Many Americans say they can't live without the rapid communication afforded by cell phones or e-mail. What they may not realize is that their survival literally depends on an instant-messaging system of a different sort: a cell-to-cell communication network made up of structures called gap junctions.
When functioning properly, gap junctions relay molecular messages that coordinate the rhythmic contraction of the heart muscle, regulate normal cell growth and aid in the control of other activities that depend on signals shared between neighboring cells and tissues. But when gap junctions are missing or damaged, serious health consequences may result.
A new study in mice led by Dr. Timothy King, a staff scientist in Dr. Paul Lampe's lab, now indicates that increased susceptibility to tumors in multiple tissues may be one of these dangerous side effects. The work is the first to demonstrate a link between defects in a protein called Connexin32 (Cx32), a building block of gap junctions in certain tissues, and an elevated level of tumor development in mice exposed to radiation.
The findings could help scientists better understand how gap-junction communication, a property often lost in cancer cells, keeps a cell's growth in check.
Mammals produce about 20 types of connexins. These proteins lodge in the surfaces of cells, where they form gap junctions. Although each form of connexin is similar to the others, some arise only in certain parts of the body or at different times during development. Six connexins of the same or different types come together at the cell surface to form a channel that constitutes one half of a gap junction. When connexin channels from adjacent cells dock up against one another, they form a complete gap junction through which small molecules can pass from cell to cell.
Cx32 is the predominant connexin form found in the liver. Previous studies have shown that mice that lack Cx32 have impaired liver function and also are more likely than normal mice to develop tumors when they are exposed to a chemical known to cause liver cancer.
King said the fact Cx32 is present in a multi-tude of other tissues prompted researchers to examine whether the protein's absence might also heighten susceptibility to tumors elsewhere in the body.
"In addition to liver, Cx32 is found in the lung, pancreas, kidney and several other organs," he said. "We thought rather than examining the effects of a tissue-specific carcinogen, we would test whether a nonspecific tumor-promoting agent — in this case radiation — would cause increased tumor formation in different mouse tissues."
Overall, the researchers found that Cx32-deficient mice were about twice as likely to develop tumors after X-ray exposure compared to mice with normal Cx32. Although liver tumors were the most common tumor types, Cx32-deficient mice also were more likely to develop lung and adrenal tumors as well as lymphomas. Liver tumors in the Cx32-deficient mice were also significantly larger than those in irradiated normal mice. Observations of increased lung-tumor development received further support by King in a recent study using a chemical known to cause lung cancer.
"We don't yet know precisely why loss of connexins and intercellular communication through gap junctions impairs growth control and increases the likelihood of tumor development," King said. "But our study revealed one pathway that seems to be involved."
The researchers found that compared to tumors that grew in normal irradiated mice, both liver and lung tumors from the connexin-deficient irradiated mice had higher levels of activated MAP kinase, a signal-sending protein that contributes to cellular division. External cues, such as growth factors, and internal cues, such as mutations, can activate MAP kinase pathways, which initiate a cascade of events that cause cells to multiply or develop specialized characteristics. Activation of MAP kinases is often a characteristic of more aggressive tumors.
King said that they do not yet know whether lack of Cx32 makes it more likely that tumors with active MAP kinase will arise or whether tumor cells with active MAP kinase pathways are simply more competent to grow and form detectable tumors.
"What we'd like to know is, why is MAP kinase overactive in these tumors? We don't currently know the direct connections between Cx32 function and the MAP kinase pathway. Our challenge now is to figure out exactly how they are linked."
King said future work would involve breeding the Cx32-deficient mice to other strains of cancer-susceptible mice, which may shed light on the genetic interactions between Cx32 and cancer-causing pathways. Recently, in collaboration with Dr. Christopher Kemp's lab, King has generated mice lacking both Cx32 and the tumor suppressor/cell cycle regulator p27Kip1. They are currently evaluating any alterations in tumor susceptibility in these mice following radiation and chemical carcinogen treatments.
