Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer

Simon Junankar, Gemma Shay, Julie Jurczyluk, Naveid Ali, Jenny Down, Nicholas Pocock, Andrew Parker, Akira Nguyen, Shuting Sun, Boris Kashemirov, Charles E. McKenna, Peter I. Croucher, Alexander Swarbrick, Katherine Weilbaecher, Tri Giang Phan, Michael J. Rogers

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their antiresorptive effects on the skeleton. However, because bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their antitumor action, particularly on cells outside of bone, remain unknown. Here, we used real-time intravital twophoton microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumors, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumor-associated macrophages (TAM), but not tumor cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumor of a patient and showed the resected tumor 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 tumors outside the skeleton and that their antitumor activity is likely to be mediated via TAMs. Significance: Bisphosphonates are assumed to act solely in bone. However, mouse models and clinical trials show that they have surprising antitumor effects outside bone. We provide unequivocal evidence that bisphosphonates target TAMs, but not tumor cells, to exert their extraskeletal effects, offering a rationale for use in patients with early disease.

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalCancer discovery
Volume5
Issue number1
DOIs
StatePublished - 2015

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