Epimorphin deletion inhibits polyposis in the Apcmin/+ mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion.

Interactions between the epithelium and surrounding mesenchyme/stroma play an important role in normal gut morphogenesis, the epithelial response to injury, and epithelial carcinogenesis. The tumor microenvironment, composed of stromal cells including myofibroblasts and immune cells, regulates tumor growth and the cancer stem cell niche. Deletion of epimorphin (Epim), a syntaxin family member expressed in myofibroblasts and macrophages, results in partial protection from colitis and from inflammation-induced colon cancer in mice. We sought to determine whether epimorphin deletion protects from polyposis in the Apcmin/+ mouse model of intestinal carcinogenesis. Epim-/- mice were crossed to Apcmin/+ mice; Apcmin/+ and Apcmin/+/Epim-/- mice were killed at 3 mo of age. Polyp numbers and sizes were quantified in small intestine and colon, and gene expression analyses for pathways relevant to epithelial carcinogenesis were performed. Primary myofibroblast cultures were isolated, and expression and secretion of selected growth factors from Apcmin/+ and Apcmin/+/Epim-/- myofibroblasts were examined by ELISA. Small bowel polyposis was significantly inhibited in Apcmin/+/Epim-/- compared with Apcmin/+ mice. Apcmin/+/Epim-/- compared with Apcmin/+ polyps and adjacent uninvolved intestinal mucosa had increased transforming growth factor-ß (TGF-ß) expression and signaling with increased P-Smad2/3 expression. Myofibroblasts isolated from Apcmin/+/Epim-/- vs. Apcmin/+ mice had markedly decreased hepatocyte growth factor (HGF) expression and secretion. We concluded that Epim deletion inhibits polyposis in Apcmin/+ mice, associated with increased mucosal TGF-ß signaling and decreased myofibroblast HGF expression and secretion. Our data suggest that Epim deletion reduces tumorigenicity of the stromal microenvironment.

Clinical experience of natalizumab in Crohn's disease patients in a restricted distribution program.

BACKGROUND: Natalizumab (NAT) is a humanized monoclonal antibody against a4-integrin initially approved for the treatment of multiple sclerosis, and then withdrawn from the market in 2005 due to the risk of progressive multifocal leukoencephalopathy. NAT was approved for the treatment of Crohn's disease in the United States in 2008 under a restricted distribution program. There has been limited data on NAT since then. The purpose of this study was to review the experience with NAT in Crohn's disease patients at a tertiary inflammatory bowel disease center. METHODS: A retrospective chart review was performed on all patients who received NAT for treatment of refractory Crohn's disease from January 2008 to August 2010 at Washington University Medical Center in St. Louis. RESULTS: A total of 20 patients were identified and included in our study. Four patients did not complete induction therapy. Seven patients had a clinical response, with 5 patients continuing treatment up to 2012. Four patients had a partial response, 3 had adverse events, and 2 experienced loss of response. Two patients were pregnant while on NAT, and neither had significant adverse pregnancy outcomes. One patient dependent on total parenteral nutrition developed recurrent line sepsis while on NAT. Of the 5 patients on long-term maintenance therapy, 4 have a positive anti-JC virus antibody. No patients developed progressive multifocal leukoencephalopathy or other neurological complications. CONCLUSION: NAT remains a valuable alternative treatment option for patients with refractory Crohn's disease under a restricted distribution program.