title: Metallothionein crypt-restricted immunopositivity indices (MTCRII) correlate with aberrant crypt foci (ACF) in mouse colon.
abstract: Metallothionein (MT) crypt-restricted immunopositivity indices (MTCRII) are colonic crypt stem cell mutation markers that may be induced early and in abundance after mutagen treatment. Metallothionein is the endogenous reporter gene for MTCRII, but is not typically implicated in the classical pathway of colorectal tumorigenesis. Hence, the oncological relevance of MTCRII is unclear. This study tests the hypothesis that MTCRII induced by N-methyl-N-nitrosourea (MNU) and lambda carrageenan (lambdaCgN) associate with aberrant crypt foci (ACF) in mouse colon. Undegraded lambdaCgN and MNU were tested alone and in combination against MTCRII and ACF in Balb/c mice, at 20 weeks after the start of treatment. MTCRII were unaffected by lambdaCgN alone. Combined lambdaCgN/MNU treatments induced greater MTCRII (P < 0.01) as well as greater number (P < 0.001) and crypt multiplicity (P < 0.01) of ACF than MNU alone. MTCRII were approximately 10-fold more numerous than ACF, although linear correlations were observed between these parameters (r = 0.732; P < 0.01). MTCRII are induced by lambdaCgN/MNU interactions in sufficient numbers to provide statistical power from relatively small sample sizes and correlate with ACF formation. MTCRII could thus provide the basis for a novel medium-term murine bioassay relevant to early-stage colorectal tumorigenesis.
authors.affiliation: Departments of Surgery, Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Clinical Sciences Building, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland, UK.
authors.forename: E T
authors.initials: ET
authors.lastname: Donnelly
authors.forename: H
authors.initials: H
authors.lastname: Bardwell
authors.forename: G A
authors.initials: GA
authors.lastname: Thomas
authors.forename: E D
authors.initials: ED
authors.lastname: Williams
authors.forename: M
authors.initials: M
authors.lastname: Hoper
authors.forename: P
authors.initials: P
authors.lastname: Crowe
authors.forename: W G
authors.initials: WG
authors.lastname: McCluggage
authors.forename: M
authors.initials: M
authors.lastname: Stevenson
authors.forename: D H
authors.initials: DH
authors.lastname: Phillips
authors.forename: A
authors.initials: A
authors.lastname: Hewer
authors.forename: M R
authors.initials: MR
authors.lastname: Osborne
authors.forename: F C
authors.initials: FC
authors.lastname: Campbell
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D007413:Intestinal Mucosa / Q000473:pathology*; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009153:Mutagens / Q000009:adverse effects; D009154:Mutation; D013234:Stem Cells / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D009153:Mutagens; D008668:Metallothionein