The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer

Background & Aims Chronic inflammation is a risk factor for colon cancer (CC). Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including inflammation and cancer. The expression of LPA receptor 2 (LPA 2 ) is up-regulated in several types of cancer, including ovarian and colon cancer, but the importance of LPA and LPA 2 in the development and progression of CC is unclear. In this study, we sought to determine whether LPA and LPA 2 regulate the progression of CC in vivo. Methods We examined the potential role of LPA in CC progression by administering LPA to mice heterozygous for the adenomatous polyposis coli (Apc) allele. We determined the loss of LPA 2 function in tumorigenesis in the colon by treating mice with genetic deletion of LPA 2 (LPA 2 −/− ) with azoxymethane and dextran sulfate sodium. Results We found that LPA increased tumor incidence in Apc min/+ mice. LPA 2 −/− mice showed reduced mucosal damage and fewer tumors than wild-type (WT) mice. Reduced epithelial cell proliferation and decreases in β-catenin, Kruppel-like factor 5, and cyclooxygenase-2 expression were observed in LPA 2 −/− mice. Unlike WT mice, induction of monocyte chemoattractant protein-1 and macrophage migration inhibitory factor was significantly attenuated in LPA 2 −/− mice with reduced infiltration by macrophages. Conclusions These results show that LPA is capable of promoting tumorigenesis in the colon. The absence of LPA 2 attenuates several effects that contribute to cancer progression in vivo, and, hence, the current study identifies LPA 2 as an important modulator of CC.