Growth Factor Receptor Signaling Critical To Intestinal Tumor Development, Studies Show

Working with laboratory mice, the researchers found that a molecule called epidermal growth factor receptor (Egfr) is necessary for most intestinal tumors to form. Their work also suggests that a drug or genetic manipulation that inhibits the receptor’s chemical signaling machinery should help treat advanced colorectal cancers in humans one day.

A report on the findings appears online today (Jan. 29) in the latest edition of the Proceedings of the National Academy of Sciences. Authors include doctoral student Reade B. Roberts and Dr. David W. Threadgill, assistant professor of genetics, both at the UNC School of Medicine’s Lineberger Comprehensive Cancer Center, and Dr. Robert J. Coffey, a cell biologist at Vanderbilt.

“This Egfr receptor is very important to all kinds of tissues and organs, but there hasn’t been any genetic proof in whole animals that it could affect a major cancer like colon cancer,” Reade said. “We think this work represents proof because it relied on genetic experiments that were highly controlled compared with just injecting mice with drugs and hoping that they would affect the receptor.”

At UNC, the researchers studied two kinds of mice. They engineered one set to include a mutation called Apc-Min, which produces both human and mouse intestinal cancers, and another mutation known as waved 2, in which the Egfr was partially impaired. The other mice, litter mates of the first group, bore the same Apc-Min mutation, but also had normal Egfr genes.

Within three months, the first group developed 90 percent fewer intestinal polyps than the second, which showed that Egfr signaling was critical to intestinal tumor formation, scientists found. Some of the first group developed no tumors at all.

“Surprisingly the size, growth and progression of the polyps appeared to be independent of Egfr, and so a small percentage of tumors might not need Egfr to grow,” Roberts said. “Microscopic examination of intestinal tissue in the youngest mice also revealed no differences in the number of lesions believed to be precursors of larger intestinal polyps and cancer. Most just failed to progress.”

Humans who inherit a bad copy of the Apc-Min gene can develop hundreds of tumors throughout their intestinal tracts, he said. That illness, however, represents only about 1 percent of human colon cancer cases.

Mice with the waved 2 mutation have wavy hair and curly whiskers but are otherwise healthy and lead essentially normal lives, Roberts said. Rodents with entirely dysfunctional Egfr die within two weeks of birth, which shows the gene is essential for life.

Related work conducted in Coffey’s laboratory at Vanderbilt involved placing human tumors in mice and then treating the mice with Egfr tyrosine kinase inhibitors -- compounds that block the action of an Egfr signaling enzyme.

“They saw a drastic reduction in tumor growth, depending on the dose they gave the mice,” Roberts said. “That showed the approach definitely holds promise for using these drugs to treat human cancers.

“How well our results in mice wind up correlating with human treatment remains to be seen, but at this point we’re excited about the possibilities.”

Several clinical trials of drugs that block Egfr already have begun, Roberts said. Results from two previous mouse studies of compounds targeting the molecule have been contradictory, probably because drugs used were not precise enough in their action.

Grants from the National Cancer Institute supported the UNC and Vanderbilt research.