Abstract
Observational/retrospective studies indicate that prostaglandin-endoperoxide synthase-2 (PTGS2) inhibitors could positively affect colorectal cancer (CRC) patients’ survival after diagnosis. To obtain an acceptable cost/benefit balance, the inclusion of PTGS2 inhibitors in the adjuvant setting needs a selective criterion. We quantified the 72 kDa, CRC-associated, glycosylated form of PTGS2 in 100 frozen CRC specimens and evaluated PTGS2 localization by IHC in the same tumors, scoring tumor epithelial-derived and stroma-derived fractions. We also investigated the involvement of interleukin-1 beta (IL1β) in PTGS2 induction, both in vitro and in CRC lysates. Finally, we used overall survival (OS) as a criterion for patient selection. Glycosylated PTGS2 can be quantified with high sensibility in tissue lysates, but the expression in both tumor and stromal cells limits its use for predictive purposes. Immunohistochemistry (IHC) analysis indicates that stromal PTGS2 expression could exert a protective role on patient OS. Stromal PTGS2 was prevalently expressed by cancer-associated fibroblasts exerting a barrier function near the gut lumen, and it apparently favored the antitumor M1 macrophage population. IL1β was directly linked to gPTGS2 expression both in vitro and in tumors, but its activity was apparently prevalent on the stromal cell population. We suggest that stromal PTGS2 could exert a positive effect on patients OS when expressed in the luminal area of the tumor.
Highlights
Prostaglandin-endoperoxide synthase-2 (PTGS2), one of the key enzymes mediating prostaglandins neosynthesis, is typically induced by inflammatory stimuli and expressed by tumor epithelial cells in about 74–78% of colorectal cancer (CRC)
CD163 staining on serial sections: prostaglandin-endoperoxide synthase-2 (PTGS2) sections: (a) Representative images of PTGS2, CD68, and CD163 staining on serial sections: PTGS2 can be in areas enriched with CD68-positive macrophages, but it shows can befound found in areas enriched with CD68-positive macrophages, butinfrequent it showsoverlapping
Our observations suggested a possible subgrouping of CRC on the basis of stromal, or tumor-derived PTGS2, the former modulated by IL1β, with a prognostic significance, the latter relatively independent
Summary
Prostaglandin-endoperoxide synthase-2 (PTGS2), one of the key enzymes mediating prostaglandins neosynthesis, is typically induced by inflammatory stimuli and expressed by tumor epithelial cells in about 74–78% of colorectal cancer (CRC) (see [1] for review). PTGS2 has been considered an ideal target for colorectal tumor chemoprevention [3,4], but the cardiotoxicity associated to the specific PTGS2 inhibitor Celecoxib determined an unfavorable cost/benefit ratio for the chemoprevention of the normal population. This phase III, multicenter trial will give a fundamental hint for the rational use of PTGS2 inhibitors in advanced CRC. The influence of tumor PTGS2 expression on CRC patient prognosis is difficult to interpret [8,9,10,11]. Despite the influence of tumor stroma and leucocyte infiltration in CRC progression [12,13,14], previous studies did not evaluate the influence of PTGS2 expressed by non-tumor cells on patient prognosis. PTGS2 was correlated with patient prognosis to evaluate its association with CRC aggressiveness
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