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

Prostaglandin E₂ (PGE₂) 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 PGE₂ in human vascular endothelial cells (HUVECs) although the amount of extracellular PGE₂ 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 PGE₂ uptake into the endothelial cells, suggesting that blockade of OATP2A1 is an additional pharmacologic strategy to improve colon cancer outcomes.

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