The Absence of LPA2 Attenuates Tumor Formation in an Experimental Model of Colitis-Associated Cancer

• Type of Material: Article
• Authors: Songbai Lin, Emory University; Dongsheng Wang, Emory University; Amr M. Ghaleb, Emory University; Hyunsuk Shim, Emory University; Vincent W. Yang, Emory University; Jerold Chun, Scripps Research Institute; Chris Yun, Emory University; Smita Iyer, Emory University
• Language: English
• Date: 2009-05
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 by the AGA Institute
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2009.01.002
• Title of Journal or Parent Work: Gastroenterologe
• ISSN: 1861-9681
• Volume: 136
• Issue: 5
• Start Page: 1711
• End Page: 1720
• Grant/Funding Information: S.L. is supported by a Research Fellowship Award from the Crohn’s and Colitis Foundation of America.; This work was supported by grants from the National Institutes of Health (DK071597 (C.C.Y.), DK052230 (V.W.Y.), MH51699, HD050685, and NS048478 (J.C.).; We acknowledge the Emory Digestive Disease Research Development Center (supported by DK064399) for the use of light microscope.
• Keywords: lysophosphatidic acid; chronic inflammation; colon cancer; ovarian cancer; LPA receptor 2
• Research Categories: Biology, Physiology; Health Sciences, Oncology

Abstract

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 (LPA2) is up-regulated in several types of cancer, including ovarian and colon cancer, but the importance of LPA and LPA2 in the development and progression of CC is unclear. In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC in vivo. Methods: We examined the potential role of LPA in CC progression by administering LPA to ApcMin/+ mice. We determined the loss of LPA2 function in tumorigenesis in the colon by treating mice with genetic deletion of LPA2 (LPA2−/−) with azoxymethane (AOM) and dextran sulfate sodium (DSS). Results: We found that LPA increased tumor incidence in Apcmin/+ mice. LPA2−/− mice showed reduced mucosal damage and fewer tumors than wild-type (WT) mice. Reduced epithelial cell proliferation and decreases in β-catenin, Krüppel-like factor 5 (KLF5), and cyclooxygenase-2 (COX-2) expression were observed in LPA2−/− mice. Unlike WT mice, induction of monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) was significantly attenuated in LPA2−/− mice with reduced infiltration by macrophages. Conclusion: These results show that LPA is capable of promoting tumorigenesis in the colon. The absence of LPA2 attenuates several effects that contribute to cancer progression in vivo and, hence, the current study identifies LPA2 as an important modulator of CC.