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 January 2, 2018; First published November 27, 2017
Citation Information: J Clin Invest. 2018;128(1):248-266. https://doi.org/10.1172/JCI92466.
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Categories: 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 1

Inflammatory cytokine and transcription factor activation in cocultures of macrophages and highly apoptotic (HA) cells.

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Inflammatory cytokine and transcription factor activation in cocultures ...
(A and B) Supernatants were collected from macrophages (MΦs) alone or cocultured with RM1(HA), PC3(HA), BMSC(HA), or MC4(HA) cells for 18–20 hours and analyzed via inflammatory cytokine array. (A) Representative images. (B) Quantification of cytokines induced. (C) mRNAs isolated from cocultures described in A were analyzed by quantitative PCR (qPCR). (D) mRNAs isolated from MΦs alone or cocultured with RM1(HA), MPEC(HA), or BMC(HA) were analyzed by qPCR for indicated genes. (E) ELISA for total CXCL1 and CXCL5 levels in supernatants of MΦs alone or cocultured with RM1(HA) or PC3(HA). (F) Transcriptional activity cell arrays (TRACER). Analysis of bone marrow–derived MΦs transfected with transcription factor (TF) reporter constructs and cocultured with RM1(HA) or MC4(HA) cells. Data from experimental repeats (n = 5 and n = 2 independent experiments for RM1 for MC4, respectively) were combined. Measurements were log2-transformed and normalized to average intensity of control reporter and then to background. Finally, data were normalized to the initial reporter measurement for each treatment condition at 0 hours. Heatmaps show TF grouping according to cluster analysis for each cell line and the statistical significance, **P < 0.01, #P < 0.001, determined using limma package. Data in B–E are mean ± SEM, n = 3 per group; *P < 0.05, **P < 0.01, #P < 0.001, †P < 0.0001 (1-way ANOVA).