Enzyme encourages cancer's deadly spread.The race for a crucial cancer gene has ended in a photo finish. Research teams in Australia and Israel have both found the long-sought gene for heparanase, an enzyme that cancer cells use to spread through the body.
Physicians have long known that for many cancers, the initial tumor doesn't prove fatal. Instead, that first tumor may shed cancerous cells that make their way into the bloodstream and later act as seeds for new tumors in other parts of the body. These displaced, or metastasized, cells generally turn out to be the real killers.
For a cancer cell to move into blood vessels Blood vessels
Tubular channels for blood transport, of which there are three principal types: arteries, capillaries, and veins. Only the larger arteries and veins in the body bear distinct names. and then out from them, it must chew through cell layers and the dense matrix of proteins and sugars that surrounds those cells. A large family of protein-cutting enzymes, called proteases, helps in this task.
Yet in the extracellular matrix extracellular matrix (eksˈ·tr·selˑ·y , considerable amounts of heparan sulfate heparan sulfate /hep·a·ran sul·fate/ (hep´ah-ran) a glycosaminoglycan occurring in the cell membrane of most cells, consisting of a repeating disaccharide unit of glucosamine and uronic acid residues, which may be acetylated and , a complex carbohydrate complex carbohydrate
A polysaccharide consisting of a chain of glucose molecules; starch. , also block the cancer cells. About 20 years ago, scientists showed that another enzyme, dubbed heparanase, cleaves this molecule.
Heparanase normally shows up in certain blood and immune cells, probably helping them travel to sites of infection or inflammation. Cancer cells, investigators have suspected, also use the enzyme to move about the body.
While scientists have measured cancer cells' heparanase activity for some time, it was only last year that Christopher R. Parish of the John Curtin School of Medical Research The John Curtin School of Medical Research (JCMSR) is a major biomedial research centre in Australia, based at the Australian National University, Canberra. The school was founded in 1948, as a result of the vision of Australian Nobel Laureate Sir Howard Florey and Prime Minister in Canberra, Australia, and his colleagues succeeded in purifying the enzyme. This allowed them to deduce its amino acid amino acid (əmē`nō), any one of a class of simple organic compounds containing carbon, hydrogen, oxygen, nitrogen, and in certain cases sulfur. These compounds are the building blocks of proteins. sequence and identify the gene encoding the enzyme. A group led by Israel Vlodavsky of the Hadassah-Hebrew University Hospital in Jerusalem found the gene in a similar manner, and both research teams describe it in the July NATURE MEDICINE.
Parish's team also showed that a highly metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.
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pertaining to or of the nature of a metastasis. line of cancer cells has much more activity of the heparanase gene than do tumor cells that don't spread as easily. The Israeli researchers provided even more direct evidence of the enzyme's importance. They added a working heparanase gene to tumor cells that rarely metastasize me·tas·ta·size
To be transmitted or transferred by or as if by metastasis.
Spread of cells from the original site of the cancer to other parts of the body where secondary tumors are formed. and injected them into rodents. Compared with the original tumor cells, the engineered cells spread more readily to multiple tissues and more quickly killed the animals.
Heparanase may do more than simply help cancer cells spread. Heparan sulfate normally sequesters cell growth factors, including ones that trigger blood vessel growth. By degrading the carbohydrate and freeing these factors, heparanase may stimulate the growth of cancer cells, in part by encouraging formation of blood vessels that feed a growing tumor.
Not surprisingly, scientists are eager to develop inhibitors of heparanase. Parish's group has worked with an Australian firm, Progen Industries in Brisbane, on a large sugar molecule called PI-88 that blocks the enzyme's actions. In animals, PI-88 shrinks primary tumors and limits the spread of cancer cells. Progen plans to soon commence tests of the drug in people with cancer.
It may prove simpler to block heparanase than to thwart the many proteases used by cancer cells: There seems to be only one heparanase in the body. "If it's true that we're dealing with only one enzyme, then it's an easier target," says Vlodavsky.
Both Progen and Insight, an Israeli firm with which Vlodavsky collaborates, have started to look for drugs that impede heparanase even more effectively than PI-88. "It's potentially a new generation of antitumor an·ti·tu·mor also an·ti·tu·mor·al
Counteracting or preventing the formation of malignant tumors; anticancer.
Adj. 1. agents," says Jeffrey D. Esko of the University of California, San Diego UCSD is consistently ranked among the top ten public universities for undergraduate education in the United States by U.S. News & World Report. It is a Public Ivy.  For graduate studies, most of UCSD's Ph.D. . "That's exciting."
By limiting immune-cell movement, heparanase inhibitors may also tackle inflammatory diseases or autoimmune disorders. Parish's group is investigating whether immune cells that cause a rodent version of multiple sclerosis can do so without heparanase.