Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone
Hernan Roca, … , Lonnie D. Shea, Laurie K. McCauley
Hernan Roca, … , Lonnie D. Shea, Laurie K. McCauley
Published November 27, 2017
Citation Information: J Clin Invest. 2018;128(1):248-266. https://doi.org/10.1172/JCI92466.
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Research Article Inflammation Oncology

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Abstract

During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.

Authors

Hernan Roca, Jacqueline D. Jones, Marta C. Purica, Savannah Weidner, Amy J. Koh, Robert Kuo, John E. Wilkinson, Yugang Wang, Stephanie Daignault-Newton, Kenneth J. Pienta, Todd M. Morgan, Evan T. Keller, Jacques E. Nör, Lonnie D. Shea, Laurie K. McCauley

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Figure 10

Cancer cell death induces accelerated tumor growth and bone osteolysis in the intratibial tumor model.

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Cancer cell death induces accelerated tumor growth and bone osteolysis i...
(A) Experimental schematic. Mice injected with RM1-iC9 cells were randomized before VEH or AP treatment. (B) Representative μCT images showing trabecular bone in VEH and AP cancer-inoculated tibiae and the corresponding contralateral controls (nontumor) (scale bars: 400 μm). (C) Bone parameters quantified by μCT: trabecular bone volume relative to total volume (Tb.BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), cortical thickness (Cortical Th), and total bone volume relative to total volume (BV/TV); VEH (n = 11) and AP (n = 12). (D) Representative images of H&E sections of tumor-inoculated VEH and AP tibiae. Tumor areas are highlighted in yellow and necrosis in green (scale bars: 400 μm). (E) Quantification of tumor area relative to total bone area (Tm.Ar/T.Ar). (F) Necrotic area relative to tumor area inside the bone. (G) Images inside the tumor areas of sections stained using F4/80 and Ly6B antibodies for VEH and AP (×50) (scale bars: 200 μm). (H) Quantification of F4/80+ (n = 11 per group) and Ly6B+ VEH (n = 11) and AP (n = 12) staining (3 fields inside tumor area at ×20 per sample). Data are mean ± SEM; *P < 0.05, **P < 0.01, †P < 0.0001 (2-tailed Student’s t test).