A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer

Abstract Prostaglandin E 2 (PGE 2 ) is associated with proliferation and angiogenesis in colorectal tumours. The role of prostaglandin transporter OATP2A1/ SLCO2A1 in colon cancer tumorogenesis is unknown. We evaluated mice of various Slco2a1 genotypes in a murine model of colon cancer, the adenomatous polyposis (APC) mutant ( Apc ∆716/ + ) model. Median lifespan was significantly extended from 19 weeks in Slco2a1 +/+ / Apc Δ716/ + mice to 25 weeks in Slco2a1 −/− / Apc Δ716/ + mice. Survival was directly related to a reduction in the number of large polyps in the Slco2a1 −/− /Apc ∆716/ + compared to the Slco2a1 +/+ / Apc Δ716/ + or Slco2a1 +/− / Apc Δ716/ + mice. The large polyps from the Slco2a1 −/− /Apc ∆716/ + mice had significant reductions in microvascular density, consistent with the high expression of Slco2a1 in the tumour-associated vascular endothelial cells. Chemical suppression of OATP2A1 function significantly reduced tube formation and wound-healing activity of PGE 2 in human vascular endothelial cells (HUVECs) although the amount of extracellular PGE 2 was not affected by an OATP2A1 inhibitor. Further an in vivo model of angiogenesis, showed a significant reduction of haemoglobin content (54.2%) in sponges implanted into Slco2a1 −/− , compared to wildtype mice. These studies indicate that OATP2A1 is likely to promote tumorogenesis by PGE 2 uptake into the endothelial cells, suggesting that blockade of OATP2A1 is an additional pharmacologic strategy to improve colon cancer outcomes.

Перевод пока недоступен