The link between aging and prostate cancer development is now better understood, based on a study by University of Wisconsin Carbone Cancer Center researchers.

The study, by urologist Dr. David Jarrard and colleagues, shows how a change in expression of a prostate cancer-associated gene leads to higher levels of cell growth. Their findings help to explain why men develop the disease commonly as they age and to provide a cellular target for preventative therapies.

In essentially all human cells, there are two copies of a gene. Around 180 of those genes are “imprinted,” where one copy’s DNA is silenced by a modification that prevents gene expression. Imprinting is not a permanent DNA mutation; rather, it is a reversible chemical modification. Typically, imprinting is found on potent pro-growth genes to reduce expression levels after normal growth and development is done. A loss of imprinting of some genes may occur as people age, due to factors such as diet, stress and environmental exposures.

“We made the observation years ago that men who have prostate cancer are more likely to have relaxation of the IGF2 gene in normal prostate tissue as well as tumor tissue,” Jarrard, the study’s senior author, said. “The question is, does that association lead to prostate cancer? This study provides evidence that it does.”

To answer their question experimentally, Jarrard and colleagues developed a mouse model where the imprinted, or silenced, copy of IGF2 was mutated such it could no longer be imprinted. Mice with this mutation were expected to always have both copies of IGF2 expressing. Then, they showed that loss-of-imprinting mice expressed around two-and-a-half times as much IGF2 compared to mice that could imprint the gene normally. This finding was important, because previous studies on the role of IGF2 in prostate cancer greatly increased IGF2 to levels much greater than are physiologically relevant.

Next, they looked at cancer and pre-cancerous lesion formation in mouse prostates, comparing loss-of-imprinting mice with imprinting-competent ones.

“We found the loss-of-imprinting mice develop more prostatic epithelial neoplasias, which are accelerated growths that develop in the epithelial cells of the prostate, than the wild type mice,” Jarrard said. “We think this increase in IGF2 may be involved early on in the transition of normal tissue to develop this hyperproliferation of epithelial cells.”

To further address the link between IGF2 and increase proliferation in prostate epithelial cells, the researchers measured changes in gene expression of several pro- or anti-cancer genes that are downstream of IGF2 in many cell signaling pathways. With most genes in the loss-of-imprinting mice, they found higher levels of expression of genes that promote cell growth and lower levels of expression of genes that put the brakes on cell growth, relative to imprinting-competent mice. Returning to examine human tissues, they also found these pathways were altered.

“So while we saw cancer formation relatively infrequently in young loss-of-imprinting mice, we think that as signaling increases through these pathways, if there’s another genetic mutation that arises or enough time passes, then the cell can develop into cancer,” Jarrard said. “These results link diet and environment to cancer formation with aging.”

With a better understanding of how IGF2 loss of imprinting is linked to prostate cancer development, Jarrard sees the potential for therapies.

“Now we can look for a nutrient or drug that would reduce growth signaling through the IGF2 pathway,” Jarrard said. “You could potentially identify men at higher risk for prostate cancer who you’d want to monitor more closely or treat them with something to reverse these changes before the changes lead to cancer formation.”

This study was published in the journal Cancer Research. Funding support was provided in part by the National Institutes of Health and National Cancer Center (5R01CA097131, 2R01CA097131-06A2 and T32 CA009135), The John Livesey Endowment, and the Nast Family Foundation.