As reported by the New Haven Register, February 1, 2004.

Researchers Making Strides in Understanding Colon Cancer

By Abram Katz

No one looks forward to a colon exam, but the alternative can be much, much worse.

Cancer of the colon is the third leading cause of cancer deaths in men and women in the United States, claiming about 57,100 lives last year.

Early detection is the key to successful treatment.

Doctors now remove suspicious growths in the colon called polyps.

However, physicians want to stop trouble before cells have a chance to become cancerous.

Scientists have been studying the complex molecular biology and genetics of colon cancer for 15 years.

Now researchers at the University of Connecticut Health Center in Farmington believe they’re closing in on a way to single out bad cells before disease starts.

Daniel Rosenberg, associate professor and co-director of the Center for Molecular Medicine at the UConn Health Center, and colleagues have identified the genetic "signature" of impending colon cancer in mice.

Dr. Joel Levine, professor of medicine and co-director of the center, said techniques developed in the lab could be ready for clinical use in two to three years.

This hopeful research is tempered by the inevitable and difficult social and ethical issues that early testing will create, Levine said.

"We don’t want two populations, one getting 2010 care and the other getting 1970s care," Levine said.

Rosenberg and Levine focus on microscopic lesions in the colon called aberrant crypt foci, or ACF.

Some ACF progress to cancer; most do not. Both types of cells look the same.

But future cancer cells contain genetic mutations and Rosenberg and Levine have found a way to identify them.

That leaves a multitude of important questions unanswered, however.

Why do some ACF progress to cancer? Is it the hostile environment of the large intestine? An immune response? Other genetic errors?

Researchers know that 10 percent to 15 percent of colon cancers are heritable, or conveyed by genes at birth.

Most colon cancers are "sporadic," meaning that normal cells acquire mutations, Levine said.

The cellular and genetic pathways could be varied and intricate.

"There isn’t one ‘colon cancer.’ There are substantial differences. Removing polyps has become the main way to deal with colon cancer," Levine said.

"Most people don’t get colon cancer. There are ‘good’ and ‘bad’ polyps. What’s happening in the ACF and polyps that become cancerous?" he said.

To take a genetic fingerprint of mice, the researchers obtained two groups of animals. One is resistant to colon cancer, while the other is prone to colon tumors.

Both groups were injected with a cancer-causing chemical.

Rosenberg and colleagues then examined ACF in both strains.

"We developed a method to view 50 cells, and isolate and amplify the RNA," Rosenberg said.

Messenger RNA is encoded to produce proteins and can reveal what a cell is making: too much or too little of a protein, or the wrong protein all together.

To identify the proteins under construction, Rosenberg uses slides coated with known RNA sequences. If cellular RNA attaches to the array, scientists can often decipher the working protein and gene.

Rosenberg and Levine have identified a tumor suppressor gene essential to preventing murine cancer.

Other genes involved in colon cancer include FAPC (familial adenomatous polyposis of the colon) and a DNA repair gene called MMR.

Some mutations probably occur because of the nature of the intestinal lining, Rosenberg said.

"The colonic epithelium is constantly regenerating, which puts it at a higher risk for mutation expression," he said.

The colon is also exposed to natural and artificial chemicals in foods, and acids. All could hasten mutations, Rosenberg said.

Ultimately, colon cancer is a fusion of genetics and the environment in the intestines, Levine said.

Using a laser capture microscope to pluck out a few dozen cells and a method to amplify 1 trillionth of a gram of RNA, Rosenberg and colleagues found that cancer-producing ACF carry distinguishing molecular structures.

"If we can replicate the mouse research in humans, we could assess the risk of colon cancer much earlier," Levine said.

"We could modify diet or administer preventative drugs," he said.

Levine, Rosenberg and collaborators are already examining human genes. Many are of unknown function, Levine said.

"The whole book on colon cancer will have to be rewritten," Levine said.

"We might be able to find genetic deficiencies that can be corrected or treated," Rosenberg said.

The research might also reveal new cancer genes and eventually help explain other forms of cancer, Levine said.

At present, the usefulness of knowing that an infant is likely to develop colon cancer at some point in his life is unclear, he said.