A team of University of Utah researchers claims to have identified a target for drugs preventive of colon cancer using selective knockout of the zebrafish adenomatous polyposis cell gene.
The research links mutations in the fish APC gene, which controls an enzyme that converts vitamin A into retinoic acid, to abnormal epithelial cells.
Mutations in the human APC gene are associated with 80 - 85 percent of colon cancers, said David Jones, the study’s principal investigator and head of the university’s Huntsman Cancer Institute Colon Cancer Scientific Program.
Previous research in Jones’s laboratory showed that human colon adenomas and carcinomas lack retinol dehydrogenases, and that APC regulates the enzyme’s gene, RDHL. Other evidence has shown that human colon cancer cells are deficient in their ability to convert vitamin A into retinoic acid, he said.
“What we did in the fish is that we can selectively knock out the APC gene or what we think is downstream of APC [zebrafish RDHL], and compare APC-knockout and retinoic acid-knockout” zebrafish embryos, said Jones. His team observed a “striking” similarity between the two sets of fish.
The researchers then rescued normal phenotypes in APC- and zRDHL-knockout fish by treating the embryos with retinoic acid. Downstream of retinoic acid production, they identified a retinoic acid-induced gene called hoxc8 that rescued phenotypes of both knockout fish when activated.
“We believe this data in fish says that the production of retinoic acid by normal APC is a fundamental function that APC needs to be able to perform in order to get normal cell growth within the intestine,” said Jones.
The results point to targets for drug interdiction, said Jones. “We’ll be organizing a study here, wherein we would look at whether we can have an effect on adenoma formation in patients that are at high risk of developing cancer … in the next year or so.”
Existing retinoic acid-derivative drugs, some of which are used to treat skin disorders and certain kinds of leukemias, could be tested immediately, “if the right patient population is available,” said Jones.
His laboratory’s results raise the possibility of screening for new drugs because it is not understood exactly how APC regulates retinoic acid production, said Jones. “So there’s a potential for identifying new molecular targets within the pathway that would reconstitute retinoic acid production without using retinoic acid itself.”