Site‐specific human breast cancer (MDA‐MB‐231) metastases in nude rats: Model characterisation and in vivo effects of ibandronate on tumour growth

Abstract

Animal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95-100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7-8.2 mm 2 /4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 g/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm 2 /4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (-0.33 to -0.81 mm 2 /4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra-arterial approach used in this new model of metastatic bone disease results in site-specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth. © Bone metastases are frequent complications of many malignant tumours, particularly of breast, prostate and lung cancers. 1,2 Animal models are important tools to study the mechanisms involved in the development of metastatic bone disease and to evaluate in vivo strategies for its prevention and treatment. 3 Most current animal models utilise suspensions from malignant cell lines that are brought to the skeleton either via direct 4 -6 or indirect inoculation. With intracardial injections, 3,7-11 cells are inoculated at a relatively high tumour dose and, in most models, malignant dissemination occurs into both skeletal and visceral peripheries, resulting in varying degrees of animal comorbidity (e.g., cachexia, paraplegia). Direct inoculation of tumour cells into the bone marrow leads to site-specific osteolyses, but these models lack the processes associated with extravasation of tumour cells, while the injection itself causes bone damage that might result in nonspecific wound responses. [12][13][14][15] Furthermore, all currently characterised animal models of metastatic bone disease use either syngeneic tumours or human xenografts in small animals ( e.g., mice) or syngeneic tumours in larger animals (e.g., rats). While small-animal models are often restricted to end-point analyses or radiographic follow-up, studies in larger animals allow the longitudinal assessment of bone turnover by s...

Treatment of Thyponium Flageliforme in Combination with Curcuma Zedoaria, and Phyllanthus Niruri Synergistically Enhances Apoptotic and Anti-Proliferative Effect on Breast Cancer

“…Another study reported by Neudert at al. also pointed out that inoculation of breast cancer into femoral artery was able to stimulate multiple osteolytic lesions in the distal femoral and proximal tibiae within 18 days after inoculation, with a success rate of 95-100 % and no additional co morbidity 17 . Lastly, inoculation of tumor cells isolated from human suffer from breast cancer into mammary fat pad of nude mice was significantly induce breast cancer develop and metastasis to multiple mouse organs 18 Nevertheless, in the present study the tumor volume resulted from breast cancer inoculation in all groups were not similar (comparable) in size.…”

Characterization of a rat model with site‐specific bone metastasis induced by MDA‐MB‐231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein

“…Recently, a model has been described that is characterized by site-specific osteolytic lesions after injection of MDA-MB-231 cells directly into the femoral artery of nude rats. 14 The disadvantage of this model is that the femoral artery has to be ligated, and spontaneous remission of lytic lesions occurred in up to 50% of animals at day 42 after tumor cell inoculation. In our model, the development of osteolytic lesions can be observed up to at least 110 days after tumor cell inoculation.…”

Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

“…(61) These models result in near 100% frequency of development of these ''experimental metastases'' and have been used to assess efficacy of therapeutic agents under development; such agents have been assessed, more specifically, for their ability to block breast cancer growth within the bone and breast cancer-mediated bone resorption. (62) They also have provided an in vivo system in which human cancer cells can be passaged through a bone microenvironment, aiding the development of breast cancer cells that have been selected for their osteotropism and thus reproducible and efficient osteotropic metastasis during subsequent rounds of growth in mice. Such cells can be used to study the genetic changes that are required for survival and proliferation of cancer cells within the bone environment, as well as the changes within the bone microenvironment induced by the disseminated cancer cells.…”