title: CD169(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer.
abstract: Skeletal metastases present a major clinical challenge for prostate cancer patient care, inflicting distinctive mixed osteoblastic and osteolytic lesions that cause morbidity and refractory skeletal complications. Macrophages are abundant in bone and bone marrow and can influence both osteoblast and osteoclast function in physiology and pathology. Herein, we examined the role of macrophages in prostate cancer bone lesions, particularly the osteoblastic response. First, macrophage and lymphocyte distributions were qualitatively assessed in patient's prostate cancer skeletal lesions by immunohistochemistry. Second, macrophage functional contributions to prostate tumour growth in bone were explored using an immune-competent mouse model combined with two independent approaches to achieve in vivo macrophage depletion: liposome encapsulated clodronate that depletes phagocytic cells (including macrophages and osteoclasts); and targeted depletion of CD169(+) macrophages using a suicide gene knock-in model. Immunohistochemistry and histomorphometric analysis were performed to quantitatively assess cancer-induced bone changes. In human bone metastasis specimens, CD68(+) macrophages were consistently located within the tumour mass. Osteal macrophages (osteomacs) were associated with pathological woven bone within the metastatic lesions. In contrast, lymphocytes were inconsistently present in prostate cancer skeletal lesions and when detected, had varied distributions. In the immune-competent mouse model, CD169(+) macrophage ablation significantly inhibited prostate cancer-induced woven bone formation, suggesting that CD169(+) macrophages within pathological woven bone are integral to tumour-induced bone formation. In contrast, pan-phagocytic cell, but not targeted CD169(+) macrophage depletion resulted in increased tumour mass, indicating that CD169(-) macrophage subset(s) and/or osteoclasts influenced tumour growth. In summary, these observations indicate a prominent role for macrophages in prostate cancer bone metastasis that may be therapeutically targetable to reduce the negative skeletal impacts of this malignancy, including tumour-induced bone modelling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Andy C
authors.initials: AC
authors.lastname: Wu
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Yaowu
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Anatomical Pathology, Mater Misericordiae Ltd., South Brisbane, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Broomfield
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.|School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Nicoll J
authors.identifier: 0000-0002-8824-1233
authors.initials: NJ
authors.lastname: Paatan
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Brittney S
authors.initials: BS
authors.lastname: Harrington
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Tseng
authors.affiliation: Department of Anatomical Pathology, Mater Misericordiae Ltd., South Brisbane, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Beaven
authors.affiliation: Department of Urology, Mater Health Services, South Brisbane, Australia.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: Kiernan
authors.affiliation: Department of Urology, Mater Health Services, South Brisbane, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Swindle
authors.affiliation: Department of Urology, Mater Health Services, South Brisbane, Australia.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: Clubb
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.affiliation: School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, Woolloongabba, Australia.|Institute for Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
authors.affiliation: Department of Anatomical Pathology, Mater Misericordiae Ltd., South Brisbane, Australia.
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Srinivasan
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Hooper
authors.affiliation: Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001859:Bone Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000276:immunology / Q000473:pathology; D010010:Osteoclasts / Q000276:immunology / Q000473:pathology; D011467:Prostate / Q000276:immunology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000276:immunology* / Q000378:metabolism
chemical_list: C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse
keywords: macrophage; prostate cancer; woven bone