The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis.
OBJECTIVE
Differences in genetic background may play a role in the development of ulcerative colitis (UC)-related neoplasia. Loss of heterozygosity (LOH) of APC has been reported in human UC-associated neoplasia. To investigate the role of genetic differences in UC-associated neoplasia, we compared differences in dextran sodium sulfate (DSS) colitis-associated neoplasia between wild-type C57BL/6J mice (WT-DSS) and C57BL/6J mice with a germline mutation in Apc (Min-DSS).


METHODS
DSS colitis was induced in female wild-type and Min mice. Age- and sex-matched non-DSS-treated Mins were also studied. Animals were sacrificed after 1 and 2 cycles of DSS. The cecums and large intestines were studied for numbers of dysplasias/cancers. Dysplasias were studied for LOH of Apc.


RESULTS
No WT-DSS, 100% of Min-DSS, and 50% of non-DSS-treated Mins had dysplasia. The mean numbers of lesions per mouse were 0 (WT-DSS), 15.6 and 29.3 (1 and 2 cycles Min-DSS, respectively), 1.2 and 1.9 (age-matched control Min, 1 and 2 cycle equivalents, respectively; P < 0.0002, Min-DSS vs. WT-DSS and non-DSS-treated Min; P = 0.03, Min-DSS 2 cycle vs. Min-DSS 1 cycle). Cancers were seen in 0%, 22%, and 40% of non-DSS Min, Min-DSS-1 cycle, and Min-DSS-2 cycle animals, respectively. LOH of Apc was observed in 90.6% of dysplasias and 6% of nondysplastic mucosa.


CONCLUSIONS
A germline mutation in Apc contributes significantly to the development of colitis-associated neoplasia. Colitis markedly accelerates the development of dysplasia and cancer in the Min mouse. Dysplasia in Min-DSS occurs through LOH of Apc.
Cooper
H S
HS
Department of Pathology, Division of Medical Science, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA. hs_cooper@fccc.edu
Everley
L
L
Chang
W C
WC
Pfeiffer
G
G
Lee
B
B
Murthy
S
S
Clapper
M L
ML
D000236:Adenoma / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D003108:Colonic Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003110:Colonic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation / Q000502:physiology*; D015994:Incidence; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D014456:Ulcer / Q000235:genetics / Q000473:pathology
D016264:Dextran Sulfate