Photo by Todd McNaught
When cancer is diagnosed and treated at its earliest stages, survival rates for many forms of the disease are 90 percent or greater. Later-stage tumors, which often invade surrounding tissue and spread to distant parts of the body, are much harder to cure. A study from Dr. Jim Roberts' lab, which sheds new light on how tumors may acquire some of these dangerous characteristics, could lead to new therapies for advanced cancers.
The study, led by Dr. Arnaud Besson, provides an explanation for how a well-known cancer protein called p27 affects a cell's ability to migrate. While movement is a fundamental activity of many normal cells, cancer cells must be especially skilled at migration in order to invade tissue around them and subsequently spread, or metastasize, to distant parts of the body.
p27 initially earned its greatest fame among cancer biologists for its effects on cell division, which is also a key function that is disrupted in tumors. Besson's illumination of p27's role in migration now elevates the protein to star status among those who hope to crack cancer's code.
"Until now, scientists have focused exclusively on p27's role in cell division," said Besson, a postdoctoral fellow in Roberts' Basic Sciences Division lab. "But its widespread misregulation in the most aggressive cancers suggested that it might be doing something more than that."
p27 and cell migration
The findings appear in the April 15 issue of Genes and Development. Co-authors included Roberts, technician Mark Gurian-West and collaborators at the MRC Laboratory for Molecular Cell Biology and Cell Biology Unit at University College in London.
The p27 protein was originally identified as a tumor suppressor, a type of protein that normally acts to prevent cells from dividing. Found in cells from all types of human cancers, abnormally low levels of p27 are associated with aggressive forms of breast, colorectal, gastric and other tumors. Those observations form the basis for a prognostic test — developed by Roberts in collaboration with Dr. Peggy Porter of the Human Biology and PHS divisions — that predicts the aggressiveness of breast tumors.
More recently, scientists have found that p27 may do more than help to control the cell-division cycle. A study published last year suggests that p27 also affects cell migration, a process integral to many healthy cells but one that is often hyperactive in cancer cells. Besson's work not only confirms that p27 affects migration, but also provides the first explanation for how it may do so. He observed that p27 interacts with a key controller of a cell's microscopic skeleton, or cytoskeleton, which is repeatedly broken down and reassembled as a cell inches along its path to a new destination.
The researchers found that p27's distinct functions depend on where in the cell the protein is found. When p27 is located in the cell's nucleus, with the chromosomes, the protein helps to keep cell division from spiraling out of control. If p27 moves out of the nucleus into the cytoplasm, two dangerous consequences result. Low levels of p27 in the nucleus lead to excessive cell division, while too much p27 outside the nucleus — in the cytoplasm — can cause aberrant migration. The researchers found that different parts of the p27 protein were responsible for these distinct functions.
Yet to be explained is exactly how p27's interaction with the cytoskeleton affects cell movement, particularly in tumors. The answer is likely to vary among cell types, since not all cells share the same innate requirement for movement in their healthy state. Besson is now using sophisticated three-dimensional microscopic techniques to examine migration in cells that lack p27.
Besson said that the new findings help to explain why so many tumors have low nuclear levels of p27, yet retain or even increase its expression in the cytoplasm — an outcome frequently associated with tumors that can invade or metastasize.
"This suggested to us that p27 was not only doing something to affect cell division and prompted us to look for additional activities," he said. "In the clinical setting, it will now be very interesting to see whether levels of p27 are associated with tumor invasion or metastasis, since no one has yet looked at this."
If p27 levels indeed correlate with tumor invasiveness and metastasis, the new results have important implications for the development of effective therapies for advanced or aggressive tumors, Roberts said.
"If we can identify the factor that causes p27 to move from the nucleus into the cytoplasm, we may be able to inhibit that activity," he said. "Given that abnormal levels of p27 are found in so many different types of cancers, a drug that works in this way could have widespread use."