Loss of LSR affects epithelial barrier integrity and tumor xenograft growth of CaCo-2 cells
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Bernd A. Czulkies1, Justin Mastroianni2, Lisa Lutz3, Sarah Lang1, Carsten Schwan1, Gudula Schmidt1, Silke Lassmann3,4,5, Robert Zeiser2,5, Klaus Aktories1,5,6, Panagiotis Papatheodorou1,7,8
1Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University (ALU), Freiburg, Germany
2Department of Hematology and Oncology, University Medical Center, ALU, Freiburg, Germany
3Department of Pathology, University Medical Center, ALU, Freiburg, Germany
4German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
5Centre for Biological Signalling Studies (BIOSS), ALU, Freiburg, Germany
6Freiburg Institute for Advanced Studies (FRIAS), ALU, Freiburg, Germany
7Present address: Institute of Pharmaceutical Biotechnology. University of Ulm, Ulm, Germany
8Present address: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany
Panagiotis Papatheodorou, email: [email protected]
Keywords: tumor growth, xenograft, epithelial barrier, cell morphology, cell-cell contact
Received: March 21, 2016 Accepted: June 13, 2016 Published: July 06, 2016
The lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor, serves as host receptor for clostridial iota-like toxins and is involved in the formation of tricellular contacts. Of particular interest is the role of LSR in progression of various cancers. Here we aimed to study the tumor growth of LSR-deficient colon carcinoma-derived cell lines HCT116 and CaCo-2 in a mouse xenograft model. Whereas knockout of LSR had no effect on tumor growth of HCT116 cells, we observed that CaCo-2 LSR knockout tumors grew to a smaller size than their wild-type counterparts. Histological analysis revealed increased apoptotic and necrotic cell death in a tumor originating from LSR-deficient CaCo-2 cells. LSR-deficient CaCo-2 cells exhibited increased cell proliferation in vitro and an altered epithelial morphology with impaired targeting of tricellulin to tricellular contacts. In addition, loss of LSR reduced the transepithelial electrical resistance of CaCo-2 cell monolayers and increased permeability for small molecules. Moreover, LSR-deficient CaCo-2 cells formed larger cysts in 3D culture than their wild-type counterparts. Our study provides evidence that LSR affects epithelial morphology and barrier formation in CaCo-2 cells and examines for the first time the effects of LSR deficiency on the tumor growth properties of colon carcinoma-derived cell lines.
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