Missing protein causes tumor-like masses: study
Albert Reynolds, Ph.D., has been tracking the role of a protein called p120 since he discovered it in 1989. Mounting evidence suggests that p120 is important in cancer, but its actual role has been difficult to discern.
In this month's issue of Developmental Cell, Reynolds, professor of Cancer Biology, and former graduate student Michael Davis, Ph.D., provide the first direct demonstration of the importance of p120 to tumor progression in animals.
Mice engineered to lack p120 in a selective tissue — the salivary gland — develop a high-grade intraepithelial neoplasia and tumor-like protrusions into the ducts of the gland, which also fails to develop normally.
Reynolds and colleagues knew that p120 was an important regulator of E-cadherin, a molecular “glue” that holds epithelial cells together. About 90 percent of human cancers arise in epithelial cell-types, and E-cadherin is probably the major molecule whose loss or malfunction determines a tumor's metastatic capacity, Reynolds noted.
“E-cadherin is a central player in tumor progression and metastasis,” he said.
It made sense, based on p120's role in regulating E-cadherin, that p120 might also be important in this process, Reynolds explained. Other scientific studies have reported reduced expression of p120 in human tumors.
“People didn't know quite what to make of this p120 downregulation because we don't fully understand what it does,” Reynolds said. “We don't know the contribution of p120 loss in tumors because it is just one of many things that go wrong in these cells. p120 loss could contribute to malignancy, as does E-cadherin loss, but we had no way of knowing that.”
To directly assess p120's role in cancer, Reynolds and Davis, now a postdoctoral fellow at the Fred Hutchinson Cancer Research Center, opted to make tissue-specific knockouts of p120 in mice.
“In mice, we can target the knockout to a particular organ and see what happens when that is the only genetic change,” Reynolds said. A conventional p120 knockout — deletion of the p120 gene from every tissue in the mouse — is fatal during embryonic development.
Davis and Reynolds originally planned to study p120's role in the mammary gland, but the mice died shortly after birth. The investigators focused instead on the salivary gland, which was also targeted in these animals and develops in its entirety prior to birth.
They were surprised to find that the salivary glands completely lacked acini, the structures responsible for production and secretion of saliva.
“In the absence of p120, there's a complete developmental block,” Reynolds said.
The tube-like ducts of the gland formed, but they were characterized by a high-grade intraepithelial neoplasia.
“In human tissue, when a pathologist sees this type of cellular disorder, there's a very high chance that it's going to progress to invasive cancer,” Reynolds said.
In addition, the ducts in the knockout mice were filled with tumor-like masses, he said.
“These animals provide the first concrete evidence of the consequence of p120 loss by itself,” Reynolds said.
“We're thrilled with the result — it strongly supports our in vitro studies, which have been pointing in the same direction in terms of p120's role in promoting tumors.”
Reynolds and colleagues are currently studying p120 loss in other tissues including colon, lung, liver, and skin, and they are working to understand the mechanisms for p120's regulation of E-cadherin and participation in tumor progression.
The research was supported by the National Cancer Institute and by the NCI SPORE in GI Cancer Grant.