BioWorld International Correspondent

LONDON - A molecule that switches on a cell's ability to move around - whether in the embryo or in a malignant tumor - could help make stem cell research more efficient, as well as provide new strategies for cancer treatment.

The molecule, called 5T4, already is being exploited for "magic bullet" therapies against cancer, because it is expressed only in the embryo and on the surface of many types of cancer cells. Clinical trials are in progress to test its efficacy as part of a therapeutic vaccine to treat colorectal cancer and as a means of targeting the immune response to cancer cells in people with renal cancer.

Researchers studying 5T4 and its effect on cells now have established that embryonic stem cells begin to express it only once they have started to differentiate. The discovery will allow scientists to select a subset of stem cells that are better able to form chimeras - the genetically mixed embryos that must be made in order to generate knockout mice, for example.

Peter Stern, head of the Cancer Research UK Immunology Group at the Paterson Institute in Manchester, UK, told BioWorld International: "Not all stem cells are the same. This finding gives us a window on the processes that lead up to the early differentiation of stem cells. It is important because it offers the opportunity to better manipulate systems that are at the root of many different types of biological research."

Tests carried out by Stern and his colleagues showed that embryonic stem cells that had not started expressing 5T4 were seven times better at making chimeras when injected into an early mouse embryo than those stem cells expressing 5T4.

Stern said, "Using this marker to select mouse stem cells that are more pluripotent could reduce the labor intensity of making knockout or knock-in mice by an order of magnitude."

The group reports its findings in a paper in the November issue of the Journal of Cell Science titled "The 5T4 oncofoetal antigen is an early differentiation maker of mouse ES cells and its absence is a useful means to assess pluripotency."

Stern's group identified 5T4 about 10 years ago. They were looking for molecules that were shared by cancer cells and trophoblast cells. The trophoblast - the layer of the placenta that forms an interface between the mother and the fetus - has several characteristics in common with cancer. It invades the endometrium, and, being genetically different from the mother, it also must avoid being rejected by her immune system.

5T4, the researchers found, was widely expressed by many different types of cancers, but was not common in normal adult tissues. Subsequent work by the same team identified the gene that encodes 5T4 and showed that its amino acid sequence was 81 percent identical in mice and humans.

Further experiments showed that when 5T4 was overexpressed in both human epithelial cells and in mouse epithelial cells in culture, the cells became more motile and more spindle shaped, the organization of their cytoskeletons changed and the expression of other adhesion molecules altered.

"The easiest way to examine the role of 5T4 in early development was to make an animal model," Stern said. "As part of our preparation for knocking out the 5T4 gene, we began working with embryonic stem cells and looked to see if they expressed 5T4. We found that they did not - but noticed that the molecule was switched on as soon as we let them begin to differentiate. The changes we had observed in cells that were overexpressing 5T4 seemed to happen naturally in embryonic stem cells, and so we conclude that this molecule is associated with the way in which stem cells move around."

It seems likely that cancer cells have "hijacked" the same mechanism, Stern added. "There is a lot of circumstantial evidence that overexpression of 5T4 somehow facilities the movement of cancer cells in tissues," he said. "Ultimately, however, to decide what 5T4 does, we will have to look at the phenotype of a knockout mouse lacking the gene for 5T4." That work is already under way.

There also will be the potential, Stern said, to try to find substances that inhibit the movement of cancer cells mediated by 5T4, with the aim of reducing the likelihood of tumor spread. "Although cancer has often already spread by the time you get the opportunity to treat it, it may be possible to stop spread from local recurrence of the tumor," Stern said.