Abstract
Background: Bone metastasis is one of the most common complications of advanced breast cancer. During dissemination to bone, breast cancer cells locate in a putative ‘metastatic niche’, a microenvironment that regulates the colonisation, maintenance of tumour cell dormancy and subsequent tumour growth. The precise location and composition of the bone metastatic niche is not clearly defined. We have used in vivo models of early breast cancer dissemination to provide novel evidence that demonstrates overlap between endosteal, perivascular, HSC and the metastatic niche in bone.Methods: Estrogen Receptor (ER) +ve and -ve breast cancer cells were labelled with membrane dyes Vybrant-DiD and Vybrant-CM-DiI and injected via different routes in BALBc/nude mice of different ages. Two-photon microscopy was used to detect and quantitate tumour cells and map their location within the bone microenvironment as well as their distance to the nearest bone surface compared to the nearest other tumour cell. To investigate whether the metastatic niche overlapped with the HSC niche, animals were pre-treated with the CXCR4 antagonist AMD3100 to mobilise hematopoietic (HSCs) prior to injection of breast cancer cells.Results: Breast cancer cells displayed a characteristic pattern of homing in the long bones, with the majority of tumour cells seeded in the trabecular regions, regardless of the route of injection, cell-line characteristics (ER status) or animal age. Breast cancer cells located in close proximity to the nearest bone surface and the average distance between individual tumour cells was higher than their distance to bone. Mobilisation of HSCs from the niche to the circulation prior to injection of cell lines resulted in increased numbers of tumour cells disseminated in trabecular regions.Conclusion: Our data provide evidence that homing of breast cancer cells is independent of their ER status and that the breast cancer bone metastasis niche is located within the trabecular region of bone, an area rich in osteoblasts and microvessels. The increased number of breast cancer cells homing to bone after mobilisation of HSCs suggests that the HSC and the bone metastasis niche overlap.
Highlights
Metastatic breast cancer remains a major cause of female cancerrelated deaths, despite the improvements in early detection and therapy introduced over the past decades [1,2]
MDA-MB-231-Green fluorescent protein (GFP)-Intra venous (IV) [29], T47D and MCF7 breast cancer cell lines (ATCC) were cultured in RPMI 1640 supplemented with 10% Foetal bovine serum (FBS) (Life Technologies, Paisley, UK /Invitrogen) at 37 °C 5%CO2, MDA-MB-231NW1-Luc2 cells were cultured in DMEM (Life Technologies, Paisley, UK) + Pyruvate medium enriched with 100 U/mL penicillin/streptomycin and 10% FBS (Sigma Aldrich Co Ltd, Poole, UK)
In previous studies we have demonstrated that the bone seeking MDA-MB-231-IV cells form detectable tumours in long bones two weeks after injection into the tail vein of 6-week old animals, in which tumour growth is supported by active bone turnover [29]
Summary
Metastatic breast cancer remains a major cause of female cancerrelated deaths, despite the improvements in early detection and therapy introduced over the past decades [1,2]. Skeletal metastasis, can develop decades after the detection and treatment of the primary tumour. Recent studies show that the risk of distant recurrence increases at a steady rate for at least 20 years [4]. Bone metastasis is one of the most common complications of advanced breast cancer. Breast cancer cells locate in a putative ‘metastatic niche’, a microenvironment that regulates the colonisation, maintenance of tumour cell dormancy and subsequent tumour growth. We have used in vivo models of early breast cancer dissemination to provide novel evidence that demonstrates overlap between endosteal, perivascular, HSC and the metastatic niche in bone
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