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 3

Efferocytosis-induced activation of Stat3 and NF-κB signaling mediates inflammatory response in macrophages.

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Efferocytosis-induced activation of Stat3 and NF-κB signaling mediates i...
(A) MΦs were cocultured 20 hours alone or with apoptotic RM1(HA) cells. Protein from cocultures was analyzed by Western blot for activation of NF-κB and Stat3 signaling using consecutively the following antibodies (panels from top): phospho–NF-κB(p65) [p–NF-κB(p65)], p-Stat3, and p100/p52. Bottom panel shows total protein for each sample. (B) Protein bands in the blots were quantified and normalized to total protein for each sample. Graphs depict the fold changes for p-p65, p-Stat3, p52/p100 ratio, and p52 relative to MΦ signal, respectively. (C) Stattic, a selective inhibitor of Stat3 activation, was incubated with MΦs (12.5 μM) for 1 hour, then removed before coculture with RM1(HA) for 5 hours. Protein was analyzed by Western blot using the p-Stat3 antibody. (D) Bay11-7082, an inhibitor of NF-κB signaling, was preincubated with MΦs (20 μM) for 1 hour before coculture with RM1(HA) for 5 hours. Protein was analyzed by Western blot using the p-p65 antibody. Graphs in C and D depict the quantification of p-Stat3 and p-p65 signals normalized to total protein (lower panel) relative to the average MΦ control (VEH), respectively. See complete unedited blots in the supplemental material. (E) mRNAs were isolated from cocultures at 5 and 20 hours of incubation as described in the experiments in C and D and analyzed by qPCR for indicated genes. Graphs show the fold change relative to MΦ control for each group. Data in B are mean ± SEM, n = 4 per group (2-tailed Student’s t test), or n = 3 per group in C–E (1-way ANOVA); **P < 0.01, #P < 0.001, †P < 0.0001.