title: Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia.
abstract: Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-ErbB negative regulator and intestinal stem cell marker down-regulated in many malignancies. We previously reported that 14 of 16 Lrig1-CreERT2/CreERT2 (Lrig1(-/-)) mice developed duodenal adenomas, providing the first in vivo evidence that Lrig1 acts as a tumor suppressor. We extended this study to a larger cohort and found that 49 of 54 Lrig1(-/-) mice develop duodenal adenomas beginning at 3 months. Most adenomas were histologically low grade and overlaid expanded Brunner glands. There was morphologic and biochemical blurring of the boundary between the epithelium and Brunner glands with glandular coexpression of ErbB2, which is normally restricted to the epithelium, and the Brunner gland marker Mucin6. Some adenomas were high grade with reduced Brunner glands. At age 4 to 5 weeks, before adenoma formation, we observed enhanced proliferation in Brunner glands and, at 2 months, an increase in the size of the Brunner gland compartment. Elevated expression of the epidermal growth factor receptor (Egfr) ligands amphiregulin and β-cellulin, as well as Egfr and phosphorylated Egfr, was detected in adenomas compared with adjacent normal tissue. These adenomas expressed the gastric-specific genes gastrokine1 and mucin5ac, indicating gastric metaplasia. Moreover, we found that a subset of human duodenal tumors exhibited features of LRIG1(-/-) adenomas, including loss of LRIG1, gastric metaplasia (MUCIN5AC and MUCIN6), and increased amphiregulin and Egfr activity.
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Yang
authors: Y
authors: Wang
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Chanjuan
authors: C
authors: Shi
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Yuanyuan
authors: Y
authors: Lu
authors: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Emily J
authors: EJ
authors: Poulin
authors: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Jeffery L
authors: JL
authors: Franklin
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Veterans Affairs Medical Center, Nashville, Tennessee. Electronic address: robert.coffey@vanderbilt.edu.
authors: Robert J
authors: RJ
authors: Coffey
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002011:Brunner Glands / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004379:Duodenal Neoplasms / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000378:metabolism; D008679:Metaplasia; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism; D013270:Stomach / Q000473:pathology*
chemical_list: C484445:LRIG1 protein, human; D008024:Ligands; C101671:Lrig1 protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors