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PLoS One. 2015 Dec 28;10(12):e0145197. doi: 10.1371/journal.pone.0145197. eCollection 2015.

The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation.

Author information

1
The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, New York, United States of America.
2
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
3
Department of Surgery, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
4
Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
5
Center for Molecular Innovation, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
6
Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.

Abstract

Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy. CNI-1493 is a selective inhibitor of macrophage function and has shown to be safe in clinical trials as an anti-inflammatory agent. In a xenograft mouse model of metastatic Ewing Sarcoma, CNI-1493 treatment dramatically reduces metastatic tumor burden. Furthermore, metastases in treated animals have a less invasive morphology. We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis. These data indicate that CNI-1493 may be a safe and effective adjuvant agent for the prevention and treatment of metastatic Ewing Sarcoma.

PMID:
26709919
PMCID:
PMC4692435
DOI:
10.1371/journal.pone.0145197
[Indexed for MEDLINE]
Free PMC Article

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