Details

Autor(en) / Beteiligte

• Bruno, Annalisa
• Contursi, Annalisa
• Tacconelli, Stefania
• Sacco, Angela
• Hofling, Ulrika
• Mucci, Matteo
• Lamolinara, Alessia
• Del Pizzo, Francesco
• Ballerini, Patrizia
• Di Gregorio, Patrizia
• Yu, Ying
• Patrignani, Paola

Titel

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

Ist Teil von

• Pharmacological research, 2022-11, Vol.185, p.106506

Ort / Verlag

Netherlands

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 mice, considered a clinically relevant model. To realize this objective, we generated an Apc mouse with a specific deletion of Ptgs1(COX-1 gene name) in megakaryocytes/platelets (Apc ;pPtgs1 mice) characterized by profound inhibition of thromboxane(TX)A biosynthesis ex vivo (serum TXB ; by 99%) and in vivo [urinary 2,3-dinor-TXB (TXM), by 79%]. Apc 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)E biosynthesis (urinary PGEM) vs. Apc mice. Extravasated platelets were detected in the intestine of Apc 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 TXA was involved in the induction of COX-2-dependent PGE in myofibroblasts since it was prevented by the selective inhibition of platelet COX-1 by aspirin or by a specific antagonist of TXA 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.