of gelatinase in CTS. Relationships were evaluated using Spearman rank correlation coefficients. Proliferative arteriosclerosis occurred with disease progression in the flexor tenosynovium, in the absence of inflammation. This event did not correlate with patient age but correlated closely with symptom duration. Immunohistochemistry with antibodies against MMP-2 and elastic van Gieson staining revealed that arterioles express high levels of MMP-2 within 3 months of symptom onset and that intimal hyperplasia proceeded rapidly between 4 and 7 months, resulting in severe vascular narrowing. Gelatin zymography showed that MMP-2 activity correlated negatively with symptom duration and positively with pain severity.

Thrombin inhibitor, argatroban, prevents tumor cell migration and bone metastasis.

It is well known that malignant cells show procoagulant activity, which is associated with their metastatic potential. Thrombin, the key enzyme of the blood coagulation system, is generated around tumor cells, promoting the migration and metastasis of tumor cells. In this study, we evaluated the effect of argatroban, a specific thrombin inhibitor, on the migration and metastasis of B16BL6 melanoma cells. In vitro argatroban dose-dependently inhibited cell migration, the maximum inhibition being observed in the presence of 10 microM argatroban (p < 0.0001). In order to investigate the antimetastatic effect of the thrombin inhibitor, we used an animal model that we have reported previously. C57BL6 mice which had received a bone (femur or tibia) transplanted into the dorsal subcutis were injected with B16 melanoma cells into the left heart ventricle. Intraperitoneal injection of argatroban (9 mg/kg/day for 4 weeks) significantly reduced the number of limbs with metastatic lesions as compared to a placebo (p < 0.05). These results suggest that argatroban was associated with reduced melanoma metastases by inhibiting cell migration. Our results showed that argatroban is effective for treatment of bone metastasis.

Metastatic bone disease: pathogenesis and new strategies for treatment.

Bone is the third leading site of metastatic disease, after the lung and liver. Pain, pathological fractures, neurological deficits, and forced immobilization significantly decrease the quality of life of patients with bone metastasis. The development of metastasis, from the migration of malignant cells from the primary tumor to their proliferation at a distant site, involves a series of sequential steps: angiogenesis, matrix degradation, cell motility, cell attachment, and cellular proliferation. A better understanding of the pathogenesis of metastasis may be expected to lead to the development of new treatment modalities for bone metastasis. Currently, antiangiogenic agents, matrix metalloproteinase (MMP) inhibitors, and hyperthermia are some of the newer therapeutic modalities that seem to hold promise for the treatment of metastatic bone disease.