Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.
J Clin Invest
; 128(1): 248-266, 2018 01 02.
Article
in En
| MEDLINE
| ID: mdl-29202471
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prostatic Neoplasms
/
Bone Neoplasms
/
Apoptosis
/
Chemokine CXCL5
/
Neoplasm Proteins
/
Neoplasms, Experimental
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Clin Invest
Year:
2018
Document type:
Article
Affiliation country:
Estados Unidos