Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2.

Abstract

Multiple steps are involved in the metastasis of cancer cells from primary sites to distant organs. These steps should be considered in the design of pharmacologic approaches to prevent or inhibit the metastatic process. In the present study, we have compared the effects of inhibiting several steps involved in the bone metastatic process individually with inhibition of both together. The steps we chose were matrix metalloproteinase (MMP) secretion, likely involved in tumor cell invasion, and osteoclastic bone resorption, the final step in the process. We used an experimental model in which inoculation of human estrogen-independent breast cancer MDA-231 cells into the left cardiac ventricle of female nude mice causes osteolytic lesions in bone. To inhibit cancer invasiveness, the tissue inhibitor of the MMP-2 (TIMP-2), which is a natural inhibitor of MMPs, was over-

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

“…MMPs are naturally inhibited by tissue inhibitors of MMPs (TIMPs) that can also inhibit the growth, invasion, and metastasis of malignant tumors. Expression of TIMP-2 in addition to bisphosphonate treatment markedly reduced the number of osteolytic lesions and increased overall survival compared with treatment with bisphosphonates alone (Yoneda et al 1997). Increased MMP-9 activity correlated with osteoclast activity in a PC-3 prostate cancer model of osteolytic bone metastases.…”

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

“…In contrast to T47D, which has been genotyped to the well-differentiated 'luminal' phenotype of breast cancer, MDA-MB231 cells lack expression of E-cadherin and express matrix metalloproteinases, which are properties associated with a more aggressive tumorigenic phenotype, consistent with its 'basaloid' phenotype (Nawrocki et al, 2001;Gordon et al, 2003). In addition, MDA-MB231 cells have a significantly higher in vitro invasive index (Nawrocki et al, 2001;Gordon et al, 2003), are metastatic in nude mice (Inoue et al, 1993;Yoneda et al, 1997;Salcedo et al, 2000;Salcedo et al, 2002) and may therefore possess additional mutations that can circumvent Nek3 regulation. Although Western-blot analysis of equal amounts of protein in both cell lines showed no remarkable differences in basal Nek3 expression (Figure 3a), differences in PRL-mediated kinase activity and consequently phosphorylation of other proteins linked to cancer motility such as Vav2, PI3K, MAPK and paxillin may be significant.…”

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

“…Infiltration of tumour cells from the blood vessels and invasion into metastatic organs are regulated by MMPs such as MMP-2 and MT1-MMP produced by host cells as well as tumour cells (MacDougall and Matrisian, 1995;Nakahara et al, 1997;Westermarck and Kahari, 1999). Yoneda et al (1997) have reported that osteolytic bone metastasis of breast cancer could be inhibited by combined treatment with bisphosphonate, a specific inhibitor of osteoclastic bone resorption, and tissue inhibitor of MMP (TIMP)-2, a natural inhibitor of MMPs. Since previous studies have shown that recombinant TIMP-1 and TIMP-2 inhibited bone resorption in vitro (Hill et al, 1993), TIMP-2 may suppress bone metastasis by inhibiting both tumour invasion and bone resorption.…”