title: Location matters: osteoblast and osteoclast distribution is modified by the presence and proximity to breast cancer cells in vivo.
abstract: Bone metastasis is a common incurable complication of breast cancer affecting around 70% of patients with advanced disease. In order to improve outcomes for these patients, the cellular and molecular mechanisms underlying bone metastasis need to be established. The majority of studies to date have focused on end-stage disease and little is known about the events taking place following initial tumour cell colonisation of bone. Here we report the results of a longitudinal study that provides detailed analysis of the spatial and temporal relationship between bone and cancer cells during progression of bone metastasis. Tumour growth in bone was initiated by intra-cardiac inoculation of MDA-MB-231-GFP breast cancer cells in immunocompromised mice. Differentiating between areas of bone in direct contact with the tumour and areas distal to the cancer cells but within the tumour bearing bone, we performed comprehensive analyses of the number and distribution of osteoclasts and osteoblasts. Tumour colonies were detectable in bone from day 10, while reduced trabecular bone volume was apparent from day 19 onwards. Cancer-induced changes in osteoblast and osteoclast numbers differed substantially depending on whether or not the cells were in direct contact with the tumour. Compared to naïve controls, areas of bone in direct contact with the tumour had significantly reduced osteoblast but increased osteoclast numbers, whereas the reverse was found in distal areas. Our data demonstrate that tumour cells induce substantial changes in the bone microenvironment prior to the appearance of bone lesions, suggesting that early therapeutic intervention may be required to oppose the tumour-induced changes to the microenvironment und thus tumour progression.
authors.affiliation: Academic Unit of Clinical Oncology, Medical School, University of Sheffield, Sheffield, UK. mdp08hkb@sheffield.ac.uk
authors.forename: H K
authors.initials: HK
authors.lastname: Brown
authors.forename: P D
authors.initials: PD
authors.lastname: Ottewell
authors.forename: C A
authors.initials: CA
authors.lastname: Evans
authors.forename: I
authors.initials: I
authors.lastname: Holen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000097:blood; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D001842:Bone and Bones / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication; D002452:Cell Count; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D048429:Cell Size; D005260:Female; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010006:Osteoblasts / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D053245:RANK Ligand / Q000097:blood; D059016:Tumor Microenvironment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D053245:RANK Ligand; C422903:SOST protein, human; C505689:Tnfsf11 protein, mouse