COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Abstract

The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E 2 (PGE 2 ) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE 2 . High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE 2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE 2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.

More than the genes, the tumor microenvironment in neuroblastoma

“…Expression of genes representing TAMs (CD33/CD16/IL-10/FCGR3) in addition to IL-6 receptor (IL-6R) contributed to 25% of the accuracy of a novel 14-gene tumor classification score [13]. Infiltration with Th2-driven macrophages expressing CD163 and CD206 was also recently observed in a subset of high-risk neuroblastoma tumors with deletion of chromosome 11q and high levels of prostaglandin-synthase and elevated levels of PGE2 [14]. …”

The Role of mPGES-1 in Inflammatory Brain Diseases

“…An increased expression of mPGES-1 in the tissues of patients of brain cancer has also been reported from another group in a subset of human glioblastoma multiforme (GBM) tumors, the most common form of adult brain cancer, astrocytoma and high-risk neuroblastoma. [45][46][47] An activated COX/mPGES-1/PGE 2 pathway has been identified in 11q-deleted neuroblastoma with high expression of mPGES-1, and elevated levels of PGE 2 as compared with low-risk tumors. Analysis of expression cohorts revealed a worse outcome for high-risk patients (INSS stage 4) with high mPGES-1 expression.…”

“…Analysis of expression cohorts revealed a worse outcome for high-risk patients (INSS stage 4) with high mPGES-1 expression. 47) In accordance with the anti-apoptotic properties of COX-2, which is known to play an important role in tumor development, in an in vitro study using the human astroglioma cell line U-87MG, PGE 2 produced by overexpression of mPGES-1 promoted glioma proliferation through activation of type 2 protein kinase A. 46) COX inhibition in an in vivo model of 11q-deleted neuroblastoma also demonstrated that PGE 2 produced by mPGES-1 resulted in promotion of tumor growth.…”

“…46) COX inhibition in an in vivo model of 11q-deleted neuroblastoma also demonstrated that PGE 2 produced by mPGES-1 resulted in promotion of tumor growth. 47) On the other hand, intracellular PGE 2 produced by mPGES-1 has been shown to promote apoptosis by activation of Bax through its physical interaction with PGE 2 . 45) Thus, the balance between extracellular and intracellular PGE 2 may be important in the control of apoptosis in glioma.…”

Sulforaphane, a Chemopreventive Compound, Inhibits Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Expression in Human HT-29 Colon Cancer Cells

“…Increased levels of mPGES-1 have been found in various cancers, including non-small-cell lung cancer, colon cancer, and prostate cancer [Larsson et al, 2015]. Animal studies have shown that chemical inhibition or the elimination of COX-2 activity results in a decreased or slower tumor formation [Jänne and Mayer, 2000;Ettarh et al, 2010].…”