Abstract
Breast cancer cells colonize the skeleton by homing to specific niches, but the involvement of osteoblasts in tumour cell seeding, colonization, and progression is unknown. We used an in vivo model to determine how increasing the number of cells of the osteoblast lineage with parathyroid hormone (PTH) modified subsequent skeletal colonization by breast cancer cells. BALB/c nude mice were injected for five consecutive days with PBS (control) or PTH and then injected with DiD-labelled breast cancer cells via the intra-cardiac route. Effects of PTH on the bone microenvironment and tumour cell colonization and growth was analyzed using bioluminescence imaging, two-photon microscopy, and histological analysis. PTH treatment caused a significant, transient increase in osteoblast numbers compared to control, whereas bone volume/structure in the tibia was unaffected. There were no differences in the number of tumour cells seeding to the tibias, or in the number of tumours in the hind legs, between the control and PTH group. However, animals pre-treated with PTH had a significantly higher number of tumour colonies distributed throughout skeletal sites outside the hind limbs. This is the first demonstration that PTH-induced stimulation of osteoblastic cells may result in alternative skeletal sites becoming available for breast cancer cell colonization.
Highlights
The majority of patients with advanced breast cancer will develop bone metastases [1], and there is emerging evidence that tumour cells disseminate to bone at very early stages of the disease [2]
We and others have recently reported that breast tumour cells appear to home preferentially in osteoblast rich areas of bone [7,10], and osteoblastic cells are in turn shown to regulate the hematopoietic stem cell (HSC) niche [11] as well as being closely linked with vascular remodeling in bone [12]
In order to assess the influence of the osteoblastic niche on tumour cell engraftment, we designed specific in vivo studies to establish whether parathyroid hormone (PTH)-mediated expansion of the osteoblastic compartment, prior to tumour cell injection, affects subsequent establishment of breast tumour cell residency or lesion formation in bone
Summary
The majority of patients with advanced breast cancer will develop bone metastases [1], and there is emerging evidence that tumour cells disseminate to bone at very early stages of the disease [2]. The areas of bone commonly colonized by tumour cells contain a number of proposed specialist niches, which are at least partly overlapping, e.g., the endosteal niche [7], the peri-vascular niche [8], and the hematopoietic stem cell (HSC) niche [9] This suggests that the biological signals regulating hematopoiesis, vascular growth/renewal and bone turnover potentially converge on the same set of structures, the functions of which are interconnected. We and others have recently reported that breast tumour cells appear to home preferentially in osteoblast rich areas of bone [7,10], and osteoblastic cells are in turn shown to regulate the HSC niche [11] as well as being closely linked with vascular remodeling in bone [12] These observations indicate that osteoblasts are important components of the bone metastatic niche, but their contribution in supporting tumour cell engraftment, dormancy and survival remains to be defined. The results may have implications for the use of PTH as a bone anabolic agent in the cancer setting and highlights the need to define the specific role(s) of osteoblasts in the development of bone metastasis in human disease
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