Roles of an inducible prostaglandin E synthase, mPGES-1 in host in enhancement of tumor-associated angiogenesis

Background: Microsomal prostaglandin (PG) E synthase 1 (mPGES)-1 is a major PGE synthase and has recently been reported to be expressed at high levels in several cancer types. We previously reported that the PGE receptor EP3 is expressed in bone marrow (BM)-derived cells, enriched in stromal tissue, and enhances the potential for tumor angiogenesis. Objective: In the present study, we examined the role of mPGES-1 in the host tissues in enhancement of tumor-associated angiogenesis. Materials and Methods: We used 8-week-old male mPGES-1 KO mice backcrossed with their wildtype counterparts (WT, C57BL6). Lewis lung carcinoma (LLC) cells were injected into the subcutaneous dorsal tissue of mice. Tumor growth was evaluated over time. Serial sections were stained with hematoxylin and eosin (H&E). Microvessel density (MVD) and microvessel area (MVA) were quantified as parameters of angiogenesis. High-dose irradiated WT mice were divided into two groups. mPGES-1 BM cells collected from each of the femurs, tibias, and pelvis were injected via the tail vein into irradiated WT mice. Another group were injected with BM cells from WT Mice. Angiogenesis was also evaluated. Results: Growth and tumor-associated angiogenesis were suppressed in mPGES-1 knockout mice (mPGES-1 -/- ) after the subcutaneous implantation of Lewis lung carcinoma cells, in comparison with those in wild-type (WT) mice. After lethal radiation, WT BMs were replaced with BM cells isolated from mPGES-1 -/- . The levels of neoangiogenesis in the sponge implants measured in mPGES-1 -/- BM chimeric mice were significantly reduced compared to those observed in WT BM chimeric mice. Tumor-associated angiogenesis as measured by histological analysis was localized to tumor stroma, and was significantly lower in mPGES-1 -/- BM chimeric mice compared to that in WT BM chimeric mice. Tumor sections probed by immunohistochemistry revealed that vascular endothelial growth factor (VEGF) that was present in the stromal tissue was markedly reduced in mPGES-1 -/- BM chimeric mice compared to wild-type BM chimeras. Conclusions: These results suggest that host mPGES-1 enhanced tumor-asaociated amgiogenesis, and that regulation of mPGES-1-expressing BM cell recruitment to the site of primary tumors may be a novel strategy for the treatment of solid tumors.