Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Shi, C; Lu, Y; Poulin, EJ; Franklin, JL; Coffey, RJ

Published Date

  • April 2015

Published In

Volume / Issue

  • 185 / 4

Start / End Page

  • 1123 - 1134

PubMed ID

  • 25794708

Pubmed Central ID

  • 25794708

Electronic International Standard Serial Number (EISSN)

  • 1525-2191

Digital Object Identifier (DOI)

  • 10.1016/j.ajpath.2014.12.014

Language

  • eng

Conference Location

  • United States