"Cancers associated with chronic irritation may be a good setting in which to determine whether stem cells are the starting place of tumors.

Normal Stem Cells Gone Bad?

At the heart of their argument, outlined in the November 18 issue of Nature, are two key chemical signals, called Hedgehog and Wnt ("wint"), that are active in the stem cells that repair damaged tissue. Recently and unexpectedly, the signals also have been found in certain hard to treat cancers, supporting an old idea that some cancers may start from normal stem cells that have somehow gone bad.

Over the last 10 years, researchers have found examples of these so-called cancer stem cells -- the cells within a tumor that are capable of regrowing the tumor -- in certain malignancies of the blood, breast and brain. In most cases, however, it's not clear whether these cancer stem cells came from the tissue's normal, primitive stem cells or from the tissue's mature cells.

"Cancers associated with chronic irritation may be a good setting in which to determine whether stem cells are the starting place of tumors," says Phil Beachy, Ph.D., professor of molecular biology and genetics in Hopkins' Institute for Basic Biomedical Sciences and a Howard Hughes Medical Institute investigator. "Successful therapy depends on targeting the cells that drive cancer's growth and its spread, so we have to know which cells are important."

Chronic Irritation Factor

Chronic irritation damages tissues -- Helicobacter infection in the stomach leads to ulcers, for example, and chronic acid reflux (heartburn) erodes the lining of the esophagus. That damage triggers a repair process that requires tissue-specific stem cells to gather, multiply and eventually replace the damaged cells.

However, if recurring irritation and damage prevent the repair's completion, those helpful stem cells, in theory, could accumulate mutations that push their growth out of control. Beachy and long-time collaborators and co-authors Sunil Karhadkar, M.D., and David Berman, M.D., Ph.D., suggest that chronic irritation might facilitate trapping of stem cells in a state of perpetual activation, and subsequent genetic or other changes in the cells may send them over the edge.

"Normal stem-cell self-renewal is a tightly regulated process, so the question is how and whether such regulation is circumvented in cancer," says Beachy.

Beachy says the place to start looking is the activity and regulation of Hedgehog and Wnt, which are best known for their roles in embryonic development, because recent studies show they are key regulators of self-renewal in at least some of the body's normal tissue stem cells and are active in numerous cancer types.

"If these stem cells are the starting point of some cancers, multiple genetic and other changes may be required to trap the stem cell during chronic irritation, and perhaps many more changes to get the rapid growth of cancer," says Beachy. "We need to figure out what those changes might be."

Blocking Hedgehog and Wnt

Hedgehog activity has been found in certain cancers of the lung, brain, stomach, esophagus, skin, pancreas, bladder, muscle and prostate. Similarly, Wnt activity has been tied to certain cancers of the colon, liver, blood, bone and lung.

In experiments at Hopkins and elsewhere, blocking Hedgehog and Wnt in laboratory-grown cancer cells and in animals has been shown to kill cancer cells, so the pathways are potential targets for anti-cancer drugs. The researchers caution that Hedgehog and Wnt blockers could affect normal processes that use these signals, including normal tissue repair, although short-term studies in mice have not yet found toxic side effects, Beachy says.

Authors of the article are Beachy, Karhadkar and Berman, all of Johns Hopkins. The authors' research is supported by the Howard Hughes Medical Institute, the National Institutes of Health, the Prostate Cancer Foundation and the Flight Attendant's Medical Research Institute.