Enzyme plays dual role in cancer spread

Before cancer cells can migrate, or metastasize, to other parts of the body, they first have to disconnect from their neighbors in the tumor. A team of University of Wisconsin–Madison and Canadian scientists has made a surprising discovery: The same enzyme that controls the ability of cancer cells to move also governs a process that binds them tightly in place.

“It’s kind of a schizophrenic enzyme in a sense, because it can control both pathways,” says Richard Anderson, a pharmacology professor in the UW–Madison School of Medicine and Public Health and lead author of the study published in the Jan. 29 issue of the Journal of Cell Biology. “But it is also so fundamental, because this enzyme is at the forefront of regulating two key aspects of cancer metastases.”

Anderson and his colleagues reported earlier how the enzyme, known scientifically as PIP kinase, dictates the growth of protein clusters that metastasizing cancer cells use to crawl through tissue. The researchers now describe PIP kinase’s role as a “master switch” in the assembly of another protein, called E-cadherin, on the outermost membrane of cells. There, E-cadherin prevents cell migration by holding cells together so tightly even the tiniest ions can’t pass between them.

“One of the hallmarks of cancer, especially metastatic cancer, is a loss of E-cadherin at the outer membrane of cells,” says Anderson. “If we could decipher how to enhance PIP kinase’s control of E-cadherin, we could block metastasis.”

The team studies a specific cell type, the epithelial cell, which is known to give rise to roughly 70 percent of all human cancers. A single layer of epithelial cells grows as a protective lining, like a row of bricks, around all the organs and compartments in the body, such as the intestines, the lungs, and the ducts in breast tissue. E-cadherin contributes to these barriers by maintaining extremely tight contacts between adjacent epithelial cells that keep materials from leaking from one compartment into another.

When epithelial cells begin growing out of their neat rows and into disorganized, cancerous masses, E-cadherin can suppress metastasis by holding the cells together. The trick is for cells to continue assembling E-cadherin at the outer membrane, says Anderson, rather than taking the protein into the cell interior. That’s where regulation by PIP kinase comes in.

Based on their data, the scientists have proposed a model in which PIP kinase first binds to E-cadherin and then links it to a specific protein complex. This event marks E-cadherin’s entry into the protein transport system of the cell. At the same time, PIP kinase produces a signaling molecule that directs E-cadherin – now in the form of a carrier known as a vesicle – to the outer membrane, where it creates the tight cell-cell connections.

The entire process is closely regulated, but the initial bond between PIP kinase and E-cadherin seems to be a critical step. As evidence, Anderson points to a particular genetic mutation in E-cadherin that prevents it from binding to PIP kinase. This mutation is sufficient to induce an inherited and highly metastatic type of gastric cancer, says Anderson, which often strikes people in their early thirties.

In response to other regulatory cues and in association with another protein, called talin, PIP kinase also controls a nearly opposite process in cancer cells – the one in which they develop an ability to crawl away from a tumor.

“I think what we’re seeing now is that this enzyme is one of the molecules that defines the fate of cells: whether cancer cells will stay together or metastasize,” says Anderson.

Anderson’s research is funded by the National Institutes of Health.