Person:

Ubellacker, Jessalyn

Background: The bone-targeting agent zoledronic acid (ZOL) increases breast cancer survival in subsets of patients, but the underlying reasons for this protective effect are unknown. ZOL modulates the activity of osteoclasts and osteoblasts, which form hematopoietic stem cell niches, and therefore may affect hematopoietic cells that play a role in breast cancer progression. Method Immunocompetent and immunocompromised strains of mice commonly used for breast cancer research were injected with a single, clinically relevant dose of ZOL (100 μg/kg) or vehicle control. The effects of ZOL on the bone marrow microenvironment (bone volume, bone cell number/activity, extracellular matrix composition) were established at various time points following treatment, using micro-computed tomography (μCT) analysis, histomorphometry, ELISA and immunofluorescence. The effects on peripheral blood and bone marrow hematopoietic progenitor populations were assessed using a HEMAVET® hematology analyzer and multicolor flow cytometry, respectively. Tumor support function of bone marrow cells was determined using an in vivo functional assay developed in our laboratory. Results: Using multiple mouse strains, we observed transient changes in numbers of hematopoietic stem cells, myeloid-biased progenitor cells, and lymphoid-biased cells concurrent with changes to hematopoietic stem cell niches following ZOL administration. Importantly, bone marrow cells from mice treated with a single, clinically relevant dose of ZOL inhibited breast tumor outgrowth in vivo. The ZOL-induced tumor suppressive function of the bone marrow persisted beyond the time point at which numbers of hematopoietic progenitor cells had returned to baseline. Conclusions: These findings provide novel evidence that alterations to the bone marrow play a role in the anti-tumor activity of ZOL and suggest possibilities for capitalizing on the beneficial effects of ZOL in reducing breast cancer development and progression. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0815-8) contains supplementary material, which is available to authorized users.

Systemic factors including cytokines, cell-free nucleic acids, microvesicles, and platelets are appreciated as important regulators of adenocarcinoma progression. Research findings using pre-clinical mouse models have revealed that many such systemically acting factors are either secreted by or responsive to peripheral tumors and impact bone and bone marrow (collectively referred to as the bone microenvironment) to initiate processes that ultimately govern disease progression, even in the absence of detectable bone metastases. In some cases, cancer-driven modulation of the bone microenvironment involves mobilization of bone marrow hematopoietic and mesenchymal cells into the circulation that are subsequently recruited into peripheral tissues and tumors. In other cases, systemic factors alter bone marrow cell (BMC) differentiation and/or gene expression to render the BMCs pro-tumorigenic even prior to their mobilization into the circulation. Given their effect on the bone microenvironment, it stands to reason that such systemic factors might also influence metastases in the bone; however, this hypothesis remains to be comprehensively tested. Here, we briefly review what is known, and not known, about systemic factors that regulate the bone microenvironment and thereby influence bone metastases. We also pose a number of currently unanswered questions in this active area of research. A better understanding of systemic processes that influence bone metastasis should aid discovery of therapeutic approaches that aim to eradicate or reduce disease burden in the bone, which is the cause of significant patient mortality and morbidity and is currently incurable.