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.
Highlights
Ewing Sarcoma is the second-most common bone and soft tissue malignancy of childhood
We first asked whether human primary M1 and M2 macrophages derived from blood monocytes altered invasion of Ewing Sarcoma cells through a basement membrane extract using three-dimensional invasion assays, and whether CNI-1493 altered that process (Fig 1A)
CNI-1493 had no effect on invasion by SK-NEP-1 cells alone or when co-cultured with M1 macrophages, indicating that CNI-1493 was not having a direct effect on tumor cells or a generalized effect on all macrophages
Summary
Ewing Sarcoma is the second-most common bone and soft tissue malignancy of childhood. Macrophages are recruited to the tumor microenvironment where they adapt an M2-like phenotype supportive of tumor growth [4,5,6,7], details of the origin and features of this phenotype have recently been debated [8] In this state, macrophages promote angiogenesis, cellular proliferation, viability, motility and invasion, tissue remodeling, and immune suppression [4, 6, 9,10,11,12,13,14,15,16,17,18]. We find that CNI-1493 markedly decreases the incidence of invasive metastasis and tumor burden in a mouse model of Ewing Sarcoma, and that it suppresses M2 macrophage-stimulated tumor cell invasion and extravasation in vitro
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