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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)248-266
Number of pages19
JournalJournal of Clinical Investigation
Volume128
Issue number1
DOIs
StatePublished - Jan 2 2018

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Roca, H., Jones, J. D., Purica, M. C., Weidner, S., Koh, A. J., Kuo, R., Wilkinson, J. E., Wang, Y., Daignault-Newton, S., Pienta, K. J., Morgan, T. M., Keller, E. T., Nör, J. E., Shea, L. D., & McCauley, L. K. (2018). Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. Journal of Clinical Investigation, 128(1), 248-266. https://doi.org/10.1172/JCI92466