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Health Center Today, December 29, 2009

Exploring Ways to Eliminate One of America’s Biggest Cancer Killers

By Jim H. Smith

Photo of Dr. Zihai Li

Dr. Zihai Li, associate professor in the Department of Immunology, in his lab.

Upwards of 50,000 Americans will die of colorectal cancer this year, according to the American Cancer Society. Even when the dimensions of the disease are measured by the separate statistics for either men or women, it is still the third leading cause of cancer deaths in the United States. When the numbers are combined, it becomes the nation’s second leading cause of cancer mortality.

Though the majority of colorectal cancers occur in people with no family history of the disease, those with a family history are at a decidedly elevated risk. Approximately 20 percent of them, in fact, will develop the disease. So the discovery, by two UConn researchers, of a way to potentially use human stem cells as a kind of vaccine against colon cancer is decidedly positive news.

The discovery was made by immunology experts Dr. Zihai Li and Dr. Bei Liu, who worked in collaboration with Dr. Ren-He Xu, director of the UConn Stem Cell Institute’s Stem Cell Core Facility. If all that their discovery did was bode well for colon cancer treatment, that alone would amount to a significant breakthrough. But the implications are far greater.

Following Schöne’s Trail

Most discoveries of potentially therapeutic uses for stem cells have occurred within the past few years, as an expanding force of researchers worldwide have scrambled to unlock the cells’ secrets, building upon the growing body of stem cell-related knowledge. So it is ironic that the genesis for Li and Liu’s exciting discovery was not a new idea, but an old one.

A hundred years ago German physician and researcher Georg Schöne observed that when animals were vaccinated with fetal tissue it prevented transplantable tumors from growing. Schöne’s observation led to research later that showed vaccination with fetal tissue could not only prevent tumors from growing, but could also prevent carcinogenesis, the process through which normal cells in the body are turned into cancer cells. Scientists continued to research these phenomena through much of the 20th century.

Then, in the 1970s, interest waned due to the contention that cancer immunity could only be triggered by the same cancers, from the same individuals, not by other cell or tissue types. Scientists also were frustrated by the lack of standardized fetal tissue or cells to aid their research.

When Li and Liu revisited that old line of inquiry, in 2008, "We were unafraid of challenging the dogma that cancer immunity can only be elicited by cancer cells," says Li. Their ambitious goal was to find nothing less than a universal cancer vaccine and they had a lot going for them.

They were supported by a $200,000 seed grant from the State of Connecticut. They had a state-of-the-art modern laboratory. And they were armed with both standard human stem cells and two new lines created by Xu’s group early in 2009, a major breakthrough that positioned UConn among a very select group of institutions conducting stem cell research. They also had Dr. Yi Li, a postdoctoral fellow, and a student named Hui Zeng, who proved to be a tireless support team during the months of intensive research that eventually paid off.

A New Paradigm for Cancer Vaccine Research

Central to Li and Liu’s research was the observation of earlier researchers – decades before the use of embryonic stem cells for genetic and developmental studies – that stem cells and cancer cells bear an uncanny similarity. The cells share many biological and molecular features. So the notion of manipulating stem cells, renowned for their malleability, to masquerade as cancer cells didn’t require much of a leap of imagination.

Like stem cells, cancer cells can reproduce themselves. They do it the way all cells in the body duplicate, through mitosis. They separate the chromosomes in their nuclei into two identical sets – around which two distinct nuclei form – and create two cells from one. Cells of the most aggressive forms of cancer perform mitosis with breathtaking speed. It’s what makes them so deadly.

The key idea driving Li and Liu’s research was the fact that immune systems can recognize antigens, such as proteins, on tumor cells. Think of antigens as a kind of "scent." All cells have them and the essence of the immune system is that it can “smell” the antigens and distinguish those which are native to the body from those which are not. Antigens that smell wrong are instantly identified as intruders. Lacking this capacity to distinguish, the immune systems of people suffering from autoimmune disorders – such as lupus, rheumatoid arthritis, Crohn’s disease and diabetes – go haywire and start attacking the body they are supposed to protect.

Nearly all current research on cancer vaccines focuses on the antigens, in fact, because they stimulate the body to produce killer lymphocytes and antibodies, the “warriors” of the body’s defense system. Killer lymphocytes are white blood cells that defend the body against infection. Antibodies are gamma globulins, proteins produced by white blood cells. Detecting invading viruses and bacteria, they move quickly to corral them and neutralize them.

The UConn team vaccinated laboratory mice with human embryonic stem cells. Skillfully manipulated and inactivated, the injected cells mimicked colon cancer cells. They would not cause cancer, but their antigens tricked the mouse immune systems into believing they would.

Right away the team perceived remarkable results. The rodents’ immune systems went on alert and released an army of antibodies and lymphocytes to defend against the “malignant” invaders. Not only did the inoculation boost the immunity of the mice to colon cancer cells, but the team also observed something else. In a majority of the vaccinated mice, which had colon cancer experimentally implanted, there was a marked decline in the size of the tumors.

The tests suggest that stem cells have the potential to prevent cancer from developing. Furthermore, Li and Liu and their colleagues are optimistic that the vaccine is also able to inhibit cancer from growing and metastasizing once it has developed.

"By immunizing the mice with stem cells, we were able to ‘fool’ their immune systems into believing that cancer cells were present," said Li. "That produced precisely the reaction we were looking for. Their immune systems initiated a tumor-combating program. This finding potentially opens up a new paradigm for cancer vaccine research. Although we have only tested the protection against colon cancer, we believe that stem cells might be useful for generating an immune response against a broad spectrum of cancers."

NIH Challenge Grant

It is the first research of its kind to highlight this use for stem cells. And while it is premature to think of it as a “universal” cancer vaccine yet, Li is confident that the model will have applicability for breast cancer, leukemia and sarcoma, cancer of the body’s connecting tissues – bone, cartilage and fat. Though is unclear how soon the discovery might lead to an actual therapy, Li believes that within five years the stem cell treatment could be ready for clinical trials.

The research breakthrough was not his only major success in 2009, though. He was also one of only three UConn Health Center researchers to receive a Challenge Grant from the National Institutes of Health. It was a significant coup, since competition for the grants – worth $1 million over two years – is intense. Only one percent of the 21,000 applications were actually funded. Li will use the funds to study the novel chaperone mechanism, proteins that play an important role in platelet disorders, diseases that prevent blood from clotting effectively.

"I’m fortunate to have a terrific research team," he says. "I owe much of my success to them. The NIH Challenge Grant, for instance, was based entirely on the creative work of my senior graduate student, Matthew Staron."