Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis.
Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
Anne E
AE
Powell
Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee;
Gregory
G
Vlacich
Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee;
Zhen-Yang
ZY
Zhao
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
Eliot T
ET
McKinley
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee;
M Kay
MK
Washington
Vanderbilt Institute for Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee; and.
H Charles
HC
Manning
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee robert.coffey@vanderbilt.edu.
Robert J
RJ
Coffey
D011125:Adenomatous Polyposis Coli / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D003113:Colonoscopy; D004195:Disease Models, Animal; D017491:Genes, APC; D006984:Hypertrophy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011230:Precancerous Conditions / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
C101671:Lrig1 protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins
colorectal cancer; mouse models; stem cells