Adenomatous polyposis coli‐deficient zebrafish are susceptible to digestive tract neoplasia

Abstract

Truncation of the tumour suppressor adenomatous polyposis coli (APC) constitutively activates the Wnt/b-catenin signalling pathway. This event constitutes the primary transforming event in sporadic colorectal cancer in humans. Moreover, humans or mice carrying germline truncating mutations in APC develop large numbers of intestinal adenomas. Here, we report that zebrafish that are heterozygous for a truncating APC mutation spontaneously develop intestinal, hepatic and pancreatic neoplasias that are highly proliferative, accumulate b-catenin and express Wnt target genes. Treatment with the chemical carcinogen 7,12-dimethylbenz [a]anthracene accelerates the induction of these lesions. These observations establish apc-mutant zebrafish as a bona fide model for the study of digestive tract cancer.

Co-injection strategies to modify radiation sensitivity and tumor initiation in transgenic Zebrafish

“…To capitalize on the powerful developmental and genetic tools available in zebrafish, researchers have created numerous zebrafish tumor models (Langenau et al, 2003Yang et al, 2004;Berghmans et al, 2005;Patton et al, 2005;Haramis et al, 2006;Sabaawy et al, 2006;Le et al, 2007). The ultimate goal of the majority of this work is to identify pathways that modify disease states.…”

Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies

“…For example, loss of Apc heterozygosity leads to spontaneously forming adenomas [64], and loss of Notch signaling drives daughter cells to differentiate into goblet and other secretory cell fates [65].…”

“…For example, the zebrafish equivalent of Apc min mice acquires spontaneous adenomas in only 11% of the fish examined [64]. Similarly conditional over-expression of a transgenic human KRAS oncogene exhibited low penetrance, leading to tumors in only one-third of the examined fish.…”

Zebrafish as a Cancer Model

“…Treatment of apc heterozygotes with 7,12-dimethylbenz[a]anthracene enhanced tumorigenesis, resulting in intestinal, hepatic, and pancreatic tumors, with frequencies 3-to 4-fold higher than treated wildtypes. The tumors displayed activated Wnt signaling, indicating that the genetic pathway is conserved (12).…”

“…N-Methyl-N ¶-nitro-N-nitrosoguanidine can also induce different tumor types, mainly liver and testicular neoplasms, as well as hemangio(sarco)mas and others (11). Some of these carcinogenic treatments have been applied to mutants with a genetic predisposition to cancer but a low spontaneous tumor incidence to show an increased sensitivity of mutants compared with treated wild-type animals (12)(13)(14). Not surprisingly, the alkylating mutagen N-ethyl-N-nitrosourea, which introduces point mutations and is commonly used in forward and reverse genetic screens, has also been found to induce cancer.…”