Details

Autor(en) / Beteiligte

• Wu, Andy C
• He, Yaowu
• Broomfield, Amy
• Paatan, Nicoll J
• Harrington, Brittney S
• Tseng, Hsu-Wen
• Beaven, Elizabeth A
• Kiernan, Deirdre M
• Swindle, Peter
• Clubb, Adrian B
• Levesque, Jean-Pierre
• Winkler, Ingrid G
• Ling, Ming-Tat
• Srinivasan, Bhuvana
• Hooper, John D
• Pettit, Allison R

Titel

CD169 super(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer

Ist Teil von

• The Journal of pathology, 2016-06, Vol.239 (2), p.218-230

Erscheinungsjahr

2016

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• 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 super(+) 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 super(+) 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 super(+) macrophage ablation significantly inhibited prostate cancer-induced woven bone formation, suggesting that CD169 super(+) macrophages within pathological woven bone are integral to tumour-induced bone formation. In contrast, pan-phagocytic cell, but not targeted CD169 super(+) macrophage depletion resulted in increased tumour mass, indicating that CD169 super(-) 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.