Unlikely Protein Boosts Metastatic Colon Cancer Growth

The protein, called periostin, is normally produced by bone cells, but the researchers found unexpectedly high levels of periostin within colon cancer cells that had spread to the liver. Upon closer examination, they discovered that periostin enabled cancer cells to escape their intended demise and to survive under the most hostile conditions, with reduced nourishment or oxygen. Moreover, periostin induced the growth of blood vessels near the tumor that would ultimately feed its growth, a process known as angiogenesis.

The results are significant because colorectal cancer is the second-leading cause of cancer death in the U.S. and is the most common cancer to spread to the liver, said the researchers from the Duke Comprehensive Cancer Center and the department of pharmacology and cancer biology at Duke University Medical Center. Once colon cancer has spread, it often turns deadly, yet scientists know little about how and why cancer cells can survive in often hostile surroundings away from the primary tumor site.

Results of the Duke study are being published in the April 20, 2004, issue of Cancer Cell.

Principal investigator of the study, Duke pharmacologist Xiao-Fan Wang, Ph.D., said the findings point toward the unexpected role of genes that are not considered classic "oncogenes" -- those which play a critical role in the development of cancer. Rather, this gene and the protein it produces, periostin, are normal genetic elements of bone growth that are somehow erroneously activated by the colon cancer machinery gone awry. They don't cause cancer, yet they modify its behavior once it has grown, he said.

"During tumor development and metastasis, cells accumulate a variety of mutations, and these mutations can activate proteins that are supposed to be dormant in that tissue type," said Wang. "Periostin does not normally cause cell proliferation, but in the case of colon cancer, it becomes activated in the wrong tissue and modifies the tumor cell's behavior and its general microenvironment in order to promote metastasis."

In the study, Wang and Shideng Bao, Ph.D., first author on the paper, searched for proteins that metastatic colorectal cancers over-produce. Unexpectedly, they found that the gene for periostin was overexpressed in more than 80 percent of human colon cancers, with metastasized cancers having the highest expression. Further studies imply that periostin is also overexpressed in some breast cancers, ovarian cancers and gliomas, though that work is still preliminary, said Wang.

Next, they injected colon cancer cells -- either with or without periostin -- into mice. The cancer cells with periostin grew into huge metastases, despite conditions in which the cancer was deprived of oxygen and growth factors. The cancer cells without periostin died quickly, the study showed. Periostin also promoted the growth of endothelial cells in nearby blood vessels, thereby strengthening the tumor's nutrient source.

Wang and Bao studied why these effects occurred, and they found that periostin activated a pathway within cells -- called Akt/PKB -- which is known to promote the survival of cells. Demonstrating how periostin enables metastasis survival can illuminate the most accessible points along the pathway at which to block its action, said Wang.

"It is useful to know which genes are elevated in cancer and to use that information to diagnose the disease, but it is extremely beneficial to understand why these genes function the way they do, so we can modify or block their actions with highly targeted therapies," Wang added.

The Duke team's next step is to identify additional genes and proteins that are elevated in various cancers and analyze their activity within tumors. Many proteins that are elevated appear to have no effect on cells, yet closer analysis of their function reveals they impact some facet of cancer growth or survival, said Wang.