Aspirin and other nonsteroidal anti-inflammatory drugs prevent some cases of
colon cancer by inhibiting
prostaglandin (PG) synthesis.
PGE(2) promotes colon
neoplasia, as shown by knockout mouse studies on
enzymes and receptors in the PG cascade. A few experiments 20 to 30 years ago suggested that
PGD(2) may suppress
tumors, but a role for biosynthetic
enzymes for
PGD(2) in
tumor development has not been studied. We report here that disruption of the gene for hematopoietic
PGD synthase in Apc(Min/+) mice led to approximately 50% more intestinal
adenomas compared with controls.
Tumor size was not affected. By immunohistochemistry, we detected hematopoietic
PGD synthase mainly in macrophages and monocytes of the gut mucosa. The mean number of
tumors did not increase with knockout of the gene for the
lipocalin type of the
enzyme, which is not produced in the intestine. On the other hand, Apc(Min/+) mice with transgenic human hematopoietic
PGD synthase tended to have 80% fewer intestinal
adenomas. The transgene produced high
mRNA levels (375-fold over endogenous). There was a suggestion of higher urinary excretion of 11beta-PGF(2alpha) and a lower excretion of a
PGE(2) metabolite in transgenic mice, but differences (30-40%) were not statistically significant. The results support an interpretation that hematopoietic
PGD synthase controls an inhibitory effect on intestinal
tumors. Further studies will be needed to prove possible mechanisms, such as routing of PG production away from protumorigenic
PGE(2) or inhibition of the
nuclear factor-kappaB cascade by
PGD(2) metabolites.