The bone microenvironment as a therapeutic target in breast cancer bone metastasis

Bone marrow environment (BME) niches are shown to play a role in the development and progression of bone metastases, but the precise underlying mechanisms are unknown. This project aimed to investigate how altering bone marrow niches in vivo impacts the BME and tumour growth in bone, comparing different mouse models. The BME was altered by induction of tumour growth, exposure to different doses of the chemotherapy agent doxorubicin and haematopoietic stem cell (HSC) mobilisation (with AMD3100 and G-CSF), comparing effects in BALB/c (immunocompetent) and BALB/c Nude (immunocompromised) female mice. Hind limb bones/bone marrow were analysed with CT, flow cytometry and histology techniques. I could detect differences in the BME between immunocompetent and immunocompromised mice, including in HSCs cells/progenitors, in immune cell populations such as B lymphocytes, monocytes, and granulocytes, in addition to T Lymphocytes being missing/defective. In a triple negative bone metastasis model in immunocompromised mice, I found that different BM cell populations can be assessed with flow cytometry techniques in the presence of a solid tumour; however, a low tumour burden was insufficient to cause significant structural bone effects. I confirmed doxorubicin-mediated bone loss (a known side effect), and bone structure and BME cell populations were affected, though these effects were dose-dependent and differed between the strains. HSC mobilisation in both strains prior to metastatic model did not affect the bone or BME, yet there was a trend towards earlier tumour progression in bone compared to control. Collectively, the work presented in this thesis supports the importance of the BME in tumour development and therapeutic response. My results highlight that different mouse strains responded differently to alterations in the BME; hence more than one model should be used in studies of bone metastasis. Finally, I showed that BME and its cell populations could be quantified with and without a tumour.