Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon.
ABSTRACT 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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ABSTRACT: Many tissues in higher animals undergo dynamic homeostatic growth, wherein damaged or aged cells are replaced by the progeny of resident stem cells. To maintain homeostasis, stem cells must respond to tissue needs. Here we show that in response to damage or stress in the intestinal (midgut) epithelium of adult Drosophila, multiple EGFR ligands and rhomboids (intramembrane proteases that activate some EGFR ligands) are induced, leading to the activation of EGFR signaling in intestinal stem cells (ISCs). Activation of EGFR signaling promotes ISC division and midgut epithelium regeneration, thereby maintaining tissue homeostasis. ISCs defective in EGFR signaling cannot grow or divide, are poorly maintained, and cannot support midgut epithelium regeneration after enteric infection by the bacterium Pseudomonas entomophila. Furthermore, ISC proliferation induced by Jak/Stat signaling is dependent upon EGFR signaling. Thus the EGFR/Ras/MAPK signaling pathway plays central, essential roles in ISC maintenance and the feedback system that mediates intestinal homeostasis.Cell stem cell 01/2011; 8(1):84-95. DOI:10.1016/j.stem.2010.11.026 · 22.15 Impact Factor
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ABSTRACT: Cetuximab is a chimeric monoclonal antibody directed against the epidermal growth factor receptor (EGFR) that has proven clinical efficacy in metastatic colorectal cancer (mCRC) and other solid tumor types. Several candidate predictive markers of cetuximab efficacy in mCRC emerged recently from clinical studies, most notably the KRAS mutation status of the tumor. Retrospective data strongly suggest that the benefit/risk ratio for cetuximab treatment in patients with wild-type KRAS mCRC tumors is greater than for patients with mutant KRAS tumors. In addition, high expression of genes encoding the EGFR ligands epiregulin and amphiregulin may also identify patients who are likely to benefit from cetuximab. In contrast, EGFR expression by immunohistochemistry and EGFR gene copy number appear to be less reliable in predicting response to cetuximab. Prospective validation of wild-type KRAS and high gene expression of epiregulin and amphiregulin as predictive markers of cetuximab activity in mCRC is still required.Current Colorectal Cancer Reports 01/2008; 4(4):184-192. DOI:10.1007/s11888-008-0030-1
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ABSTRACT: Therapy for metastatic colorectal cancer has been improved in terms of response rate, time to progression and overall survival by the emergence of anti-EGFR monoclonal antibodies (cetuximab and panitumumab) in combination with standard cytotoxic chemotherapy (oxaliplatin or CPT-11-based combinations). However, the benefits of cetuximab and panitumumab are confined to KRAS wild-type (KRAS-wt) colorectal tumours; KRAS-mutated tumours rarely respond to these drugs. Of all colorectal tumours, 65% are KRAS-wt tumours, but anti-EGFR therapies are effective for only 60-70% of these. Therefore, other biomarkers and molecular pathways must be involved in the response to anti-EGFR therapies in KRASwt colorectal tumours. Factors that may explain the lack of response include EGFR ligands, EGFR phosphorylation levels, the number of EGFR copies, the status of the KRAS effector B-RAF and the alternative intracellular PIK3CA/ PTEN/AKT and JAK/STAT signalling pathways. A battery of biomarkers is needed to select the patients that will be most sensitive to anti-EGFR therapies. Such patterns may be a novel and cost-effective tool to develop tailored treatments. This manuscript will review biomarkers and molecular pathways that are involved in the tumour response to anti-EGFR therapies.Clinical and Translational Oncology 11/2009; 11(11):737-47. DOI:10.1007/s12094-009-0436-5 · 1.60 Impact Factor