Study summary · research use only
Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study used mouse models (PepT1-overexpressing 'TG' mice and PepT1-knockout 'PepT1-KO' mice, with colitis-associated cancer induced by AOM/DSS) together with analysis of human colonic biopsies to examine the role of the peptide transporter PepT1 in colitis-associated cancer. The abstract reports that TG mice had larger tumor sizes, increased tumor burden, more intestinal inflammation, and more proliferating crypt cells than wild-type mice, while PepT1-KO mice showed decreases in these measures. Human colonic biopsies showed increased PepT1 expression in patients with colorectal cancer. The anti-inflammatory tripeptide KPV (Lys-Pro-Val), transported by PepT1, was reported to prevent carcinogenesis in wild-type mice but did not produce this effect in PepT1-KO mice.
Abstract
The human intestinal peptide transporter 1, hPepT1, is expressed in the small intestine at low levels in the healthy colon and upregulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have demonstrated that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC). Hence, we assessed here the role of PepT1 in CAC. Mice with hPepT1 overexpression in intestinal epithelial cells (TG) or PepT1 (PepT1-KO) deletion were used and CAC was induced by AOM/DSS. TG mice had larger tumor sizes, increased tumor burdens, and increased intestinal inflammation compared to WT mice. Conversely, tumor number and size and intestinal inflammation were significantly decreased in PepT1-KO mice. Proliferating crypt cells were increased in TG mice and decreased in PepT1-KO mice. Analysis of human colonic biopsies revealed an increased expression of PepT1 in patients with colorectal cancer, suggesting that PepT1 might be targeted for the treatment of CAC. The use of an anti-inflammatory tripeptide KPV (Lys-Pro-Val) transported by PepT1 was able to prevent carcinogenesis in WT mice. When administered to PepT1-KO mice, KPV did not trigger any of the inhibitory effect on tumorigenesis observed in WT mice. The observations that pepT1 was highly expressed in human colorectal tumor and that its overexpression and deletion in mice increased and decreased colitis associated tumorigenesis, respectively, suggest that PepT1 is a potential therapeutic target for the treatment of colitis associated tumorigenesis.
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