Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon

Department of Internal Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
Oncology Reports (Impact Factor: 2.3). 02/2008; 19(1):105-10. DOI: 10.3892/or.19.1.105
Source: PubMed


Amphiregulin and epiregulin belong to the epidermal growth factor family and mediate the biological functions of epithelial and mesenchymal cells through epidermal growth factor receptors. In this study, we evaluated the amphiregulin and epiregulin expression in neoplastic and inflammatory lesions from the human colon. Surgically-obtained specimens were stained using standard immunohistochemical procedures. Amphiregulin and epiregulin were not expressed in the normal colonic mucosa, but were clearly detectable in adenomas and carcinomas. Weak immunostaining was also detected in mesenchymal cells from the tumor tissues. In the active mucosa of patients with ulcerative colitis and Crohn's disease, amphiregulin was mainly expressed by the epithelial cells. In addition, positive immunostaining was also detectable in the surrounding mesenchymal cells. In conclusion, amphiregulin and epiregulin may play important roles in colonic tumor growth and mucosal repair in the inflamed mucosa of inflammatory bowel disease.

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    • "We have also noted a reduction in the ErbB4-specific NRG4 ligand in active UC and CD compared to uninflamed controls 17. On the other hand, some groups have described increased expression of specific ligands such as amphigregulin in inflamed tissue 40 or increased EGFR 41 and EGFR ligand 42 in rodent colitis models. These apparently contradictory results may be in part a result of assaying expression at different phases of disease (e.g., acute vs. chronic vs. recovery), but may also reflect the natural complexity and interdependency of the different ErbBs and their ligands. "
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    ABSTRACT: The ErbB tyrosine kinases (epidermal growth factor receptor (EGFR), ErbB2/HER2, ErbB3, and ErbB4) are cell surface growth factor receptors widely expressed in many developing mammalian tissues, including in the intestinal tract. Signaling elicited by these receptors promotes epithelial cell growth and survival, and ErbB ligands have been proposed as therapeutic agents for intestinal diseases of pediatric populations, including inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and inflammation associated with total parenteral nutrition (TPN). Furthermore, emerging evidence points to reduced ErbB ligand expression and thus reduced ErbB activity in IBD, NEC, and TPN models. This review will discuss the current understanding of the role of ErbB receptors in the pathogenesis and potential treatment of pediatric intestinal inflammation, with focus on the altered signaling in disease and the molecular mechanisms by which exogenous ligands are protective.Pediatric Research (2014); doi:10.1038/pr.2013.210.
    Pediatric Research 11/2013; 75. DOI:10.1038/pr.2013.210 · 2.31 Impact Factor
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    • "These findings suggested to us that the secretion of mediators from intestinal myofibroblasts might play a role in growth modulation via paracrine pathways. In support of this possibility there is work showing a role for stromal myofibroblast production of amphiregulin and epiregulin in promoting colon tumor growth in the setting of inflamed human colon [27]. Our approach was guided by earlier findings demonstrating that small intestinal epithelial cells from Mttp-IKO mice undergo lipotoxic injury following short term high fat feeding [22]. "
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    ABSTRACT: Gut derived lipid factors have been implicated in systemic injury and inflammation but the precise pathways involved are unknown. In addition, dietary fat intake and obesity are independent risk factors for the development of colorectal cancer. Here we studied the severity of experimental colitis and the development of colitis associated cancer (CAC) in mice with an inducible block in chylomicron secretion and fat malabsorption, following intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO). Mttp-IKO mice exhibited more severe injury with ∼90% mortality following dextran sodium sulfate (DSS) induced colitis, compared to <20% in controls. Intestinal permeability was increased in Mttp-IKO mice compared to controls, both at baseline and after DSS administration, in association with increased circulating levels of TNFα. DSS treatment increased colonic mRNA expression of IL-1β and IL-17A as well as inflammasome expression in both genotypes, but the abundance of TNFα was selectively increased in DSS treated Mttp-IKO mice. There was a 2-fold increase in colonic tumor burden in Mttp-IKO mice following azoxymethane/DSS treatment, which was associated with increased colonic inflammation as well as alterations in cytokine expression. To examine the pathways by which alterations in fatty acid abundance might interact with cytokine signaling to regulate colonic epithelial growth, we used primary murine myofibroblasts to demonstrate that palmitate induced expression of amphiregulin and epiregulin and augmented the increase in both of these growth mediators when added to IL-1βor to TNFα. These studies demonstrate that Mttp-IKO mice, despite absorbing virtually no dietary fat, exhibit augmented fatty acid dependent signaling that in turn exacerbates colonic injury and increases tumor formation.
    PLoS ONE 06/2013; 8(6):e67819. DOI:10.1371/journal.pone.0067819 · 3.23 Impact Factor
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    • "Therefore, induction of these EGFR ligands in response to mucosal injury or inflammation is necessary to repair the epithelial defects; however, sustained production of AR results in colitis-associated tumorigenesis. This idea is supported by the fact that AR expression is increased in UC mucosa and colorectal cancer tissue [33]. "
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    ABSTRACT: Chronic inflammation has long been implicated as a predisposition for cancer, but the underlying mechanism for how this occurs has remained obscure. Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine which is known to be highly linked to colorectal cancer. During chronic inflammation the intestinal mucosa is in a constant cycle of injury and repair resulting in aberrant epithelial proliferation, a process that increases the risk of neoplastic transformation. In particular, the coexistence of commensal flora in the intestine plays an important role in the regulation of mucosal restitution after epithelial injury. It has become apparent that signaling through toll-like receptors (TLRs), the receptor family recognizing pathogen-associated molecular patterns, is crucial to intestinal epithelial proliferation and mucosal restitution. We have recently described two important downstream pathways underlying TLR4-mediated epithelial proliferation in a mouse model of colitis-associated cancer; i.e., cyclooxygenase 2 (COX-2)-mediated production of prostaglandin E2 (PGE2), and induction of specific ligands for epidermal growth factor receptor (EGFR). These two pathways are closely involved with mucosal levels of PGE2 and other prostanoids such as 15-deoxy-delta 12,14-prostaglandin-J2 (15d-PGJ2). Understanding the fine interplay between the TLR signaling and intestinal tumorigenesis in the setting of chronic inflammation can contribute to establishing a novel treatment strategy for inflammation-associated cancers.
    Cancers 12/2011; 3(3):3104-13. DOI:10.3390/cancers3033104
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