Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumour actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis

Combined therapy with the RANKL inhibitor RANK-Fc and rhApo2L/TRAIL/dulanermin reduces bone lesions and skeletal tumor burden in a model of breast cancer skeletal metastasis

“…4 Additionally, RANKL inhibition will selectively reduce skeletal tumor growth, but does not have direct antitumor effects on cells in vitro, nor does RANKL inhibition reduce subcutaneous tumor growth in animal models. 11,12 These findings support the hypothesis that osteoclastic bone resorption creates a fertile soil for tumor growth.…”

“…These results are consistent with published observations that RANKL inhibition does not have a direct effect on MDA-MB-231 tumor cell growth in vitro nor does it affect the growth of MDA-MB-231 subcutaneous tumors in xenograft models. 11,12 There was no dose dependent effect observed from 30-90 mg/kg with rhApo2L/TRAIL in this subcutaneous xenograft model. These experiments indicate that rhApo2L/TRAIL has direct effects on tumor growth, while RANK-Fc does not.…”

“…We used multiple parameters to assess the efficacy of rhApo2L/TRAIL and RANK-Fc in our skeletal metastasis study, including measurement of tumor observed in the bone microenvironment and not observed in tumors implanted subcutaneously, which, along with the unique effect of RANKL inhibition to reduce osteoclastogenesis, supports the hypothesis that RANK-Fc is disrupting the vicious cycle as observed with previous studies using other RANKL inhibitors. 11,12 Bisphosphonates reduce osteoclast function via a mechanism distinct from RANKL inhibition and one study has demonstrated that both agents reduce MDA-MB-231 skeletal tumor burden to an equivalent extent. 12 This observation provides further support that the inhibition of MDA-MB-231 skeletal tumor growth by RANKL inhibition is predominately indirect, via inhibition of osteoclasts.…”

Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

“…Indirect evidence that MMPs play an integral role in bone metastasis comes from therapeutic studies. The bisphosphonate class of drugs has become a mainstay in the treatment of bone metastasis as well as in other bone degrading disorders [44][45][46][47][48][49]. However, when MDA-MB-231, an estrogen independent breast cancer cells, are injected into the left ventricle of mice and allowed to form bone metastases, expression of TIMP-2 in addition to bisphosphonate treatment markedly reduces the number of osteolytic lesions and increases the overall survival compared to treatment with bisphosphonates alone.…”

Management of bone metastases: recent advances and current status

“…RANKL inhibition has decreased osteolytic and osteoblastic skeletal changes and associated tumor progression in several animal models of cancer and bone metastases including breast, prostate, lung and multiple myeloma [74][75][76][77][78][79].…”