Journal Article

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

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

2018

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Animal models / Animals / Apoptosis / Apoptosis - genetics / Apoptosis - immunology / Bone cancer / Bone growth / Bone marrow / Bone Neoplasms - genetics / Bone Neoplasms - immunology / Bone Neoplasms - pathology / Bone Neoplasms - secondary / Bone tumors / Cancer metastasis / Cell culture / Cell death / Cell Line, Tumor / Chemokine CXCL5 - genetics / Chemokine CXCL5 - immunology / Cytokines / Development and progression / Growth / Immune clearance / Immune system / Immunocompetence / Inflammation / Inflammation - genetics / Inflammation - immunology / Inflammation - pathology / Investigations / Macrophages / Male / Metastases / Metastasis / Mice / Monocytes / Myeloid Cells - immunology / Myeloid Cells - pathology / Neoplasm Metastasis / Neoplasm Proteins - genetics / Neoplasm Proteins - immunology / Neoplasms, Experimental - genetics / Neoplasms, Experimental - immunology / Neoplasms, Experimental - pathology / NF-κB protein / Peripheral blood / Phagocytes / Phagocytosis - genetics / Phagocytosis - immunology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - immunology / Prostatic Neoplasms - pathology / Serum levels / Stat3 protein / Transcription factors / Vertebrae