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 2

Efferocytosis of apoptosis-inducible prostate cancer RM1-iC9 cells.

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Efferocytosis of apoptosis-inducible prostate cancer RM1-iC9 cells. (A) ...
(A) Apoptosis-inducible RM1-iC9 cells were treated with VEH or AP and analyzed by Western blot for the activation of inducible caspase-9 (iC9) and apoptosis-associated caspase-3. AP treatment increased processed caspase-9 and cleaved caspase-3, reflecting apoptosis (see complete unedited blots in the supplemental material). (B) Bone marrow MΦs were cocultured with RM1-iC9 cells stained with Cell Trace–CFSE (Invitrogen), and treated with VEH or AP for 18 hours. The cocultures were stained with F4/80-APC antibody and analyzed by flow cytometry. Representative FACS images from ImageStream showing MΦs alone (APC+, red gate), RM1-iC9 alone (CFSE+, green gate), and 3 different examples of MΦs engulfing RM1-iC9 (APC+CFSE+, yellow gate). (C) Bar graphs indicating the percentage of efferocytic MΦs (APC+CFSE+ cells), MΦs with high internalization of RM1-iC9, and engulfed RM1-iC9 (APC+CFSE+) relative to total cancer cells (CFSE+ plus APC+CFSE+) after treatment with VEH or AP. (D) mRNAs isolated from APC+CFSE+ gated cells (efferocytic MΦs) of MΦ+RM1-iC9(AP) and APC+ gated cells (nonefferocytic MΦs) of MΦ+RM1-iC9 (VEH) samples were analyzed by qPCR for selected genes. Fold changes were expressed relative to the nonefferocytic MΦ values (VEH). Data in C and D are mean ± SEM, n = 3 per group; **P < 0.01, #P < 0.001 (2-tailed Student’s t test).