Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer.
Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer.
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DOI：
10.1158/2159-8290.cd-14-0621
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发表时间：
2015-01
期刊：
影响因子：
28.2
通讯作者：
Rogers MJ
中科院分区：
文献类型：
--
作者：
Junankar S;Shay G;Jurczyluk J;Ali N;Down J;Pocock N;Parker A;Nguyen A;Sun S;Kashemirov B;McKenna CE;Croucher PI;Swarbrick A;Weilbaecher K;Phan TG;Rogers MJ
最近的临床试验表明，双膦酸盐药物可以改善乳腺癌患者的生存，而不依赖于其对骨骼的抗吸收作用。然而，由于双膦酸盐与骨矿物质结合迅速，其抗肿瘤作用的确切机制，特别是对骨外细胞的作用，仍不清楚。在这里，我们使用实时活体双光子显微镜显示了4T1小鼠乳腺肿瘤血管中荧光双膦酸盐的广泛渗漏，它最初与被肿瘤相关巨噬细胞（tam）吞噬的小颗粒微钙化区域结合，而不是肿瘤细胞。重要的是，我们还观察到患者原发性乳腺肿瘤中放射性标记双膦酸盐的摄取，并显示切除的肿瘤被tam浸润，并含有类似的颗粒状微钙化。这些数据代表了第一个令人信服的体内证据，即双膦酸盐可以靶向骨骼外的肿瘤细胞，并且它们的抗肿瘤活性可能是通过tam介导的。
Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their anti-resorptive effects on the skeleton. However, since bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their anti-tumour action, particularly on cells outside of bone, remain unknown. Here we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumours, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumour-associated macrophages (TAMs), but not tumour cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumour of a patient and showed the resected tumour to be infiltrated with TAMs and to contain similar granular microcalcifications. These data represent the first compelling in vivo evidence that bisphosphonates can target cells in tumours outside the skeleton and that their anti-tumour activity is likely to be mediated via TAMs.