Bone Abstracts

Background: Cancer patients often receive a combination of drugs that target both the microenvironment and the tumour cells. However, the role of the bone microenvironment (BME) in mediating peripheral breast cancer growth remains poorly understood. This is the first study to determine whether reduced subcutaneous tumour growth following combination therapy is due to direct interactions between the drugs and tumour cells or through zoledronic acid induced alterations to the BME.

Methods: 5×10⁵ MDA-G8 cells were subcutaneously inoculated into female BALB/c nude mice. Animals received combination therapy (2 mg/kg doxorubicin (DOX, i.v.) followed 24 h later by 100 μg/kg zoledronic acid (ZOL, i.p.)) or PBS control weekly for 5 weeks. Tumour fragments (~14 mm³, from mice receiving combination therapy) were subcutaneously transplanted into naïve BALB/c nude mice that had been pre-treated with 100 μg/kg ZOL or control. Tumour growth was monitored using callipers and alterations to the BME assessed (μCT, immunofluorescence, histology). Effects on bone marrow derived cells were determined by flow cytometry using markers for CD11b/Gr1+ and LSK cells.

Results: Weekly combination therapy successfully suppressed tumour growth (Tumour volume day 33: DOX/ZOL: 82.9±13.9 mm³, n=13 vs. PBS: 330.9±125.3 mm³, n=5, P≤0.0001). Trabecular bone volume increased after both combination therapy (DOX/ZOL: 15.53±0.91% vs. PBS: 10.25±0.36%, n=3/group) and ZOL pre-treatment (ZOL: 37.04±1.80%, n=4 vs. PBS: 9.59±0.40%, n=6, P≤0.01). Growth of re-transplanted tumour fragments resumed at equal rates whether transplanted into ZOL or PBS pre-treated hosts (Tumour volume day 33: ZOL: 223.9±45.36 mm³, n=8 vs. PBS: 175.5±44.39 mm³, n=7). Alterations in tumour and bone vasculature were observed following both ZOL or combination therapy.

Conclusion: Here we demonstrate that modification of the BME with ZOL is not sufficient to supress peripheral breast cancer growth following cessation of combination therapy suggesting that both the tumour and microenvironment need to be targeted for successful anti-cancer therapy.

Experiments performed under UK Home Office Authority (PPL40/3531).