The specific deletion of cyclooxygenase-1 in megakaryocytes/platelets reduces intestinal polyposis in Apc^Min/+ mice

Clinical and experimental evidence sustain the role of cyclooxygenase (COX)-1 in intestinal tumorigenesis. However, the cell type expressing the enzyme involved and molecular mechanism(s) have not been clarified yet. We aimed to elucidate the role of platelet COX-1 (the target of low-dose aspirin in humans) in intestinal tumorigenesis of Apc^Min/+ mice, considered a clinically relevant model. To realize this objective, we generated an Apc^Min/+ mouse with a specific deletion of Ptgs1(COX-1 gene name) in megakaryocytes/platelets (Apc^Min/+;pPtgs1^-/-mice) characterized by profound inhibition of thromboxane(TX)A₂ biosynthesis ex vivo (serum TXB₂; by 99%) and in vivo [urinary 2,3-dinor-TXB₂(TXM), by 79%]. Apc^Min/+ mice with the deletion of platelet COX-1 showed a significantly reduced number (67%) and size (32%) of tumors in the small intestine. The intestinal adenomas of these mice had decreased proliferative index associated with reduced COX-2 expression and systemic prostaglandin(PG)E₂ biosynthesis (urinary PGEM) vs. Apc^Min/+mice. Extravasated platelets were detected in the intestine of Apc^Min/+mice. Thus, we explored their contribution to COX-2 induction in fibroblasts, considered the primary polyp cell type expressing the protein. In the coculture of human platelets and myofibroblasts, platelet-derived TXA₂ was involved in the induction of COX-2-dependent PGE₂ in myofibroblasts since it was prevented by the selective inhibition of platelet COX-1 by aspirin or by a specific antagonist of TXA₂ receptors. In conclusion, our results support the platelet hypothesis of intestinal tumorigenesis and provide experimental evidence that selective inhibition of platelet COX-1 can mitigate early events of intestinal tumorigenesis by restraining COX-2 induction.