Alberta Innovates- Health Solutions

The effects of viral pathogens on human health can range from the mild indisposition of a cold spread from one office worker to the next, to the devastation of developing nations by the AIDS pandemic. Appearing deceptively simple compared to a human cell, viruses can alter the basic functions of cells in a number of ways, speeding up cell division, breaking down the cell structure, or inactivating enzymes that stop the growth of tumours. Some, like HIV, can bury themselves deep in the genetic grid of the host for years, only to emerge with deadly results. To alter cell functions, host-cell genetic machinery is harnessed for the viruses' needs.

But the very infectiousness of viruses coupled with their simple genetic makeup makes them useful tools for scientific inquiry. Scientists can remove part of the genetic machinery of a cold virus and substitute genes that correct disease. When introduced into an organism, these vectors can "infect" diseased cells with healthy copies of genes. Their genetic simplicity belies the fact that viruses still work in mysterious ways: we still haven't found the cure for either the common cold or AIDS. But we may be getting closer to how one particular gene, originally discovered in a virus, works to cause cancers.

About 90 years ago, a virus was identified that caused cancer in chickens. Later work showed that the Rous sarcoma virus, as it was called, was composed of just four genes. Scientists were delighted with this new research model. Its small genetic makeup (genome) and proven cancer-causing abilities allowed researchers to determine which of its four genes was carcinogenic. In the laboratory, the gene, called v-src, transformed cells in culture and did, indeed, cause cancer in experimental animals.

It was later found that virtually all multicellular organisms humans included have a homologue that is a copy similar to many of the cancer-causing genes in animal tumour viruses, including v-src. In a normal state, cSrc, the product of the cellular c-src gene that encodes it, has important functions in the body, such as interacting with growth factor to produce cells for wound healing. Many other members of the nine-to-ten protein Src family are required for growth and development of blood cells and blood-forming cells. When somehow mutated or expressed in a non-normal manner, they are capable of causing cancer.

Heritage researcher Dr. Don Fujita has spent more than fifteen years teasing out the secrets of the Src protein and the c-src gene that encodes it. His lab, in collaboration with Dr. H. J. Kung of the United States, was the first to clone the human cellular src gene. "We were fairly certain that its protein product Src would be found to be implicated in at least some human cancers. Sure enough, it has been found to be involved in human colon and breast cancers. Now we want to try to determine the various mechanisms through which Src is regulated and abnormally activated in cancers," says Dr. Fujita.

Recently, two papers were published in the leading scientific journals Oncogene, and Nature Genetics, clarifying some of these mechanisms. In one of them, Dr. Fujita's lab describes a mechanism through which the cSrc protein may be activated in breast cancer cells. The other study, in which Dr. Fujita collaborated with scientists from the United States, showed that c-src mutations were involved in the development of a class of highly metastatic colon cancers. Defining these mechanisms and pathways of Src activation should help scientists develop therapies specifically targeted to a particular type of cancer with hopefully greater effectiveness and fewer side effects than most current drugs.

Dr. Don Fujita is a Heritage Medical Scientist in the Faculty of Medicine at the University of Calgary. He also receives funding from the National Cancer Institute of Canada and the Canadian Breast Research Initiative, the Medical Research Council of Canada, the Canadian Breast Cancer Foundation (Alberta Chapter), and the Alberta Cancer Board.