Background: High-risk neuroblastomas present a tumor promoting microenvironment with infiltrating cancer associated fibroblasts (CAFs) expressing the mPGES-1 enzyme, essential for prostaglandin E2 (PGE2) synthesis regulating tumor inflammation and immune suppression, angiogenesis, genetic instability, tumor progression and therapy resistance. We investigated the impact of novel therapy targeting the COX/mPGES-1/PGE2 pathway.
Methods: Human neuroblastomas were investigated for immunosuppressive microenvironment and expression of the COX/mPGES-1/PGE2/EP-receptor pathway. High-risk in vivo models, human 11q-deleted xenografts and transgenic MYCN-driven tumors, were treated with a novel specific mPGES-1 inhibitor. Tumor-fibroblast co-cultures examined cell migration. Inflammatory lipid mediators were analyzed by LC-MS/MS. Tumor tissues were analyzed by immunohistochemistry, immunofluorescence and FACS.
Results: Tumor microenvironment in human high-risk neuroblastomas and both 11q-deleted xenografts and MYCN-driven transgenic mice displayed mPGES-1 expression in PDGFRb+ cancer associated fibroblasts. MPGES-1 expression correlated with high-risk neuroblastoma prognosis and infiltration of tumor-promoting macrophages with M2-polarization markers CD163 and CD206. The inflammatory regulator STAT3 was active in mPGES-1 expressing CAFs. Expression of the inflammatory COX/mPGES-1/PGE2/EP-receptor pathway in experimental tumors resembled high-risk primary human neuroblastomas.
Targeting mPGES-1 with a novel compound decreased PGE2, induced M1 polarization of macrophages, decreased cancer associated fibroblasts and reduced angiogenesis significantly in treated tumors. Tumor development in the xenograft model was delayed 50% (median 38 vs. 25.5days) and growth of established xenografts and transgenic tumors was significantly decreased by non-toxic treatment in vivo when compared to neuroblastoma tumors in untreated animals. Tumor cell stimulated CAF migration and infiltration was inhibited by targeting mPGES-1.
Conclusions: Tumor-promoting inflammation and suppression of anti-tumor immunity in neuroblastoma is mediated through prostaglandin E2 and STAT3 expression in cancer associated fibroblasts in the tumor microenvironment. Early targeting of mPGES-1 may inhibit CAF infiltration and tumor development. This novel tumor treatment targeting mPGES-1 decreases inflammatory mediators, modulates tumor-promoting microenvironment, decreases cancer cell migration and inhibits significantly aggressive tumor growth and progression. We conclude that treatment targeting non-malignant cells in the neuroblastoma microenvironment may constitute a novel clinical therapeutic approach.