Abstract
Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.
Highlights
The skeleton, a favored organ for metastasis, is associated with significant morbidity for cancer patients
Prostate cancer cell localization and growth in bone was increased when a single dose of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, was administered prior to intracardiac tumor inoculation [10]. This was associated with a transient expansion of myeloid cells and increased cytokines with myelogenic potential including C-C chemokine ligand 2 (CCL2), interleukin-6 (IL-6), and VEGF-A that primed the environment for tumor growth
The macrophage Fas-induced apoptosis (MAFIA) mouse provides for conditional macrophage depletion of cells that express GFP under the c-FMS promoter (CSF-1 receptor) [21]
Summary
The skeleton, a favored organ for metastasis, is associated with significant morbidity for cancer patients. Macrophages are myeloid phagocytic cells recruited in response to infection, inflammation and tissue injury, playing roles in the innate and adaptive immune response [3, 4] They are activated differentially according to stimuli provided, M1 anti-tumorigenic macrophages are classically activated and M2 protumorigenic macrophages ( known as tumor associated macrophages or TAMs) are alternatively activated [5, 6]. Prostate cancer cell localization and growth in bone was increased when a single dose of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, was administered prior to intracardiac tumor inoculation [10]. This was associated with a transient expansion of myeloid cells and increased cytokines with myelogenic potential including C-C chemokine ligand 2 (CCL2), interleukin-6 (IL-6), and VEGF-A that primed the environment for tumor growth. TAMs have been implicated in tumor growth, progression and metastasis of different types of cancer, but little is known about their role in skeletal metastasis
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