Check Up: Hormone deficit and colon cancer

Posted: November 05, 2012

Could colon cancer be a hormone deficiency disease? And could that deficiency also play a role in obesity?

Thomas Jefferson University researcher Scott Waldman has been awarded a $1.2 million "provocative questions" grant from the National Cancer Institute to try to find answers.

His search is focused on a hormone called guanylyl cyclase that binds to a cell "receptor," called GCC, in the intestines. The hormone activates GCC, which in turn tells intestinal cells to make more hormones.

Over the last two decades, Waldman and his team have shown that a lack of the hormone that activates GCC can trigger uncontrolled cell growth, leading to colorectal cancer. They also found that, since GCC is normally found in the intestines, testing for it in lymph nodes of newly diagnosed colon cancer patients can reveal whether the malignancy has spread.

They speculated that restoring the missing hormone could activate GCC and ward off colon cancer. Sure enough, it worked - at least, in genetically altered mice.

Waldman is now planning human tests of hormone replacement using Ironwood Pharmaceuticals' new drug Linzess, which relieves chronic constipation by stimulating GCC.

"Just as diabetes is a loss of insulin and can be fixed by giving the hormone, we believe colon cancer is a disease of hormone deficiency," Waldman said.

The possible obesity link is equally intriguing.

Obesity has long been known to increase the risk of colon cancer. And Waldman's team noticed that GCC-impaired mice grew obese. Last year, they reported a previously unknown signaling loop between the intestines and the brain involving GCC.

It turned out that when food was digested by the mice, their guts released hormones that traveled through the blood to GCC in the brain. Mice with activated GCC knew when to stop eating, but those with "silenced" receptors kept eating and got fat.

"We believe this system is malfunctioning in [human] obesity," Waldman said.

He acknowledged that obesity research is full of promising leads that don't pan out.

"It's a pretty complicated field. This is a new player on the scene," he said. "But we're extremely excited."

- Marie McCullough

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