Abstract
Background:
Tumor promoting inflammation is important for Neuroblastoma development and progression. We have previously shown that the inflammatory prostaglandin E2 (PGE2) acts as an autocrine survival factor in NB and that high expression of microsomal prostaglandin E synthase-1 (mPGES-1), essential for PGE2 synthesis, is coupled to poor clinical outcome in high risk NB. We have also shown that mPGES-1 promotes growth and survival of several malignancies.
In this study we investigate the impact of specific PGE2 targeting in NB by using a novel mPGES-1 inhibitor in vivo.
Methods: The in vivo effect of the mPGES-1 inhibitor on tumor growth was carried out using the MYCN driven transgenic mouse model that spontaneously develops an aggressive form of neuroblastoma (tg TH-MYCN model). Protein and mRNA expression of mPGES-1 and the COX enzymes in the tumors was determined by immunohistochemistry (IHC) and RT-qPCR.
Infiltration and polarization of macrophages in treated and nontreated tumors was assessed by IHC using the PAN-marker F4/80 and the M2 polarized macrophage marker CD206.
The effect of mPGES-1 inhibition on angiogenesis was determined by IHC by using the endothelial marker CD31.
Results: Expression of mPGES-1 and COX-1 could be detected in tumours from the tg TH-MYCN model. By treating the animals with the mPGES-1 inhibitor we could significantly delay the tumor growth with reduced tumor weights at sacrifice compared to tumors from untreated control animals.
To study the effect of inflammation we analyzed macrophage abundance and polarization in the treated and untreated tumors. There was no diffrence in the total level of macrophage infiltration while a significant decrese of M2 polarized macrophages was seen in the treated tumors.
Furthermore, mPGES-1 inhibition significantly reduced angiogenesis in the tumors.
Conclusion: Our results demonstrate that specific PGE2 inhibition by targeting mPGES-1 is a way of reducing NB growth.
Note: This abstract was not presented at the meeting.
Citation Format: Anna Kock, Karin Larsson, Raouf Joan, Marina Korotkova, John-Inge Johnsen, Per-Johan Jakobsson, Per Kogner. Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1632. doi:10.1158/1538-7445.AM2015-1632
- ©2015 American Association for Cancer Research.
Volume 75, Issue 15 Supplement
