An association of gallbladder
carcinoma with
cholelithiasis suggests that chronic
inflammation may modulate
tumorigenesis and/or progression of the
carcinoma. An enhanced expression of
cyclooxygenase-2 (COX-2) is observed frequently in advanced
carcinomas of gastrointestinal tracts, which in turn suggests that potentiated arachidonate metabolism may play a crucial role in
tumor biology. In the present study, the expression levels of COX-2 and
prostaglandin E receptor subtypes were determined in 16 cases of gallbladder
carcinomas of different depths of invasion (pT(1) 3, pT(2) 2, pT(3) 4, and pT(4) 7) to determine the role of arachidonate metabolism in
tumor growth and progression. The
mRNA levels of COX-2 were increased significantly in pT(3) and pT(4)
carcinomas compared with the levels in pT(1) and pT(2)
carcinomas. Immunohistochemistry and in situ hybridization revealed the existence of COX-2
mRNA and
protein in both the cancerous epithelia and adjacent stroma of pT(1)-pT(4)
carcinomas. Only in pT(3) and pT(4)
carcinomas was intense expression of COX-2 observed in the adjacent stroma. The tissue concentration of
PGE(2) was significantly increased in pT(3) and pT(4)
carcinomas. The mRNAs of
PGE receptor subtypes EP(2), EP(3), and EP(4) were amplified in pT(1)-pT(4) gallbladder
carcinomas, in which their mRNAs and EP(4)
protein were expressed mostly in the cancerous epithelia. Treatment with a specific EP(4) agonist, as well as
PGE(2) but not EP(2) and EP(3) agonists, up-regulated the expression of c-fos, an induced growth response gene, and increased colony formation. In advanced gallbladder
carcinoma, enhanced expression of COX-2 is observed in the adjacent stroma rather than in the cancerous epithelia, and the stroma is a potent source of PG synthesis. In epithelial-stromal interactions, the increased
PGE(2) synthesis in the adjacent stroma and its biological effect via EP(4) on the
carcinoma cells may contribute to
tumor growth and progression of gallbladder
carcinoma.